Definition, Assessment and Treatment of Wheezing Disorders in Preschool Children: an Evidence-Based Approach

Eur Respir J 2008; 32: 1096–1110 DOI: 10.1183/09031936.00002108 CopyrightßERS Journals Ltd 2008

ERS TASK FORCE Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

P.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 Soue¨f, 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 AFFILIATIONS wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to For affiliation details, please see the Acknowledgements section. 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 CORRESPONDENCE only needed when in doubt about the diagnosis. P.L.P. Brand Princess Amalia Children’s Clinic Based on the limited evidence available, inhaled short-acting b2-agonists by metered-dose Isala klinieken inhaler/spacer combination are recommended for symptomatic relief. Educating parents P.O. Box 10400 regarding causative factors and treatment is useful. Exposure to tobacco smoke should be 8000 K Zwolle avoided; allergen avoidance may be considered when sensitisation has been established. The Netherlands Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; Fax: 31 384247660 E-mail: [email protected] 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. Received: Given the large overlap in phenotypes, and the fact that patients can move from one phenotype January 06 2008 to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost Accepted after revision: May 26 2008 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 STATEMENT OF INTEREST to improve the present recommendations on the treatment of these common syndromes. Statements of interest for P.L.P. Brand, E. Baraldi, H. Bisgaard, A.L. Boner, J.A. Castro-Rodriguez, KEYWORDS: Asthma, episodic viral wheeze, inhaled corticosteroids, montelukast, multiple- A. Custovic, J.C. de Jongste, E. Eber, trigger wheeze M.L. Everard, U. Frey, M. Gappa, L. Garcia-Marcos, W. Lenney, S. McKenzie, G. Piacentini, CONTENTS G.A. Rossi, P. Seddon, M. Silverman, A. Valiulis, W.M.C. van Aalderen, Methods ...... 1097 J.H. Wildhaber, G. Wennergren and Results ...... 1097 A. Bush can be found at Definitions ...... 1097 www.erj.ersjournals.com/misc/ Definitions of temporal pattern of wheeze ...... 1098 statements.shtml 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 European Respiratory Journal Investigations ...... 1100 Print ISSN 0903-1936 Recommendations: assessment (based on very low-level evidence) ...... 1101 Online ISSN 1399-3003

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Treatment ...... 1101 Methodological considerations ...... 1104 Environmental manipulation ...... 1101 Recommendations for treatment (based on low-level evidence Parent and patient education ...... 1101 unless otherwise specified) ...... 1104 Pharmacological therapy ...... 1102 References ...... 1106 Delivery devices ...... 1104

opulation studies have shown that approximately one The details of the search strategies are available on request. in three children has at least one episode of wheezing In most cases, the results were limited to English language P prior to their third birthday, and the cumulative material. No date limits were applied. prevalence of wheeze is almost 50% at the age of 6 yrs [1, 2]. Each subgroup, consisting of at least three people, reviewed the Most wheeze in preschool children is associated with viral retrieved references for relevant papers, adding additional upper respiratory tract infections, which recur frequently in papers from personal files if required. The evidence from the this age group. As a result, recurrent wheeze is a very common retrieved relevant papers was graded, according to recent clinical problem facing practitioners throughout the world. It recommendations [13], as high-, moderate-, low- or very low- has been estimated that the problem of preschool wheeze grade evidence based on the following criteria: study design utilises 0.15% of the total healthcare budget in the UK [3]. and quality (systematic reviews and randomised controlled Despite its high prevalence, there is a lack of evidence trials: high quality; observational studies: low quality; any other regarding the pathophysiology and treatment of preschool type of article: very low quality), consistency of the data and wheeze. relevance. A draft report was prepared by each subgroup. This The understanding of preschool wheezing illness has been was submitted to the whole Task Force for comments. The enhanced by a number of birth cohort studies, in particular by individual reports were then combined by the Task Force chairs highlighting the existence of different phenotypes [1, 4, 5]. (P.L.P. Brand and A. Bush), and the present manuscript was However, the possible implications of these different pheno- organised into three main sections: Definitions, Assessment and types for treatment are poorly acknowledged in current Treatment. Based on the evidence reviewed and graded by each international guidelines on the diagnosis and management of subgroup, the Task Force chairs put together a list of asthma [6–8]. Indeed, although two paediatric societies recently recommendations that were graded according to the Grading published guidelines on preschool wheezing disorders [9, 10], of Recommendations Assessment, Development and Evaluation comprehensive evidence-based guidelines on the diagnosis and (GRADE) methodology [13]. Instead of the usual system of management of wheezing disorders in preschool children have grading the strength of recommendations as A, B, C or D, the not been published to date. The present ERS Task Force was GRADE working group proposal to use a different, and more instituted for exactly that purpose. The Task Force defined a readily interpretable, system of categorising recommendations phenotype as a cluster of associated features that are useful in in four groups was followed: should (or should not) be done, or some way, such as in managing the child or understanding the possibly should (or should not) be done. Recommendations mechanisms of disease. Given the multifactorial nature of all could only be categorised as should (or should not) be done wheezing disorders (including asthma) in general, and pre- when the entire Task Force unanimously endorsed this school wheezing disorders in particular, it is highly likely that recommendation. clinical phenotypes described in the literature are the extremes of a broad spectrum of wheezing disorders [11, 12]. The Task RESULTS Force therefore realises that the phenotypes defined in the One of the main findings of the present Task Force was that the present report are not exhaustive, and that many individual evidence on which to base recommendations is limited in this patients may not fit into the categories described. There may be age group. When no evidence was available from original overlap between phenotypes and they may change over time. studies, narrative reviews and published expert opinions were considered for inclusion in the present report. All of the The purpose of the present Task Force was to produce evidence presented is of low quality unless specifically stated guidelines for the treatment of wheezing in children aged otherwise. The present recommendations are likely to change ,6 yrs based on all of the available evidence. when more evidence becomes available.

METHODS DEFINITIONS Literature searches were performed in order to identify Definitions used in children aged ,6 yrs are often confusing. material relating to preschool wheeze. Eleven relevant study Although many individuals later diagnosed with asthma areas were identified, and, for each area, a literature search exhibit their first symptoms during the preschool age period, was carried out based on a predefined series of key clinical making a diagnosis of asthma in preschool children is difficult. questions and keywords by a single clinical librarian. Search According to the latest edition of the Global Initiative for strategies were constructed by the clinical librarian in Asthma (GINA) guidelines, asthma is a syndrome with a collaboration with a representative of each group in the Task highly variable clinical spectrum, characterised by airway Force. Searching included the Cochrane library, PubMed and inflammation [6]. Inflammation, however, has been poorly EMBASE, and the strategies included filters to limit the results studied in preschool children, and may be absent in very by study type (reviews, randomised controlled trials and other young children who wheeze [14]. Therefore, a symptoms-only c types of experimental research) and age range (0–5 yrs). descriptive approach, outlined in table 1, was adopted.

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The majority of the Task Force agreed not to use the term Causative factors for recurrent wheeze may vary from child to asthma to describe preschool wheezing illness since there is child and within a child over time, due to a large number of insufficient evidence showing that the pathophysiology of interactions between genetic factors and the environment [24]. As preschool wheezing illness is similar to that of asthma in older in adults [25], specific combinations of genetic and environmental children and adults. factors determine the individual patient’s phenotype. In clinical practice, however, most of these factors are unknown. Wheeze is defined as a continuous high-pitched sound with musical quality emitting from the chest during expiration. It is The phenotypes used in epidemiological studies (transient one of a number of forms of noisy breathing in preschool versus persistent wheeze) can only be applied retrospectively children [15]. Parents differ widely in their understanding and [1, 4, 5]. Although the use of these phenotypes has improved definition of wheeze; some think it is a sound such as mechanistic understanding, they are of little use to the whistling, squeaking or gasping, whereas others define it as clinician. Although the epidemiological phenotype of transient a different rate or style of breathing, or think it is the same as wheeze is often assumed to be equivalent to the clinical cough [15–19]. If based on parental report alone, therefore, phenotype of episodic wheeze, this has never been demon- children may be labelled as having wheeze when they do not. strated. Therefore, definitions of temporal pattern of wheeze If possible, therefore, wheeze should be confirmed by a health (which are useful to clinicians) were distinguished from the professional, bearing in mind that not all healthcare workers retrospective definitions of duration of wheeze (which are are equally accurate in estimating the severity of wheeze [20]. used in epidemiological studies; table 1).

By definition, the present Task Force has not addressed the Definitions of temporal pattern of wheeze clinical problem of isolated cough without wheeze. Guidelines Episodic (viral) wheeze on the diagnosis and management of chronic cough in Episodic (viral) wheeze is defined as wheeze in discrete childhood are available elsewhere [21]. Since wheeze is the episodes, with the child being well between episodes. end result of narrowing of intrathoracic airways and expira- Although not unique to the preschool age group [26, 27], this tory flow limitation, irrespective of the underlying mechanism, phenotype appears to be most common in preschool children there are numerous reasons for a child to wheeze, including [1, 4, 5]. It is usually associated with clinical evidence of a viral anatomical abnormalities of the airways, cystic fibrosis and respiratory tract infection, although microbiological diagnostic bronchomalacia. The Task Force unanimously agreed that the studies are rarely performed in clinical practice. The most differential diagnosis of wheeze in preschool children should common causative agents include rhinovirus, respiratory not be discussed in detail in the present report for a number of syncytial virus (RSV), coronavirus, human metapneumovirus, reasons. First, there is very little, if any, evidence to support parainfluenza virus and adenovirus [28]. Repeated episodes recommendations regarding the diagnostic approach to a tend to occur seasonally. wheezing infant. Secondly, the differential diagnosis of wheeze in preschool children has been discussed in detail in textbooks Factors underlying the frequency and severity of episodes are [22, 23]. Thirdly, it was felt that most clinicians and researchers only partially understood, but the severity of the first episode would recognise the clinical problem of recurrent wheezing in (which is, in turn, related to pre-existent impaired lung preschool children without an in-depth discussion of its function and younger age), atopy, prematurity and exposure differential diagnosis. to 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

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the initial episode is classified as bronchiolitis is irrelevant. to be atopic and show normal lung function at birth and through Similarly, it is not known whether or not the causative agent of the teenage years [42]. the initial episode plays a major role in determining long-term Children who wheezed in the first 3 yrs and continued beyond outcome. Both RSV and rhinovirus have been linked to an the age of 6 yrs were termed persistent wheezers [1]. This was increased risk of persistent wheezing over time [36–38]. In the associated with normal lung function during the first year of case of RSV, most studies show that this has disappeared by life, but reduced lung function from the preschool age period the age of 11 yrs, and is not associated with an increased risk of and through adulthood (in most but not all cohort studies), atopy [37]. For rhinovirus, such long-term data are lacking. with atopy and a family history of asthma [1, 4, 5]. Episodic (viral) wheeze most commonly declines over time, disappearing by the age of 6 yrs, but can continue as episodic Long-term outcome wheeze into school age, change into multiple-trigger wheeze or Long-term studies have shown that ,25% of children with disappear at an older age [1, 26]. persistent asthma had started to wheeze by the age of 6 months and 75% by the age of 3 yrs [1, 4, 5, 43]. Although Multiple-trigger wheeze the long-term outcome of asthma in school-age children has Although a viral respiratory tract infection is the most common been extensively studied, both at the general population level trigger factor for wheeze in preschool children, some young and in patients with more severe disease, little evidence children also wheeze in response to other triggers (multiple- regarding the outcome of preschool wheezing into adulthood trigger wheeze; table 1). Others have used the term persistent is available. Ongoing birth cohort studies should be able to wheeze for this syndrome, but this is confusing because this provide information on the outcome in general populations term is also used to describe the long-term temporal outcome during the 2010s. Considering more severe early wheeze, half of wheeze (discussed further later). of the children hospitalised with acute wheeze before the age of 2 yrs were symptom-free by the age of 5 yrs and 70% by Systematic studies of other such triggers are lacking. A textbook, 10 yrs, but only 57% by 17–20 yrs [44–46], illustrating the written by two experts in the field, suggests that tobacco smoke tendency for relapse during adolescence. Female sex, passive and allergen exposure are important triggers, and that some smoking during infancy and early sensitisation to allergens children may also wheeze in response to mist, crying, laughter or were risk factors for symptoms continuing into early adult- exercise [23]. Although many believe that multiple-trigger hood, but type of virus and premature birth were not. wheeze in preschool children reflects chronic allergic airway inflammation (and could, therefore, be classified as asthma), Recommendations: definitions of phenotypes (based on there is little evidence to support this (see Investigations section). low-level evidence) 1) For clinical purposes, wheeze should be described in terms Retrospective epidemiological description of duration of of its temporal pattern and classified as episodic (viral) or wheeze multiple-trigger wheeze. The outcome and related characteristics of preschool wheeze have been determined by prospective birth cohort studies; 2) Use of the terms transient, late-onset and persistent wheeze however, in individuals, these categories can only be recog- should probably be limited to population-based cohort studies nised retrospectively [1, 4, 5]. Therefore, these phenotypes can and should not be used clinically. only be used in epidemiological studies and are of no value in 3) The term asthma should probably not be used in preschool clinical practice. Three groups have been recognised (table 1) children because data regarding underlying inflammation are but it should be stressed that the overlap between these groups lacking. is considerable and that the age limits applied are arbitrary. ASSESSMENT In the Tucson birth cohort, 34% of children wheezed during the History and physical examination first 3 yrs of life but 60% of these had ceased to wheeze by the The purpose of history-taking and physical examination is to age of 6 yrs. As a group, these infants with transient wheeze show reduced lung function prior to the first respiratory confirm that the preschool child has a wheezing disorder, to identify the pattern of symptoms, the severity of the condition illness, are exposed to maternal smoking, and are not and any possible trigger factors, and to look for features characterised by a personal history of eczema or a family history of asthma [1]. In an attempt to predict which preschool suggestive of another diagnosis or associated condition. The detailed diagnostic tests for these conditions are beyond the scope wheezers continue to wheeze beyond the age of 6 yrs, these of the present report and have been discussed by others [23]. history data have been combined with characteristics such as blood eosinophilia into an asthma predictive index [39]. History Although groups of children with a positive asthma predictive History-taking is the main diagnostic instrument in the index respond to inhaled corticosteroid (ICS) therapy [40, 41], assessment of preschool wheeze in those who are not the predictive value of this index for the disappearance or wheezing during the consultation. Accurately identifying persistence of wheeze over time in individual patients is of wheeze from the history can be difficult since the term is used only modest clinical value [39]. by parents and healthcare workers to describe a variety of The 15% of children who started wheezing after the age of 3 yrs symptoms [15, 17–19]. Children with doctor-confirmed wheeze and were still wheezing at the age of 6 yrs were defined as exhibit greater airways resistance than children with only having late-onset wheeze. This was associated with maternal reported wheeze [47], even though interobserver agreement c asthma, male sex and a history of rhinitis [1]. This group tended between doctors is poor [48]. A video questionnaire may help

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parents to distinguish wheeze from upper airway noises [49]. Sensitisation to inhalant allergens in 1–4-yr-old children from Symptom scoring systems have been insufficiently validated to general practice increases the likelihood of the presence of justify general use, and validated questionnaires for this asthma at the age of 6 yrs by a factor of two to three [54]. purpose in this particular age group are needed. Noisy Sensitisation to hen’s egg at the age of 1 yr is a reasonable breathing is common among infants aged ,6 months but only marker for allergic sensitisation to aeroallergens at the age of a small proportion have wheeze [15]. Reported noisy breathing 3 yrs, with a specificity of .90% and sensitivity of .30% [55]. that responds to bronchodilator therapy is likely to be genuine Total serum immunoglobulin E measurements in early life are wheeze and to be caused, at least in part, by constriction of not predictive of outcome [56]. Although elevated eosinophilic airway smooth muscle [50]. cationic protein levels in preschool wheezers are associated Physical examination with symptom persistence [57], the degree of overlap between groups renders such measurements useless for clinical No evidence is available regarding the usefulness of physical purposes. Blood eosinophilia can be used as part of an asthma examination in wheeze assessment. A textbook states that the predictive index, but the predictive value of this index (in degree of airway narrowing can only be estimated crudely and particular, that of a positive result) is low [39]. indirectly, by assessing work of breathing (chest retractions, nasal flaring and use of accessory respiratory muscles) and by Radiological examinations auscultation of the chest to assess the ratio of expiration to There is no evidence that chest radiographs help in the inspiration and the degree of wheeze [23]. Upper airway diagnosis or treatment of preschool children with acute or obstruction (in particular, nasal congestion) can contribute to recurrent wheezing [58]. Improvements in diagnostic imaging respiratory distress. The aim of further physical examination is techniques may improve understanding of the mechanisms the identification of unusual or atypical features that would and long-term outcome of early childhood wheezing disorders suggest another underlying condition [23]. by providing details about airway structure, airway wall thickness and airway calibre. At present, however, specialised Investigations imaging should be restricted to unusual or severe disease [22]. The diagnosis of a preschool wheezing disorder can be made by history-taking alone. The type, invasiveness and number of Measurement of gastro-oesophageal reflux any investigation largely depends upon the degree of Although gastro-oesophageal reflux is common among infants morbidity and the doubt about the diagnosis [23]. This is a and preschool children with chronic or recurrent respiratory matter of clinical judgement. Most clinicians would agree that symptoms [59], a beneficial effect of demonstrating and investigations are only justified when symptoms are present treating gastro-oesophageal reflux in infants with wheeze has from birth, airway obstruction is abnormally severe, recovery not been shown. is very slow or incomplete (resulting in prolonged or repeated hospital admission in the first few years of life), episodes Lung function tests continue in the absence of a viral infection or, sometimes, in Studies have shown reduced forced expiratory flows asso- cases when parents are very anxious [22, 23]. There is little ciated with wheeze [50, 52, 60, 61]. Low lung function in research evidence to guide the choice of investigations. Among school-age children [62–64] and infants [65] appears to track infants and preschool children with severe persistent symp- into early adulthood. It is not known, therefore, whether lung toms who were investigated according to a fixed diagnostic function deficits in school-age children with wheezing reflect protocol, a considerable number of pathological findings were developmental characteristics of the lung and airways in observed suggesting that invasive investigations are justified wheezy children, disease activity while symptomatic or in this category [51, 52]. remodelling secondary to airway inflammation. The presence of airway reactivity in infancy is associated with lower Microbiological investigations childhood lung function and increased risk of asthma in later With current viral culture and PCR technology, a wide range of childhood [66], but the mechanisms of airway reactivity in this respiratory viruses can be identified, including the most age group are poorly understood and probably include factors common causative viruses [28]. There is no evidence, however, other than inflammation [67]. that this contributes to management, either in the short term (the acute episode) or in the long term, and it is recommended There are no studies supporting the usefulness of pulmonary only for research purposes. function tests in children with nonspecific symptoms, or in distinguishing between episodic and multiple-trigger wheeze. Tests of sensitisation to allergens In the individual patient, however, determination of lung The reported prevalence of sensitisation in preschool children function (and bronchodilator response) in preschool children with wheeze in population studies varies widely [1, 4, 5]. can help in the discrimination of common wheezing disorders Limited evidence is available regarding the prevalence of from other conditions [68, 69]. sensitisation in preschool children presenting to healthcare workers with wheeze. One study comparing children aged 2– Exhaled nitric oxide and other assessments of airways 5 yrs with doctor-confirmed wheeze who were responding inflammation favourably to a bronchodilator to healthy non-wheezing Elevated exhaled nitric oxide fractions (FeNO) have been found in children found that 32% of wheezy children gave positive wheezing infants, especially when they are atopic [70, 71], and skin-prick test results to one or more aeroallergens, compared these normalise during treatment with ICSs [72] and montelukast to 11% of healthy children (likelihood ratio 2.9) [53]. [73, 74]. FeNO in infants are affected by environmental exposures

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and genetic predisposition to atopy [75]. Reference values for using environmental control in the treatment of preschool age FeNO are only available for children aged o4 yrs [76]. For wheezing to reduce existing symptoms (secondary prevention) uncooperative children aged ,4 yrs, measurement of FeNO has is the notion that allergen exposure contributes to the severity of not been standardised and there is no evidence supporting the symptoms [80]. There is some evidence that exposure to usefulness of measuring or monitoring FeNO in this age group. allergens in early life increases the risk of wheezing, but this is Other tests of inflammation, such as analysis of induced sputum, dependent upon the allergen, the population and other have not been studied at all in preschool children. environmental factors [81]. The combination of sensitisation and high exposure to sensitising allergen in early life is Airway wall biopsy and bronchoalveolar lavage associated with significantly poorer lung function at the age of Few studies have applied bronchoalveolar lavage or bronchial 3 yrs [82]. Sensitisation to perennial allergens during the first biopsy in preschool wheezing disorders. Most such investiga- 3 yrs of life is associated with reduced lung function at school tions have been performed in children with severe or unusual age, with concomitant high exposure to perennial allergens clinical features, limiting the generalisability of findings. Both early in life aggravating this [83]. High allergen exposure during the degree of inflammation and the composition of the infiltrate preschool age enhances the development of airway hyperre- have been variable, with neutrophils dominating in some sponsiveness in sensitised children with wheeze (with later-life studies, eosinophils in others and no evidence of either in sensitisation and exposure having much weaker effects) [83]. others [77]. The only consistent finding was thickening of the reticular basement membrane in wheezy children [77], but not Moving school-age atopic asthmatic children from their homes in infants (median age 12 months), even when reversible airflow to the low-allergen environment of high-altitude sanatoria obstruction and atopy were demonstrated [14]. A recent study temporarily improves levels of markers of airway inflamma- showed that, by a median age of 29 months, some children with tion and asthma severity [84]. Some studies suggest that confirmed wheeze exhibit eosinophilic airway inflammation allergen avoidance at home may also be of some benefit and reticular basement membrane thickening, implying an age amongst children of this age range [85, 86]. It remains unclear, window at 12–30 months during which interventions aimed at however, whether the required major reduction in exposure preventing established airway inflammation might be possible can be achieved in normal life and whether it would be of [78]. Further studies of airway inflammation using bronchoal- beneficial effect in young children since no studies on the veolar lavage and bronchial biopsy in large groups of effects of allergen avoidance have been performed in preschool representative patients with episodic and multiple-trigger children with wheeze [87]. wheeze are urgently needed in order to improve understanding of the pathophysiology of preschool wheezing disorders. Parent and patient education Unfortunately, such studies are hindered by ethical and Parental knowledge and understanding of wheezing disorders practical constraints. At present, such invasive investigations in preschool children and their treatment is often inadequate should only be used in unusual cases in specialised centres. (especially with respect to medication and the preceding signs and preventive actions) [88]; however, few educational studies Recommendations: assessment (based on very low-level in wheezy children have explicitly focused on the preschool evidence) age group. 1) The pattern and triggers of wheeze, personal and family Many educational studies have included children aged as history of atopy, and household smoking should be assessed young as 2 yrs, but the age range of the study group is by history-taking. frequently not described, and there is rarely an analysis of 2) Parentally reported wheeze should be confirmed by a health whether outcomes are different in younger children. For professional whenever possible. example, the Cochrane Review on educational interventions in children and adolescents aged 2–18 yrs with asthma included 3) Tests of allergic sensitisation should be performed in no separate analysis of outcomes in younger children [89]. patients requiring long-term treatment and follow-up. Indeed, of the 32 studies included in the review, only one 4) Other investigations should probably not be carried out studied preschool children exclusively [90]; two other studies unless wheeze is unusually severe, therapy-resistant or that included children aged ,2 yrs were excluded. accompanied by unusual clinical features. Of the few studies in preschool children, those that have utilised multiple teaching sessions have shown improvements TREATMENT in morbidity, with more symptom-free days and better Environmental manipulation caregiver quality of life [90, 91], as well as improved knowl- Reducing tobacco smoke exposure edge and improved self-efficacy [92], and outcomes similar to There is consistent strong evidence that passive exposure to those in older children. These studies all used different environmental tobacco smoke is harmful, in terms of both formats: reading of a home booklet followed by practitioner induction and exacerbation of preschool wheeze [79], and review on next consultation [92], small group teaching by should be firmly discouraged. nurses [90] and home-based education [91]. One other large randomised controlled trial in preschool children with acute Allergen avoidance wheeze found no effect of an education programme upon Allergen avoidance to prevent the development of symptoms, in subsequent healthcare utilisation, disability score, parent’s either the population as a whole or high-risk subgroups quality of life and parental knowledge of asthma [93]. This c (primary prevention), is not discussed here. The rationale for study included two structured 20-min one-to-one sessions, the

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first during hospital attendance and the other 1 month later. Inhaled corticosteroids in treatment of symptoms of multiple- This raises the possibility that multiple educational sessions of trigger wheeze longer duration might be more effective in preschool children. A systematic review of randomised double-blind controlled trials of inhaled glucocorticosteroids in preschool children with Virtually all studies in preschool children have targeted multiple-trigger wheeze has shown significant improvements in education at parents or carers. However, young children important health outcomes, including symptoms, exacerbation themselves may benefit from asthma education and practical rates, lung function and airway hyperresponsiveness [106]. The training in skills. One study found that children aged 2–5 yrs treatment effect appears to be smaller than that seen in school- who were exposed to a developmentally appropriate educa- age children and adults. For example, studies of ICSs in tional intervention that included a picture book and video tape preschool children with multiple-trigger wheeze have reported showed improved asthma knowledge, as well as better a reduction in exacerbations by ,50% [107, 108]. Compared to compliance and health, compared to controls [94]. placebo, children using 200 mg?day-1 fluticasone exhibit a mean of 5% fewer days with symptoms [106]. Therefore, although educating parents of preschool children with wheeze (and perhaps also the children themselves) The dose–response relationship of ICSs in preschool children is appears effective, and is advised, more work is needed before not entirely clear. Dose-related effects have been shown for specific educational approaches can be recommended. exacerbation rate on treatment with daily ICS doses of up to 400 mg?day-1 beclometasone equivalent (or 200 mg?day-1 flutica- Pharmacological therapy sone) via pressurised metered-dose inhaler (pMDI) with spacer (pMDI-S) [107], without any further benefit from higher doses. Short-acting b2-agonists Comparison of 0.25, 0.5 and 1.0 mg nebulised budesonide daily, Inhaled rapidly acting b -agonists are the most effective 2 however, showed similar improvement to that with placebo in bronchodilators available, and, therefore, the drugs of choice one study [109], whereas another suggested a dose relation in for acute symptoms of wheeze. Double-blind placebo-con- the range 0.25–1.0 mg nebulised budesonide b.i.d. [110]. Marked trolled studies have demonstrated significant bronchodilatory individual variations in response are seen between patients. In a effects [95–98] and protective effects against bronchoconstric- post hoc analysis of two large randomised controlled trials in tor agents [99, 100] in infants and preschool children treated young children (aged 12–47 months), those with frequent b with rapidly acting inhaled 2-agonist. Thus, infants possess symptoms, aged .2 yrs and/or with a family history of asthma b functional 2-receptors from birth, and stimulation of these showed the best response to treatment with fluticasone receptors can produce the same effects as in older children, (200 mg?day-1), whereas those with less frequent symptoms, b although paradoxical responses to inhaled 2-agonists have without a family history of asthma and aged ,2 yrs showed no been reported in infants [50, 101]. Oral administration of b2- significant treatment effect [111]. Two recent studies using agonist is also effective but is limited by systemic side-effects inhaled fluticasone to treat wheezy infants and preschool [102]. Intravenous infusion of b2-agonists has only shown an children failed to find any improvement in lung function [112, advantage over hourly inhaled treatment in very severe acute 113]. Atopic markers, such as a history of atopic dermatitis or wheeze in young children [103]. allergic rhinitis, did not improve the chance of responding to ICSs [111]. However, preschool children with wheeze, selected After inhalation, b -agonists are usually well tolerated. Side- 2 based on the asthma predictive index for the prediction of effects, such as muscle tremor, headache, palpitations, agita- persistent wheeze (including atopic dermatitis, allergic rhinitis tion and hypokalaemia, are only seen when high doses are and eosinophilia), respond to ICSs as a group [40, 41]. used [104]. Local side-effects, such as hoarseness and candidiasis, are rare Single-isomer R-albuterol is theoretically preferable (although in preschool children [114], probably because medication is much more expensive) to the racemic mixture of albuterol usually delivered by metered-dose inhaler with spacer (MDI-S) since the S-isomer is therapeutically inactive [104]. There is, combination. Studies on the systemic side-effects of inhaled however, no evidence regarding the clinical effectiveness or steroids have yielded inconsistent results. In a 1-yr study of superiority of the use of R-albuterol compared to the racemic 200 mg?day-1 fluticasone in preschool children, height growth mixture in this age group. was similar in the fluticasone-treated children to that in the cromoglycate-treated children [114]. In another study, how-

Long-acting inhaled b2-agonists ever, height growth was reduced by 1.1 cm after 2 yrs of -1 Formoterol and salmeterol have shown long-lasting broncho- inhaled 200 mg?day fluticasone compared with placebo [41]. dilatory and bronchoprotective effects in preschool children The long-term consequences of inhaled steroid therapy on [99, 105]. There are no published double-blind randomised growth in preschool children have not been studied. Clinically placebo-controlled trials in preschool children on the addition relevant effects on adrenal function have only been observed in children receiving high doses of ICSs (.400 mg?day-1 beclo- of long-acting inhaled b2-adrenergic agents to ICSs. metasone equivalent) [106]. The risk of cataract was not Inhaled corticosteroids increased in a study of 358 children aged 1–3 yrs receiving daily treatment with ICSs for o1 yr [114]. No other potential Treatment with ICSs may be considered for the treatment of systemic side-effects have been studied in preschool children. current symptoms, or possibly for the prevention of progression of symptoms (disease modification). Each is considered in Thus ICSs are effective in preschool children with multiple- turn, as follows. trigger wheeze, but the effect is smaller than that in older

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children, and there is some concern about the effect on height. needed to treat 3) [121]. Although that review included several This justifies a more critical approach to long-term ICS use in studies in preschool children, they were not analysed preschool children with multiple-trigger wheeze than in older separately. A systematic review of two studies found no children and adults with asthma. Many clinicians tend first to evidence that parent-initiated oral corticosteroids are asso- give a trial of ICS for a period of ,3 months. If there is no ciated with a benefit in terms of hospital admissions, improvement, the treatment should not be stepped up but unscheduled medical reviews, symptoms scores, bronchodi- stopped, and further investigations should be carried out in lator use, parent and patient impressions, physician assess- order to identify the cause of symptoms. If preschool children ment, or days lost from work or school [122]. with multiple-trigger wheeze respond well to ICS therapy, it is unclear whether this is due to treatment or the natural Leukotriene modifiers resolution of symptoms. It is recommended, therefore, that Montelukast is the only cysteinyl leukotriene receptor antago- treatment be withdrawn in children who become (almost) nist licensed for the treatment of young children, at a dosage of completely free of wheeze after ICS therapy. There are also 4 mg orally once daily. No clinically relevant side-effects have clinicians who only continue treatment with ICSs in multiple- been reported [123]. trigger wheeze if symptoms recur after withdrawal, and respond to reintroduction of the medication. Montelukast in multiple-trigger wheeze In two studies, montelukast provided protection against Inhaled corticosteroids in treatment of symptoms of episodic bronchoconstriction induced by hyperventilation with cold (viral) wheeze dry air, and improved airways hyperresponsiveness by one The clinical benefits of ICSs for episodic (viral) wheeze are doubling dose after 4 weeks, compared to placebo [124, 125]. controversial [106]. Systematic reviews have concluded that The bronchoprotective effect was independent of concurrent episodic high-dose inhaled glucocorticosteroids (1,600– steroid treatment. In a multicentric study of 689 young children 3,200 mg?day-1 budesonide) provide some benefit in episodic with multiple-trigger wheeze, montelukast improved symp- (viral) wheeze (with a 50% reduction in the requirement for oral toms and achieved a 30% reduction in exacerbations [123]. One steroids, but no effect on hospitalisation rates or duration of recent study showed that nebulised budesonide was more symptoms), but that maintenance treatment with 400 mg?day-1 effective at reducing exacerbation rates in 2–8-yr-old children beclometasone equivalent does not reduce the number or the with multiple-trigger wheeze than oral montelukast [126]. Since severity of wheezing episodes in episodic (viral) wheeze [106, preschool children were not analysed separately, it is not known 115]. It should be emphasised that the available evidence is whether this difference in efficacy also applies to this age range. based on a few small trials that may be underpowered for the detection of a treatment effect. For example, the study on the Montelukast in episodic (viral) wheeze effect of maintenance treatment with ICSs in episodic (viral) Daily use of montelukast over a 1-yr period reduced the rate of wheeze analysed only 41 patients [116]. The most recent study, wheezing episodes in 549 children with episodic (viral) wheeze published only in abstract form, showed that intermittent by 32% compared to placebo (number needed to treat 12) [127]. treatment with 1.5 mg?day-1 fluticasone for f10 days for A trial of intermittent montelukast, started when patients episodic (viral) wheeze reduced the severity and duration of developed signs of a common cold, compared with placebo in symptoms but at a cost of slightly reduced height [117]. Thus, 220 children with episodic wheeze showed a 30% reduction in the use of high-dose intermittent steroids in this age group unscheduled health visits (number needed to treat 11), but no requires careful consideration. effect on hospitalisations, duration of episode, and b-agonist and prednisolone use [128]. Nasal corticosteroids to reduce episodic (viral) wheeze Although treatment of allergic rhinitis may help to ameliorate Cromones asthma in school-age children and adolescents, a randomised Clinical documentation regarding sodium cromoglycate use in controlled trial of nasal corticosteroids in preschool children preschool children is sparse and there are no reports on with recurrent wheeze failed to demonstrate any benefit [118]. infants. The Cochrane Review concluded that a beneficial effect of cromolyn therapy in preschool children with multiple- Treatment of episodic (viral) wheeze in preschool children to trigger wheeze could not be proven [129]. Most studies were of reduce risk of persistent wheeze during later childhood poor quality, but one well-designed randomised controlled Three randomised controlled trials (two on daily ICSs and one trial found no effect on symptom scores or exacerbation on intermittent use when the child was wheezy) have shown frequency in children aged 1–4 yrs with multiple-trigger that use of ICSs in preschool children with episodic (viral) wheeze [130]. No studies have been performed with nedocro- wheeze does not reduce the risk of persistent wheeze at the age mil in preschool children. of 6 yrs, and that symptoms return when steroid therapy is discontinued [41, 119, 120]. Xanthines The Cochrane Review on the effects of xanthines (theophylline Systemic glucocorticosteroids and aminophylline) in the chronic treatment of children with A systematic review of systemic corticosteroids in hospitalised asthma, the effects on symptoms and exacerbations of wheeze children with acute asthma found that corticosteroid-treated in preschool children were small and mostly nonsignificant children were seven times more likely to be discharged early [131]. The studies were all small however. There have been no than placebo-treated children, and five times less likely to good studies comparing xanthines to other medications in c relapse within 1–3 months following discharge (number preschool wheeze.

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Anticholinergic agents use of pMDI-S as the preferred means of delivery of inhaled In the Cochrane Review it was concluded that inhaled drugs in preschool children. ipratropium may be beneficial in older children [132], but Although there is no formal evidence to support this, there is there is no good evidence in preschool children [133]. There are consensus that cooperative children should use a spacer device no important side-effects when ipratropium is inhaled by with a mouthpiece wherever possible [137]. Noncooperative MDI-S combination. children aged ,3 yrs should use a spacer with a face mask; a tight face mask seal is considered important for optimal drug Antihistamines delivery. Crying children are unlikely to receive any drug to The antihistamines ketotifen and cetirizine have been studied the lower airways [139]. in preschool wheeze. In the Cochrane Review it was concluded that children treated with ketotifen were 2.4 times as likely to Filter studies have shown high day-to-day variability in be able to reduce or stop bronchodilator treatment than those delivered doses in preschool children [140]. This should be treated with placebo. There were also less consistent benefits borne in mind when prescribing therapy and judging its effects. with respect to asthma symptoms and exacerbations [134]. The If a spacer is used, it should be noted that electrostatic charge interpretation of these studies, however, is hampered by the reduces MDI-S delivery. New unwashed and unprimed plastic fact that the description of patients is insufficient to classify spacers are electrostatically charged, and, therefore, yield them as having episodic (viral) wheeze or multiple-trigger reduced drug delivery [141]. This can be overcome by washing wheeze. In addition, the initial favourable reports in the 1980s the plastic spacer in detergent and allowing it to drip dry, were never confirmed in later studies. There are no good priming it with 5–10 puffs of aerosol or using a metal spacer. studies comparing ketotifen to other asthma medications. There are no data on the safety of the detergent washing method Cetirizine was compared to placebo in a randomised trial in however. Since priming with aerosol is the most expensive and infants with atopic dermatitis, with the aim of preventing the wasteful method of the three, it is not recommended. development of asthma. At the age of 3 yrs, there was no difference in wheeze prevalence between the two groups. In a Methodological considerations post-hoc analysis in a subgroup of patients radioallergosorbent In accordance with others [106], the Task Force found it test-positive for cat, house dust mite or grass pollen, there difficult to synthesise the evidence on the efficacy of treatment appeared to be a protective effect of cetirizine [135]. This needs in preschool wheeze for a number of reasons. First, inclusion to be confirmed in further studies. There are no studies of criteria were commonly unclear. Studies have included cetirizine in preschool children with wheeze. children with asthma or wheeze without further specification. Even when inclusion criteria were specified, pooling such Other treatment options studies was frequently impossible because of clinical hetero- geneity or the lack of distinction of different phenotypes. No studies have been performed on the effects of immu- Secondly, treatment (agents, dosages and delivery devices) notherapy or influenza immunisation in preschool children differed considerably between studies. Thirdly, different out- with wheeze. come parameters have been studied, most of which were neither standardised nor validated. Fourthly, the number of Delivery devices studies and the number of patients enrolled was generally As a general principle, inhaled drug delivery is preferable to quite low, especially for studies on ICSs in episodic wheeze. the oral and parenteral routes, in order to provide rapid relief Fifthly, given the fact that symptoms of wheeze in preschool of symptoms and minimise systemic side-effects. Inhalation children tend to resolve spontaneously and that the most therapy in preschool children is hampered by numerous troublesome symptoms occur episodically, adherence to factors, including narrower airways, increased turbulence, treatment by parents and caregivers is probably low, although deposition high in the respiratory tree, and lack of cooperation few studies have examined this. The one study specifically and coordination. Although there is anecdotal evidence addressing this found that parents of preschool children with suggesting that some preschool children may be able to use troublesome wheeze would not give their child a broncho- dry powder inhalers effectively and reliably [136], there is dilator on 40% of the occasions when the child was wheezy, consensus among experts that these devices should not be even though they knew their adherence was monitored and used in preschool children because they lack the ability to even though they were instructed to administer inhaled generate sufficiently high inspiratory flows [137]. Similarly, bronchodilator when their child was wheezing [142]. Finally, pMDIs cannot be used by preschool children without the use age appears to be an important effect modifier, in that the of a spacer device because of difficulties in the appropriate younger the child is, the poorer the response to any treatment. timing of the inspiratory effort. The two inhalation systems to be considered, therefore, are pMDI-S and nebuliser. Recommendations for treatment (based on low-level evidence unless otherwise specified) A systematic review has shown that the delivery of inhaled b - 2 1) Passive smoking is deleterious to preschool children with agonists by pMDI-S in acutely wheezy infants and preschool wheeze, as at all ages (high-level evidence), and should be children is more effective than by nebuliser; recovery was firmly discouraged. quicker and the risk of hospital admission was reduced by 60% [138]. There are no studies comparing the two delivery devices 2) There is insufficient evidence on which to base recommend- for long-term management. The economic, practical and ations for the reduction of exposure to environmental allergens hygienic advantages of pMDI-S over nebulisers support the in the treatment of preschool wheezing.

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3) An educational programme using multiple teaching sessions 7) A trial of montelukast may be considered in preschool on causes of wheeze, recognising warning signals and children with multiple-trigger wheeze. treatment should be provided to parents of wheezy preschool 8) Cromones, ketotifen and xanthines are not recommended children. for use in preschool children with wheeze. 4) A pMDI-S combination should be used as the preferred 9) Immunotherapy is not recommended for preschool children delivery device for inhalation therapy in preschool children with wheeze outside the setting of a randomised controlled (high-level evidence). trial. 5) In cooperative children, spacers with a mouthpiece should 10) Influenza immunisation is not recommended for preschool probably be used. children with wheeze. 6) In uncooperative young children, spacers with a tight-fitting face mask should probably be used. Maintenance treatment of episodic (viral) wheeze 1) Montelukast 4 mg once daily should probably be given for 7) Plastic spacers should be treated with detergent before use the treatment of episodic (viral) wheeze. in order to reduce their electrostatic charge. 2) A trial of inhaled corticosteroids may be considered in Acute wheezing episode preschool children with episodic (viral) wheeze, in particular 1) Inhaled short-acting b2-agonists on an as-needed basis when episodes occur frequently or if the family history of should be used for the symptomatic treatment of acute asthma is positive. wheezing in preschool children. These drugs should be used cautiously in infants since paradoxical responses have been ACKNOWLEDGEMENTS reported in this age group. The affiliation details of the present study’s authors are as follows. P.L.P. Brand: Princess Amalia Children’s Clinic, Isala 2) Alternative routes of administration (oral and intravenous) Clinics, Zwolle; J.C. de Jongste: Dept of Paediatric Respiratory should not be used. Medicine, Erasmus Medical Centre/Sophia Children’s 3) Single-isomer salbutamol should not be used. Hospital, Rotterdam; P.J.F.M. Merkus: Dept of Paediatrics, Division of Respiratory Medicine, Children’s Hospital, b 4) Addition of ipratropium bromide to short-acting 2-agonists Radboud Medical Centre Nijmegen, Nijmegen; and W.M.C. may be considered in patients with severe wheeze. van Aalderen: Dept of Paediatric Pulmonology, Emma 5) A trial of oral corticosteroids should probably be given to Children’s Hospital, Academic Medical Centre, Amsterdam preschool children with acute wheeze of such severity that (all the Netherlands). E. Baraldi: Dept of Paediatrics, Unit of they need to be admitted to hospital. Respiratory Medicine and Allergy, Unit of Neonatal Intensive Care, University of Padua School of Medicine, Padua; A.L. 6) Parent-initiated treatment with a short course of oral Boner and G. Piacentini: Dept of Paediatrics, G.B. Rossi corticosteroids should not be given. Polyclinic, Verona; F. Midulla: Dept of Paediatric Emergency, 7) Although high-dose ICS therapy appears to have a small University of Rome La Sapienza, Rome; and G.A. Rossi: beneficial effect in the treatment of acute wheezing in Pulmonary Disease Unit, G. Gaslini Institute, Genoa (all Italy). preschool children, this treatment is not recommended because H. Bisgaard: Danish Paediatric Asthma Centre, Copenhagen of high cost and lack of comparison to bronchodilator therapy. University Hospital, Copenhagen, Denmark. J.A. Castro- Rodriguez: School of Medicine, Pontifical Catholic University Maintenance treatment of multiple-trigger wheeze of Chile, Santiago, Chile. A. Custovic: North West Lung 1) ICSs at a daily dose of up to 400 mg?day-1 beclometasone Research Centre, Wythenshawe Hospital, Manchester; M.L. equivalent should be given for the treatment of preschool Everard: University Division of Child Health, Sheffield children with multiple-trigger wheeze. Children’s Hospital, Sheffield; J. Grigg: Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts and 2) When the response to this treatment is poor, patients should The London Medical School, London; S. McKenzie: Fielden not be treated with higher doses but should probably be referred House, Royal London Hospital, Barts and The London NHS to a specialist for further evaluation and investigations. Trust, London; N. Wilson: Dept of Paediatrics, Royal 3) If response to inhaled steroids is favourable, treatment Brompton Hospital, London; A. Bush: Dept of Paediatric should probably be discontinued after several weeks or Respirology, National Heart and Lung Institute, Royal months, in order to judge whether symptoms have resolved Brompton Hospital and Imperial College, London; W. or whether ongoing treatment is needed. Lenney: Academic Dept of Child Health, University Hospital of North Staffordshire, Stoke-on-Trent; J.Y. Paton: University 4) Linear growth should be measured in preschool children Division of Developmental Medicine, Yorkhill Hospitals, using ICSs. Glasgow; P. Seddon: Royal Alexandra Children’s Hospital, Brighton; and M. Silverman: Dept of Infection, Inflammation 5) Infants younger than 1 yr should probably not be prescribed and Immunology, University of Leicester, Leicester (all UK). ICSs. J. de Blic: Paediatric Pneumology and Allergology Service, 6) Infants aged 1–2 yrs should only be prescribed ICSs if their Paris Public Assistance Hospitals, Necker Hospital for Sick symptoms are troublesome and they show a clear-cut response Children, Paris, France. E. Eber: Respiratory and Allergic c to treatment. Disease Division, Dept of Paediatrics and Adolescent

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Medicine, Medical University of Graz, Graz, Austria. U. Frey: 13 Atkins D, Best D, Briss PA, et al. Grading quality of Paediatric Respiratory Medicine, Inselspital, Berne University evidence and strength of recommendations. BMJ 2004; Hospital and University of Berne, Berne; and J.H. Wildhaber: 328: 1490–1494. Dept of Paediatrics, Fribourg Bertigny Hospital, Fribourg (all 14 Saglani S, Malmstrom K, Pelkonen AS, et al. Airway Switzerland). M. Gappa: Dept of Paediatric Pulmonology and remodeling and inflammation in symptomatic infants Neonatology, Medical University of Hanover, Hanover, with reversible airflow obstruction. Am J Respir Crit Care Germany. L. Garcia-Marcos: Institute of Respiratory Health, Med 2005; 171: 722–727. University of Murcia, Murcia, Spain. P. Le Soue¨f: School of 15 Elphick HE, Sherlock P, Foxall G, et al. Survey of Paediatrics and Child Health; P.D. Sly: Division of Clinical respiratory sounds in infants. 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Gastroesophageal 42 Taussig LM, Wright AL, Holberg CJ, Halonen M, reflux in infants with wheezing. Pediatr Pulmonol 1999; 28: Morgan WJ, Martinez FD. Tucson children’s respiratory 181–186. study: 1980 to present. J Allergy Clin Immunol 2003; 111: 60 Neve V, Edme JL, Devos P, et al. Spirometry in 3–5-year-old 661–675. children with asthma. Pediatr Pulmonol 2006; 41: 735–743. 43 Hess J, de Jongste JC. Epidemiological aspects of 61 Young S, Arnott J, O’Keeffe PT, Le Soue¨f PN, Landau LI. paediatric asthma. Clin Exp Allergy 2004; 34: 680–685. The association between early life lung function and 44 Gokso¨r E, Amark M, Alm B, Gustafsson PM, wheezing during the first 2 yrs of life. Eur Respir J 2000; Wennergren G. Asthma symptoms in early childhood – 15: 151–157. what happens then? Acta Paediatr 2006; 95: 471–478. 62 de Gooijer A, Brand PLP, Gerritsen J, Koe¨ter GH, 45 Wennergren G, Hansson S, Engstrom I, et al. Character- Postma DS, Knol K. Changes in respiratory symptoms istics and prognosis of hospital-treated obstructive and airway reactivity after 27 years in a population-based bronchitis in children aged less than two years. Acta sample of school children. Eur Respir J 1993; 6: 848–854. Paediatr 1992; 81: 40–45. 63 Roorda RJ, Gerritsen J, van Aalderen WMC, et al. Follow- 46 Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K, up of asthma from childhood to adulthood: influence of Korppi M. Asthma and lung function 20 years after potential childhood risk factors on the outcome of wheezing in infancy: results from a prospective follow- pulmonary function and bronchial responsiveness in up study. Arch Pediatr Adolesc Med 2004; 158: 1070–1076. adulthood. J Allergy Clin Immunol 1994; 93: 575–584. 47 Lowe L, Murray CS, Martin L, et al. Reported versus 64 Sears MR, Greene JM, Willan AR, et al. A longitudinal, confirmed wheeze and lung function in early life. 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Maternal atopic disease a multidisciplinary education protocol in children with modifies effects of prenatal risk factors on exhaled nitric asthma (0–4 years) in primary health care. J Asthma 1994; oxide in infants. Am J Respir Crit Care Med 2004; 170: 31: 347–359. 260–265. 93 Stevens CA, Wesseldine LJ, Couriel JM, Dyer AJ, 76 Buchvald F, Baraldi E, Carraro S, et al. Measurements of Osman LM, Silverman M. Parental education and guided exhaled nitric oxide in healthy subjects age 4 to 17 years. J self-management of asthma and wheezing in the pre- Allergy Clin Immunol 2005; 115: 1130–1136. school child: a randomised controlled trial. Thorax 2002; 77 Wildhaber JH, Sennhauser FH, Brand PLP. Asthma in 57: 39–44. school-aged children and adolescents. In: Frey U, 94 Holzheimer L, Mohay H, Masters IB. Educating young Gerritsen J, eds. Respiratory Diseases in Infants and children about asthma: comparing the effectiveness of a Childrend. Eur Respir Mon 2006; 11: 191–216. developmentally appropriate asthma education video 78 Saglani S, Payne DN, Zhu J, et al. Early detection of tape and picture book. Child Care Health Dev 1998; 24: airway wall remodelling and eosinophilic inflammation 85–99. in preschool wheezers. Am J Respir Crit Care Med 2007; 95 Holmgren D, Bjure J, Engstrom I, Sixt R, Sten G, 176: 858–864. Wennergren G. Transcutaneous blood gas monitoring 79 Strachan DP, Cook DG. Parental smoking and lower during salbutamol inhalations in young children with acute respiratory illness in infancy and early childhood. Thorax asthmatic symptoms. Pediatr Pulmonol 1992; 14: 75–79. 1997; 52: 905–914. 96 Kraemer R, Frey U, Sommer CW, Russi E. Short-term 80 Murray CS, Poletti G, Kebadze T, et al. Study of modifiable effect of albuterol, delivered via a new auxiliary device, in risk factors for asthma exacerbations: virus infection and wheezy infants. Am Rev Respir Dis 1991; 144: 347–351. allergen exposure increase the risk of asthma hospital 97 Conner WT, Dolovich MB, Frame RA, Newhouse MT. admissions in children. Thorax 2006; 61: 376–382. Reliable salbutamol administration in 6- to 36-month-old 81 Torrent M, Sunyer J, Garcia R, et al. Early-life allergen children by means of a metered dose inhaler and exposure and atopy, asthma, and wheeze up to 6 years of Aerochamber with mask. Pediatr Pulmonol 1989; 6: age. Am J Respir Crit Care Med 2007; 176: 446–453. 263–267.

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98 Pool JB, Greenough A, Gleeson JG, Price JF. Inhaled preschool children: randomized controlled trial. Pulm bronchodilator treatment via the nebuhaler in young Pharmacol Ther 2008; 21: 88–97. asthmatic patients. Arch Dis Child 1988; 63: 288–291. 114 Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, 99 Nielsen KG, Bisgaard H. Bronchodilation and broncho- Davies P. Twelve-month safety and efficacy of inhaled protection in asthmatic preschool children from formo- fluticasone propionate in children aged 1 to 3 years with terol administered by mechanically actuated dry-powder recurrent wheezing. Pediatrics 2004; 113: e87–e94. inhaler and spacer. Am J Respir Crit Care Med 2001; 164: 115 McKean M, Ducharme F. Inhaled steroids for episodic 256–259. viral wheeze of childhood. Cochrane Database Syst Rev 100 Avital A, Godfrey S, Schachter J, Springer C. Protective 2000; Issue 1: CD001107. effect of albuterol delivered via a spacer device 116 Wilson N, Sloper K, Silverman M. Effect of continuous (Babyhaler) against methacholine induced bronchocon- treatment with topical corticosteroid on episodic viral striction in young wheezy children. Pediatr Pulmonol wheeze in preschool children. Arch Dis Child 1995; 72: 1995; 17: 281–284. 317–320. 101 Prendiville A, Green S, Silverman M. Airway respon- 117 Ducharme FM, Lemire C, Nova FJ, et al. Randomized siveness in wheezy infants: evidence for functional beta controlled trial of intermittent high dose fluticasone versus adrenergic receptors. Thorax 1987; 42: 100–104. placebo in young children with viral-induced asthma. Am 102 Fox GF, Marsh MJ, Milner AD. Treatment of recurrent J Respir Crit Care Med 2007; 175: Suppl. 1, A958. acute wheezing episodes in infancy with oral salbutamol 118 Silverman M, Wang M, Hunter G, Taub N. Episodic viral and prednisolone. Eur J Pediatr 1996; 155: 512–516. wheeze in preschool children: effect of topical nasal 103 Browne GJ, Penna AS, Phung X, Soo M. Randomised trial corticosteroid prophylaxis. Thorax 2003; 58: 431–434. of intravenous salbutamol in early management of acute 119 Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, severe asthma in children. Lancet 1997; 349: 301–305. Buchvald F. Intermittent inhaled corticosteroids in 104 Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, infants with episodic wheezing. N Engl J Med 2006; 354: Baumgartner RA. Evaluation of the safety and efficacy of 1998–2005. 120 levalbuterol in 2–5-year-old patients with asthma. Pediatr Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A. Secondary prevention of asthma by the use Pulmonol 2005; 40: 477–486. of inhaled fluticasone propionate in wheezy infants 105 Primhak RA, Smith CM, Yong SC, et al. The bronchopro- (IFWIN): double-blind, randomised, controlled study. tective effect of inhaled salmeterol in preschool children: Lancet 2006; 368: 754–762. a dose-ranging study. 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Walton-Bowen K, Smith JA. Efficacy and safety of Comparative study of budesonide inhalation suspension budesonide inhalation suspension (Pulmicort Respules) and montelukast in young children with mild persistent in young children with inhaled steroid-dependent, persis- asthma. J Allergy Clin Immunol 2007; 120: 1043–1050. tent asthma. J Allergy Clin Immunol 1998; 102: 789–796. 127 Bisgaard H, Zielen S, Garcia-Garcia ML, et al. 111 Roorda RJ, Mezei G, Bisgaard H, Maden C. Response of Montelukast reduces asthma exacerbations in 2- to 5- preschool children with asthma symptoms to fluticasone year-old children with intermittent asthma. Am J Respir propionate. J Allergy Clin Immunol 2001; 108: 540–546. Crit Care Med 2005; 171: 315–322. 112 Hofhuis W, van der Wiel EC, Nieuwhof EM, et al. 128 Robertson CF, Price D, Henry R, et al. Short-course Efficacy of fluticasone propionate on lung function and montelukast for intermittent asthma in children: a symptoms in wheezy infants. 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DISCUSSION PAPER

Setting the standard for routine asthma consultations: a discussion of the aims, process and outcomes of reviewing people 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, UK c General Practitioner, The Park Medical Practice, Shepton Mallet, UK d General Practitioner, The Rycote Practice, East Street, Thame, UK UK e Team Leader: Respiratory & Asthma, Education for Health, The Athenaeum, Warwick, UK f Professor of Primary Care Respiratory Medicine, Centre of Academic Primary Care, University of Aberdeen; Foresterhill Health Centre, Westburn Road, Aberdeen, Scotland, UK g Honorary Clinical Senior Lecturer at the National Heart and Lung Institute, Imperial College,Society London, UK h Executive Director of Research and Policy, Asthma UK, London, UK i 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 Respiratory Abstract prohibited Globally, asthma morbidity remains unacceptably high. If outcomes are to be improved, it is crucial that routine review consultations in primary care are performed to a high standard. Key componentsCare 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 anPrimary assessment of compliance, inhaler technique, smoking status, triggers, and rhinitis, identification of poor control should result in a step-upReproduction 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, and should include personalised self-management education Regular review of people with asthma coupled with provision of self-management education improves outcomes. Underpinned by a theoretical framework integratingCopyright 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 Introduction: the burden of asthma general practice suggest that 5.8% of the population have Worldwide, asthma is an important cause of morbidity, ‘active asthma’ (defined as a diagnosis of asthma and a economic cost, and mortality. It is estimated that about 300 prescription for asthma treatment in the previous 12 months).2 million people have asthma, with the highest prevalence in the Despite the focus in international guidelines on assessing UK, Australasia and North America.1 In England, data from and achieving good disease control in international

* Corresponding author: Dr Hilary Pinnock, Allergy and Respiratory Research Group, Centre of Population Health Sciences: GP Section, University of Edinburgh, 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]

PRIMARY CARE RESPIRATORY JOURNAL 75 www.thepcrj.org doi:10.4104/pcrj.2010.00006 http://www.thepcrj.org Copyright PCRS-UK - reproduction prohibited H Pinnock et al.

guidelines,3 surveys have consistently shown unacceptable conditions.23-27 The widely cited Long-Term Conditions morbidity associated with low expectations on the part of pyramid of care (LTC pyramid) emphases the importance of patients.4-8 It has been estimated that up to three-quarters of self-management to “ensure patients and carers have the the 80,000 admissions for asthma in the UK in 2004 might skills and knowledge they need to understand how to best have been prevented with improved long-term care.9 A key handle their condition, including how to deal with flare-ups, strategy for reducing the burden of asthma is a shift in to adjust medicines, improve their life-styles and access health emphasis from acute management to long-term care and care services”26. Routine reviews operate in the boundary supported self-management, in order to reduce chronic between patient self-care and professional management,28,29 morbidity and impairment of quality of life, as well as not only offering opportunities specifically to reinforce and reducing exacerbations, admissions and mortality.3,10 Proactive refine self-management skills, but also more generally to care, with structured reviews provided by clinicians with build the trusted relationship valued by patients (see Figure training in asthma care, improves outcomes.11-15 2).29 After describing the policy and theoretical framework linking regular reviews and guided self-management, this Asthma reviews discussion paper sets out the evidence base supporting the Asthma reviews in primary care should incorporate three key recommended content of good asthma reviews in primary steps: care. It then discusses the role of ‘pay-for-performance’ – 1. Assessing control in orderUK to target care appropriately exemplified by the UK Quality and Outcomes Framework16 – 2. Responding to that assessment by identifying reasons for as a driver for improving treatment outcomes. An Opinion poor control and adjusting management strategy sheet providing practical guidance for clinicians is available accordinglySociety from www.pcrs-uk.org. 3. Exploring patients’ ideas, concerns and expectations, and guiding self-management to facilitate on-going control Policy and theoretical framework The framework for monitoring chronic disease described by 1. Assessing control Glasziou et al. emphasises the inter-relationship between RespiratoryAsthma control reflects the degree to which symptoms are professional review and patient self-management,17 using reduced,prohibited exacerbations are prevented and normal lung asthma as an exemplar condition (see Figure 1). Cochrane function is maintained by treatment,30 with current guidelines reviews provide support for this concept, concludingCare that defining ‘control’ as no symptoms, no exacerbations and improved outcomes are the result of training in asthma self- normal lung function9 (see Table 1). Occasional daytime management coupled with regular review.18-20 This dual symptoms (defined as less than twice a week) may be approach is summarised in the GINA asthma guideline as consistent with good control, but disturbed sleep due to 9 Primary ‘guided self-management’, is explicitly recommendedReproduction (Grade asthma signals loss of control. Challenge tests for assessment A) in the 2008 update of the BTS/SIGN asthma guideline,10 and is a core strategy of national programmes to improve Figure 2. The long-term condition pyramid with the 21,22 asthma care in Finland and Australia. boundary between professional and self care (adapted Self care is a ‘key pillar’ ofCopyright the policy approach to meeting from Degeling et al.28). the challenge of providing care for people with long-term

Figure 1. The inter-relationship between professional and self-monitoring (adapted from Glaziou et al.17 to Level 1 Self- illustrate the management and self-management of At risk of a long- Communication Self-care management term condition for health asthma).

Exacerbation Professional management Pre Initial treatment, Stepping Boundary regaining Maintenance treatment gaining control Maintenance control down Best peak flow Level 2 Care 80% With a long-term condition management

60%

Level 3 Case Complex co-morbidities management Arrows are professional reviews Line is patient self-management

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http://www.thepcrj.org Copyright PCRS-UK - reproduction prohibited Routine asthma reviews

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

Characteristic Controlled (All of Partly Controlled (Any measure Uncontrolled the following) present in any week) Daytime symptoms None (twice or less/week) More than twice/week Three or more features Limitations of activities None Any of partly controlled Nocturnal symptoms/awakening None Any asthma present in Need for reliever/rescue treatment None (twice or less/week) More than twice/week any week iii Lung function (PEF or FEV1) 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. of bronchial hyper-responsiveness are unlikely to be practical suitable for use in clinical practice, which can facilitate measures of control in primary care settings, though detection of poor control. A review of some asthma control UK estimation of exhaled nitric oxide as a measure of tools is available on the web-site of the International Primary inflammation may have a place in clinical care in the future.30 Care Respiratory Group.38,39 Common to all these tools is In primary care, asthma control is normally assessed on specific enquiry about the presence of symptoms, the basis of symptoms, supplemented by examination of the interference withSociety activities and disturbance at night. clinical records. Frequent use of reliever inhalers implies poor There are two short, well-validated questionnaires widely control, and intermittent requests for preventer treatment used in research which may be suitable for use in clinical signals the need to address patients’ perception of, and fears practice.10,30 The Asthma Control Questionnaire40,41 uses five about, regular treatment.10 The occurrence of an acute morbidity questions plus an optional measure of the forced exacerbation is evidence of poor control over a longer time- Respiratoryexpiratory volume in one second (FEV1), has been tested for frame than the duration of current symptoms.31 A primary use prohibitedin clinical practice, and a score of more than 1.5 indicates care clinician with access to patient records can easily check poor control.42 The Asthma Control Test uses similar morbidity the number of courses of oral steroid required overCare the questions but also includes a rating of overall control, with a previous year. A ‘one-off’ peak expiratory flow (PEF) or score of 20 or more indicating good control.43,44 Both are spirometry reading taken in clinic is of limited value in available in a number of languages and have been validated assessing the control of a variable condition,Primary though if the for self-administration. patient is well-controlled it can provide an up-to-dateReproduction ‘best’ However, validity of questionnaires is determined under reading for use in action plans. Although few patients will carefully controlled conditions, since the mode, circumstances maintain an accurate paper-based PEF diary on a daily and place of administration may affect the responses.45 By basis,32,33 use of mobile technology may engage some patients contrast, conditions of administration in routine clinical with on-going PEF and symptomCopyright monitoring. 34,35 practice are likely to be very variable, with some practices Surveys have consistently shown unacceptably high levels of arranging completion prior to the asthma review at home or asthma morbidity.4-8 Trials demonstrate that by adopting a policy in the waiting room, whilst others administer them formally in of ‘zero tolerance’ to symptoms, patients with asthma can the consultation. Some clinicians may explain or paraphrase achieve good control;36 however, it remains unclear to what the questions to assist with completion. There is, therefore, a extent good control as defined by guidelines can be achieved in need to establish the value of such scores for assessing real-life practice.37 Patients will wish to balance the benefits of stepping up therapy until control is achieved against perceptions Table 2. The Royal College of Physicians three questions46. of, and preferences for, long-term treatment, and the In the last month practicalities of short consultations may restrict the time available 1. Have you had difficulty sleeping because of asthma symptoms 37 to address all the diverse factors which result in poor control. (including cough)? • Measures of morbidity 2. Have you had your usual asthma symptoms during the day Patients’ perception of control may differ markedly from that (cough, wheeze, chest tightness or breathlessness)? based on objective assessment of symptoms,5,8 and clinicians over-estimate improvements in asthma control.6 This has 3. Has your asthma interfered with your usual activities (eg housework, work, school, etc)? given impetus to the development of morbidity scores,

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control in a range of normal clinical scenarios. training is required to maintain good technique.55,56 Those The ‘Royal College of Physicians (RCP) three questions’ unable to master or maintain good technique with one device represent a consensus UK view on a short symptom should be offered an alternative.51 This has been specifically questionnaire,46 which correlates with the Asthma Control highlighted in children, where inadequate technique – Questionnaire and is responsive to change.47 A refinement of resulting either from poor training or from choosing a device the RCP three questions which scores the number of days in poorly suited to the child – significantly reduces drug delivery the previous week affected by symptoms has been suggested to the lungs and results in poor asthma control.58 to improve discriminatory power. The questions (or very Practical training when a device is first prescribed, similar precursors of the ‘RCP three questions’) have been supported by review of inhaler technique at every asthma used successfully to target care,48 including use by postal consultation (whether with a nurse, doctor, pharmacist or questionnaire49 and during telephone reviews.50 Whilst other healthcare professional) is good practice.3,10,55,56,58 occasional symptoms (e.g. on two or less days a week) may • Assessing adherence be acceptable, any nocturnal waking or activity limitation Adherence with regular preventative medication is known to should be considered as less than well-controlled disease, and be poor, and under-use should be considered when there is a management should be adjusted accordingly.3,10 failure to control asthma symptoms.59,60 Patients self-reporting 2. Response to assessment and adjustment of and health care professional assessment both overestimate management regular use of prophylacticUK medication. 59,61,62 In primary care, If control is good, a reminder of action to be taken if asthma repeat prescribing records provide an indication of adherence deteriorates may be all that is necessary. However, if with prescribed asthma regimens.10 assessment of symptoms, taken in conjunction with the Simple, verbalSociety and written instructions and information on reported and recorded use of short-acting bronchodilators asthma and its treatment for patients and carers may help to and any recent history of any acute attacks, suggests that overcome unintentional non-adherence.10 Patents balance control is not ideal, the reasons for this should be considered their perceived need for treatment against their concerns and addressed appropriately before increasing asthma about taking a medication.51 Enquiry, based on a non- 10 therapy. A recent primary care review has considered the Respiratoryjudgemental assumption of non-adherence, can facilitate an causes for poor control in detail.51 Here, we present a openprohibited discussion of the rationale and potential benefits of summary of the key implications for routine practice: regular therapy versus the disadvantages of taking a drug • Reviewing the diagnosis Care with (perceived or real) side effects, thus enabling the patient An increase in symptoms, or failure to respond to treatment, to reach an informed decision about concordance with should lead to reconsideration of the diagnosis.10,52 An clinical advice on the use of inhaled steroids. unrecognised diagnosis (for example chronic obstructive • Asking about, and treating rhinitis Primary pulmonary disease (COPD) in a smoker, gastro-oesophagealReproductionRhinitis and asthma are common diseases which co-exist in reflux as a trigger for cough, obesity as a cause of 75-80% of patients52 and are associated with substantial cost breathlessness), or the development of a co-morbid to patients, employers and health care systems. The condition, may be responsible for apparent poor control.52 A relationship between rhinitis and asthma is strongly wide range of rare conditionsCopyright in childhood may be initially supported by epidemiological, pathophysiological and clinical misdiagnosed as asthma.53 evidence.63-71 Patients with co-existent asthma and rhinitis • Checking and correcting inhaler technique incur greater prescription drug costs and experience more Poor inhaler technique is a well documented problem which general practitioner (GP) visits and hospitalisations for asthma results in ineffective and wasteful use of therapy, and is an than those with asthma alone.72,73 important cause of poor control.51-56 As few as a quarter of Treatment of concomitant allergic rhinitis, particularly with patients make no mistakes when using a pressurised intranasal steroids and/or leukotriene receptor antagonists, is metered-dose inhaler (pMDI), while just over a half can use associated with significant reductions in risk of emergency dry powder inhalers, breath-actuated pMDI or pMDI with a room treatment and hospitalisation for asthma.74-76 Rhinitis spacer without errors.57 Provision of a spacer for use in an (including seasonal rhinitis) should therefore be sought as a acute situation may improve effectiveness at a time when co-morbidity in all patients with uncontrolled asthma and breathlessness makes usual pMDI technique more difficult. treated appropriately.52 Meta-analysis of the effect of teaching inhaler technique • Assessing smoking status and offering cessation advice shows significant improvement after an educational Smoking adversely affects asthma control. This may signal a intervention with a ‘number needed to teach’ (to achieve an diagnosis of COPD, either as a co-morbidity or because the COPD ‘ideal’ technique) of 2.6 patients.57 However, repeated has been incorrectly diagnosed as asthma. Smoking also reduces

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the effectiveness of inhaled steroids.63,77,78 It is therefore important preference (e.g. preferred degree of autonomy versus to enquire about smoking status and to offer cessation advice to frequency of professional review; peak flow versus symptom patients with poorly controlled asthma. Persistent smokers may monitoring) as well as the severity of asthma, risk of very need relatively high doses of inhaled steroids.10 severe attacks and the maintenance treatment plan.19 • Adjusting therapy according to evidence-based • Implementation in primary care guidelines The challenge for primary care is that of implementing these After consideration of diagnosis, compliance, inhaler evidence-based recommendations. Studies have shown technique, smoking status, triggers and rhinitis, the consistently that provision of self-management education is identification of poor control should result in a step-up of poorly implemented in practice.8,83,84 Some of the recognised treatment in accordance with the evidence-based advice of barriers, such as time and resources, are practical issues which international or national guidelines.3,10 Discussion of the need to be addressed when planning routine care for people advantages and disadvantages of treatment options, and with asthma.85,86 Confusion about details of action plans (such acknowledgement of patient preferences – i.e. whether to as the relevance of increasing inhaled steroids) are a further accept symptoms, or whether to accept a change or an barrier.87 Despite the growing body of evidence from primary increase in treatment such as a higher dose of inhaled care,88-92 there is scepticism about whether the evidence steroids, an additional therapy, a combination inhaler instead applies to the relatively low risk mild patients in whom benefit of separate inhalers, an inhaled long-acting bronchodilator or is harder to demonstrate.84UKMore fundamentally, provision of an oral leukotriene receptor antagonist – is good consulting asthma action plans is often perceived as an optional task practice and would seem likely to optimise future delegated to a nurse educator.80 Recognition that self-care concordance.79 and professionalSociety care are inextricably linked as Control should be maintained on the lowest possible dose complementary aspects of the management of all people and stepping down treatment is an important and frequently- with long-term conditions – as illustrated in the framework overlooked step for patients who are consistently well for monitoring and self-monitoring (see Figure 2)17 – may be controlled, especially in children who often ‘grow out’ of their the conceptual key that will help unlock implementation. 3,10 asthma. RespiratoryA systematic review of the implementation of asthma 3. Exploring perceptions and supporting actionprohibited plans highlighted the importance of this inter- self-management relationship between the facilitation of regular, structured • Guideline recommendations Care review and the provision of self-management education.93 All International guidelines emphasise that “Patient education is three primary care studies in this review demonstrated the key to success of every aspect of asthma management and increased ownership of asthma action plans,92,94,95 and showed prevention”,3 as many of the obstacles to achieving best a consistent trend to improved clinical outcomes, though the Primary control relate to misunderstanding of the condition,Reproduction under- only significant benefits were a reduction in episodes of estimation of the potential benefits of regular treatment, and ‘speech limiting wheeze’,92 and night time waking.94 Similarly, exaggerated fears about side effects of asthma treatment. The within managed care programmes, nurse-led telephone- UK national guideline includes the Grade A recommendation based reviews incorporating self-management education that “Patients with asthmaCopyright should be offered self- supported by written information can increase the use of management education that should focus on individual needs, inhaled steroids.96,97 This inter-relationship is encompassed in and be reinforced by a written action plan”.10 international guidelines as the concept of ‘guided self- The provision of self-management education, management’.3 incorporating a written asthma action plan, can reduce hospitalisation,80 unscheduled consultations, time lost from Ensuring access to professional advice work and nocturnal asthma, as well as improving self-efficacy Patients value flexible access to professional advice in order to and asthma-related quality of life.16,81 Similar benefits have support self-care,29,98 but not all patients are willing to attend been shown in school age children,20 though an innovative a pre-arranged appointment for a regular review.83,99 Repeat approach may be required for pre-school children.81 prescribing arrangements should aim to be sufficiently flexible Clear advice from a systematic review on the components to enable patients to order more inhalers promptly when of effective asthma action plans – i.e. written instructions, 2- needed, but should include checks to ensure that those 3 action points triggered by symptoms or based on best peak patients requesting reliever inhalers frequently are reminded flow, advice on increasing inhaled steroids and commencing to arrange a review. oral steroids – is now available.82 Health professionals should There is now evidence to inform the appropriate role of tailor the self-management intervention to allow for patient telephone asthma reviews.10,50,101,102 Telephone asthma reviews

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

• 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. increase the proportion of patients reviewed without loss of spanning a range of countries,UK professionals and disease clinical effectiveness,100 though patients whose asthma is areas concluded that audit and feedback can be moderately causing concern prefer a face-to-face review.101 Asking effective at improving professional practice.105 The process of standard morbidity questions by telephone can identify those asthma reviews, particularly when the consultations are who should be invited for a face-to-face review whilst recorded on computerSociety templates, offers ready opportunities offering a convenient telephone option to those currently for repeated audit cycles. However, detailing and auditing all under good control.50 The provision of a telephone asthma the possible functions of an asthma review, whilst potentially review option within routine practice showed that improving process, risks automating the consultation and opportunistic telephone calls could provide consultations to making it less responsive to individual patient needs. The UK non-responders who would otherwise not have had a RespiratoryQuality and Outcomes Framework (QOF) – a ‘pay for review.102 A suggested model of care incorporating this performance’prohibited scheme which was introduced as part of the UK evidence is given in Table 3. General Medical Services Contract in 2004 and which Care rewards practices for achieving pre-determined standards of Ensuring quality care for a range of long-term conditions16 – recognised this Appropriate training potential risk, and the approach adopted was to reward the Asthma reviews should be undertakenPrimary by healthcare ‘provision of an asthma review’ recorded as a single coded professionals with appropriate training to enable themReproduction not only entry in the computerised clinical records.106 Concerns remain to assess control but also to adjust treatment as necessary.20 In about the quality of the review represented by this ‘tick box’, the UK, this is frequently an experienced practice nurse, though serial detailed audits in 60 representative practices though a survey published in 2007 highlighted that 20% of showed significant progress in assessing control by the nurses did not have any specialistCopyright asthma training.103 Whilst recording of specific symptoms, and checking inhaler guidelines (and clinical governance) might recommend that at technique as part of the review.107 Disappointingly, despite least one member of the primary care team has specialist uniformly high achievement in the process measures for respiratory training, this raises concerns about the potential QOF,108 the proportion of well-controlled patients varies deskilling of other members of the team.84 Poorly defined inter- considerably between practices.109 professional roles and inadequate communication between colleagues can act as barriers to the implementation of Conclusion guideline recommendations,86 an issue of particular importance Too many of the 300 million people around the world living in the context of guided self-management. Although a with asthma are coping on a daily basis with a variable specialist clinician may initiate education, it is incumbent on all condition that significantly affects their quality of life, despite members of the team to provide the on-going, consistent the existence of treatment which could substantially improve support for guided self-management.104 Multi-disciplinary their symptoms. At the core of a routine review is the education and support for professionals was a core component opportunity to identify patients with sub-optimal control and of the successful Finnish programme.21 (for both patients and professionals) the need to adopt an Audit and standards approach of ‘zero tolerance’ to symptoms. Recognition of the A systematic review of 118 randomised controlled trials inter-relationship of professional reviews and patient self-

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management underpins the partnership as future 15. Griffiths C, Foster G, Barnes N, et al. Specialist nurse intervention to reduce management strategies are negotiated. unscheduled asthma care in a deprived multiethnic area: the east London randomised control trial for high risk asthma. BMJ 2004;328:144-7. Funding http://dx.doi.org/10.1136/bmj.37950.784444.EE No direct funding. HP is supported by a Primary Care Research Career Award from 16. NHS Confederation, British Medical Association New GMS Contract 2003: the Chief Scientist’s Office, Scottish Government. investing in general practice. London. March 2003 17. Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. Conflict of interest declarations BMJ 2005;330:644-8. http://dx.doi.org/10.1136/bmj.330.7492.644 None known. 18. Gibson PG, Powell H, Wilson A, et al. Self-management education and regular practitioner review for adults with asthma. Cochrane Database of Systematic Acknowledgements Reviews 2002, Issue 3. Art. No.: CD001117. http://dx.doi.org/ This paper builds on work on asthma reviews, commissioned by the Primary Care 10.1002/14651858.CD001117 Respiratory Society UK (PCRS-UK) formerly known as the General Practice Airways Group (GPIAG), together with the British Thoracic Society, Education for Health and 19. Powell H, Gibson PG. Options for self-management education for adults with Asthma UK, in preparation for a joint submission to the UK QOF review panel. We asthma. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: thank Professor Chris Griffiths for his helpful comments on an earlier draft. CD004107. http://dx.doi.org/10.1002/14651858.CD004107 20. Wolf FM, Guevara JP, Grum CM, Clark NM, Cates CJ. Educational interventions Contributorship for asthma in children. 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Yawn BP, Yunginger JW, Wollan PC, Reed CE, Silverstein MD, Harris AG. asthma control in routine clinical practice: use of the RoyalReproduction College of Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and Physicians ‘3 Questions’. Prim Care Resp J 2009;18:83-8. impact on health care charges. J Allergy Clin Immunol 1999;103:54-9. http://dx.doi.org/10.3132/pcrj.2008.00045 http://dx.doi.org/10.1016/S0091-6749(99)70525-7 48. Jones KP, Bain DJG, Middleton M, Mullee MA. Correlates of asthma morbidity 68. Neukirch F, Pin I, Knani J, et al. Prevalence of asthma and asthma-like symptoms in primary care. BMJ 1992;304:361-4. http://dx.doi.org/10.1136/ in three French cities. Resp Med 1995;89:685-92. bmj.304.6823.361 Copyright 69. Wright AL, Holberg CJ, Halonen M, Martinez FD, Morgan W, Taussig LM. 49. Jones KP, Charlton IH, Middleton M, Preece WJ, Hill AP. Targeting asthma care Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics in general practice using a morbidity index. BMJ 1992;304:1353-9. 1994;94:895-901. http://dx.doi.org/10.1016/0954-6111(95)90136-1 http://dx.doi.org/10.1136/bmj.304.6838.1353 70. Huovinen E, Kaprio J, Laitinen LA, Koskenvuo M. Incidence and prevalence of 50. Gruffydd-Jones K, Hollinghurst S, Ward S, Taylor G. Targeted routine asthma asthma among Finnish men and women of the Finnish Twin Cohort from 1975 care in general using telephone triage. Br J Gen Pract 2005;55:918-23. to 1990, and their relation to hay fever and chronic bronchitis. Chest 51. Haughney J, Price D, Kaplan A, et al. Achieving asthma control in practice: 1999;115:928-36. http://dx.doi.org/10.1378/chest.115.4.928 Understanding the reasons for poor control. Respir Med 2008;102:1681-93. 71. Greisner W. Co-existence of asthma and allergic rhinitis: a 23-year follow-up http://dx.doi.org/10.1016/j.rmed.2008.08.003 study of college students. Allergy Asthma Proceedings 1998;19:185-8. 52. Thomas M, Price D. Impact of co-morbidities on asthma. Expert Rev Clin http://dx.doi.org/10.2500/108854198778557836 Immunol 2008;4:731-42. http://dx.doi.org/10.1586/1744666X.4.6.731 72. Thomas M, Kocevar VS, Zhang Q, Yin DD, Price D. Asthma-Related Health Care 53. Keeley DJ Silverman M. Are we too ready to diagnose asthma in children? Resource Use Among Asthmatic Children With and Without Concomitant Thorax 1999;54:625-8. http://dx.doi.org/10.1136/thx.54.7.625 Allergic Rhinitis. Pediatrics 2005;115:129-34. 54. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated 73. Price D, Zhang Q, Kocevar VS, Yin DD, Thomas M. Effect of a concomitant with decreased asthma stability. Eur Respir J 2002;19:246-51. diagnosis of allergic rhinitis on asthma-related health care use by adults. Clin http://dx.doi.org/10.1183/09031936.02.00218402 Exp Allergy 2005;35:282-7. http://dx.doi.org/10.1111/j.1365-2222. 55. Virchow JC, Crompton GK, Dal Negro R et al. Importance of inhaler devices 2005.02182.x in the management of airway disease. Respir Med 2008;102:10-19. 74. Corren J, Manning B, Thompson S, Hennessy S, Strom B. Rhinitis therapy and

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the prevention of hospital care for asthma: A case-control study. J Allergy Clin thorax.58.1.30 Immunol 2004;113:415-19. http://dx.doi.org/10.1016/j.jaci.2003.11.034 92. Glasgow NJ, Ponsonby A-L, Yates R, Beilby J, Dugdale P. Proactive asthma care 75. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the in childhood: general practice based randomised controlled trial. BMJ 2003; risk of emergency department visits for asthma. J Allergy Clin Immunol 2002; 327:659-65. doi:10.1136/bmj.327.7416.659 109:636-42. http://dx.doi.org/10.1067/mai.2002.123237 93. Ring N, Malcolm C, Wyke S, et al. Promoting the use of Personal Asthma 76. Price DB, Swern A, Tozzi CA, Philip G, Polos P. Effect of montelukast on lung Action Plans: a systematic review. Prim Care Resp J 2007;16:271-83. function in asthma patients with allergic rhinitis: analysis from the COMPACT http://dx.doi.org/10.3132/pcrj.2007.00049 trial. Allergy 2006:61:737-42. http://dx.doi.org/10.1111/j.1398- 94. Heard AR, Richards IJ, Alpers JH, Pilotto LS, Smith BJ, Black JA. Randomised 9995.2006.01007.x controlled trial of general practice based asthma clinics. Med J Aust 1999; 77. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur 171:68-71. Respir J 2004;24:822-33. http://dx.doi.org/10.1183/09031936.04.00039004 95. Kemple T, Rogers C. A mailed personalised self-management plan improves 78. Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on attendance and increases patients' understanding of asthma. Prim Care Respir lung function and airway inflammation in smokers with asthma. Am J Respir J 2003;12:110-14. Crit Care Med 2006;174:127-33. http://dx.doi.org/10.1164/rccm.200510- 96. Delaronde S, Peruccio DL, Bauer BJ. Improving asthma treatment in a managed 1589OC care population. Am J Managed Care 2005;11:361-8. 79. Kurtz S, Silverman J. The Calgary-Cambridge Observation Guides: an aid to 97. Feifer RA, Verbrugge RR, Khalid M, Levin R, O'Keefe GB, Aubert RE. defining the curriculum and organising the teaching in Communication Improvements in asthma pharmacotherapy and self-management: An example Training Programmes. Med Education 1996;30:83-9. http://dx.doi.org/ of a population-based disease management program. Dis Manage Health 10.1111/j.1365-2923.1996.tb00724.x Outcomes 2004;12:93-102. http://dx.doi.org/10.2165/00115677-200412020- 80. Adams RJ, Smith BJ, Ruffin RE. Factors associated with hospital admissions and 00003 UK repeat emergency department visits for adults with asthma. Thorax 2000, 98. Kennedy A, Rogers A, Bower P. Support for self care for patients with chronic 55:566-73. http://dx.doi.org/10.1136/thorax.55.7.566 disease. BMJ 2007;335:968-70. http://dx.doi.org/10.1136/ 81. Stevens CA, Wessledine LJ, Couriel JM, Dyer AJ, Osman LM, Silverman M. bmj.39372.540903.94 Parental education and guided self management of asthma and wheezing in 99. Gruffydd-Jones K,Society Nicholson I, Best L, Connell E. Why don't patients attend the the pre-school child: a randomised controlled trial. Thorax 2002;57:39-44. asthma clinic? Prim Care Resp J (formerly Asthma in Gen Pract) 1999;7:36-8. http://dx.doi.org/10.1136/thorax.57.1.39 100.Pinnock H, Bawden R, Proctor S, et al. Accessibility, acceptability and 82. Gibson PG, Powell H. Written action plans for asthma: an evidence-based effectiveness of telephone reviews for asthma in primary care: randomised review of the key components. Thorax 2004;59:94-9. http://dx.doi.org/ controlled trial. BMJ 2003;326:477-9. http://dx.doi.org/10.1136/ 10.1136/thorax.2003.011858 bmj.326.7387.477 83. Price D, Wolfe S. Delivery of asthma care: patient's use of and views on Respiratory101.Pinnock H, Snellgrove C, Madden V, Sheikh A. Telephone or surgery asthma healthcare services, as determined from a nationwide interview survey. Asthma reviews?prohibited Preferences of participants in a primary care randomised controlled J 2000;5:141-4. trial. Prim Care Resp J 2005;14:42-6. http://dx.doi.org/10.1016/ 84. Wiener-Ogilvie S, Pinnock H, Huby G, Sheikh A, Partridge MR, GilliesCare J. Do j.pcrj.2004.10.002 practices comply with key recommendations of the British Asthma Guideline, 102.Pinnock H, Adlem L, Gaskin S, Harris J, Snellgrove C, Sheikh A. Accessibility, and if not, why not? Prim Care Resp J 2007;16:369-77. clinical effectiveness and practice costs of providing a telephone option for http://dx.doi.org/10.3132/pcrj.2007.00074 routine asthma reviews: controlled implementation study. Br J Gen Pract 2007; 85. Thoonen BPA, Jones KP, van Rooij HA, et al. Self-treatmentPrimary of asthma: 57:714-22. possibilities and perspectives from the practitioner's point of view.Reproduction Fam Practice 103.Upton J, Madoc-Sutton H, Sheikh A, Frank TL, Walker S, Fletcher M. National 1999;16:117-22. http://dx.doi.org/10.1093/fampra/16.2.117 survey on the roles and training of primary care respiratory nurses in the UK in 86. Weiner-Ogilvie S, Huby G, Pinnock H, Gillies J, Sheikh A. Practice organisational 2006: are we making progress? Prim Care Resp J 2007;16:284-90. characteristics can impact on compliance with the BTS/SIGN asthma guideline: http://dx.doi.org/10.3132/pcrj.2007.00068 qualitative comparative case study in primary care. BMC Family Practice 104.Cabana MD, Le TT. Challenges in asthma patient education. J Allergy Clin 2008;9:32. http://dx.doi.org/10.1186/1471-2296-9-32Copyright Immunol 2005;115:1225-7. http://dx.doi.org/10.1016/j.jaci.2005.03.004 87. Levy M, Pinnock H, Crockett A, Haughney J. Clinical Information Analyst 105.Jamtvedt G, Young JM, Kristoffersen DT, O'Brien MA, Oxman AD. Audit and (ATTRACT). BTS/SIGN Guidelines - Query for Committee. Prim Care Resp J feedback: effects on professional practice and health care outcomes. Cochrane 2003;12:72-3. Database of Systematic Reviews 2006, Issue 2. Art. No.: CD000259. 88. Hayward SA, Jordan M, Golden G, Levy M. A randomised controlled evaluation http://dx.doi.org/10.1002/14651858.CD000259.pub2 of asthma self-management in general practice. Prim Care Resp J (formerly 106.Roland M. Linking Physicians’ Pay to the Quality of Care - A Major Experiment Asthma in Gen Practice) 1996;4:11-13. in the United Kingdom. N Engl J Med 2004;351:1448-54. http://dx.doi.org/ 89. Moudgil H, Marshall T, Honeybourne D. Asthma education and quality of life in 10.1056/NEJMhpr041294 the community: a randomised controlled study to evaluate the impact on white 107.Campbell S, Reeves D, Kontopantelis E, Middleton E, Sibbald B, Roland M. European and Indian subcontinent ethnic groups from socioeconomically Quality of Primary Care in England with the Introduction of Pay for deprived areas in Birmingham, UK. Thorax 2000;55:177-83. Performance. N Engl J Med 2007;357:181-90. http://dx.doi.org/10.1056/ http://dx.doi.org/10.1136/thorax.55.3.177 NEJMsr065990 90. Guendelman S, Meade K, Benson M, Chen Y, Samuels S. Improving asthma 108.Doran T, Fullwood C, Gravelle H, et al. Pay-for-Performance Programs in Family outcomes and self-management behaviors of inner-city children. Arch Pediatr Practices in the United Kingdom. N Engl J Med 2006;355:375-84. Adolesc Med 2002;156:114-20. http://dx.doi.org/10.1056/NEJMsa055505 91. Thoonen BPA, Schermer TRJ, van den Boom G, et al. Self-management of 109.Price D, Horne R, Ryan D, Freeman D, Lee A. Large variations in asthma control asthma in general practice, asthma control and quality of life: a randomised between UK general practices participating in the asthma control, concordance controlled trial. Thorax 2003;58:30-6. http://dx.doi.org/10.1136/ and tolerance (ACCT) Initiative. Prim Care Resp J 2006;15:206 (ABS74)

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Clinical Review

CLINICAL REVIEW

Managing wheeze in preschool children

1 Andrew Bush professor of paediatrics and head of section (paediatrics) professor of paediatric 2 3 respirology consultant paediatric chest physician , Jonathan Grigg professor of paediatric respiratory 4 3 5 and environmental medicine , Sejal Saglani reader in paediatric respiratory medicine

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

Lower respiratory tract illnesses with wheeze are common, on had had at least one episode of wheeze by the age of 18 occurring in around a third of all preschool children (here months.9 defined as aged between 1 and 5 years). They are a major source of morbidity and healthcare costs, including time off work for What is the best clinical approach to the carers, and are often difficult to treat. This review focuses on the two areas in which there have been recent developments. preschool wheezer? The first is the classification of these children by symptom Once it is established that the child has actual wheeze, history 1 pattern into “episodic viral” and “multiple trigger” wheezers. and a careful physical examination should be used to place the 2 These phenotypes can change within an individual over time, child in one of four categories (table⇓). History and physical but they are a useful guide to current treatment, and there are examination are used to categorise the child and to decide 3 4 also physiological and pathological rationales for their use. whether further investigation is needed. In general, there are The second area is the recent series of large randomised three reasons for a referral: if diagnosis is in doubt, if treatment controlled trials of treatment, specifically related to the roles of is not working, and if any party (general practitioner, parent) is intermittent montelukast and inhaled and oral corticosteroids. unhappy with progress. A report of two cross sectional, These trials have shown clearly that inhaled corticosteroids and community based observational studies found that isolated dry prednisolone in particular have been misused and overused in cough in a community setting, without wheeze or breathlessness, the past, mandating a reappraisal of treatment algorithms. is most unlikely to be caused by any form of asthma.9 Most What is wheeze? preschool wheezers do not require any additional tests. Confusion arises from the different uses of the term Wheeze is a term that is often used imprecisely, as has been “bronchiolitis.” In the United Kingdom, this is an illness shown in studies with a video questionnaire and direct characterised by respiratory distress and showers of fine crackles quantification of wheeze.5-8 Indeed, some European languages in a child aged under 1 year; though wheeze can be present as do not even have a word for wheeze. Our definition is high well, it is the crackles that define the illness. It should be pitched whistling sounds usually in expiration and associated emphasised that any rigid definitions based on age are likely, with increased work of breathing, but which can also sometimes to some extent, to be artificial. In the United States and be heard in inspiration. In research studies, wheeze can be elsewhere, “bronchiolitis” is used synonymously with wheezing quantified directly by using surface microphones, which is the illness. We have not discussed the approach to bronchiolitis as ideal. With this technique, it was shown that physicians 10-12 defined in the UK; interested readers are referred elsewhere. auscultating the chest accurately identify wheeze8; parents and nurses were much less reliable. Should preschool wheezers be subdivided How common is wheeze in preschool (phenotyped)? children? Several approaches have been used to categorise preschool wheezers. The first two are mentioned because they are of Preschool wheeze is common. In the Avon Longitudinal Study scientific importance and are widely quoted in the literature, of Parents and Children (ALSPAC) study, a prospective but they are not useful in guiding treatment. longitudinal observational study, 26% of 6265 infants reported

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

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CLINICAL REVIEW

Summary points

Preschool wheeze should be divided into “episodic viral” and “multiple trigger” according to the history, and these categories, which can change over time, should be used to guide treatment No treatment has been shown to prevent progression of preschool wheeze to school age asthma, so treatment is driven solely by current symptoms In all but the most severe cases, episodic symptoms should be treated with episodic treatment If trials of prophylactic treatment are contemplated, they should be discontinued at the end of a strictly defined time period because many respiratory symptoms remit spontaneously in preschool children Prednisolone is not indicated in preschool children with attacks of wheeze who are well enough to remain at home and in many such children, 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 last 5 years”, “humans”, “English” activated, with the subject age range “infant” (0-23 months) and “preschool” (2-5 years). Additionally, we separately searched the Cochrane database and Clinical Evidence, as well as our personal archives of references, extending beyond the previous 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 base for treatment. We eliminated all manuscripts that also included children of school age and above unless we could differentiate data from pre-schoolers aged 5 and under from data from older children because the pathophysiology of wheeze and the treatment algorithms are different in these two age spans. We also eliminated small trials and case series if the findings had been subsumed into a meta-analysis or Cochrane review.

• Epidemiological: patterns such as transient early (wheeze the definition includes evidence of airway eosinophilic only in the first three years of life) and persistent (wheeze inflammation, the answer is more difficult as few if any have throughout the first six years of life).9 13 These studies have the ability to measure this in preschool children. What most led to many insights into the evolution of symptoms and parents actually want to know is whether their child will go on lung function, but the categories can be determined only with symptoms and the need for treatment into school age and retrospectively and give no guide to treatment, so are not beyond. The evidence from cross sectional physiological work useful for the clinician and studies of endobronchial biopsies in children with severe • Atopic versus non-atopic: early aeroallergen sensitisation preschool wheeze is that multiple trigger wheeze is associated is certainly predictive of ongoing symptoms and loss of with more airflow obstruction than episodic viral wheeze, and 14 the airway pathology (eosinophilic inflammation and lung function at school age, but does not predict the 16 response to treatment with inhaled corticosteroids15 remodelling) is similar to childhood and adult asthma. By contrast, episodic viral wheeze is not associated with evidence • Symptom pattern: the European Respiratory Society Task 1 of eosinophilic inflammation, so the use of inhaled Force suggested that preschool wheezers should be placed corticosteroids in this group is questionable. into one of two pragmatic categories. This is our favoured categorisation for planning treatment: Does preschool wheeze lead to asthma? – Episodic viral wheeze (EVW): the child wheezes only with usually clinically diagnosed viral upper respiratory Several clinical predictive indices for future risk of asthma have infections and is otherwise totally symptom free been developed based on combinations of the presence of atopic – Multiple trigger wheeze (MTW): the child wheezes with manifestations, indirect evidence of airway inflammation, such as peripheral blood eosinophil count, and severity of preschool clinically diagnosed upper respiratory infections but also 17-19 with other triggers, such as exercise and smoke and wheeze. They all have a high negative predictive value and allergen exposure. a poor positive predictive value (typically positive predictive values 44-54, negative 81-8817-19). Children who have episodic This last classification is used to guide treatment (see below). viral wheeze only have no increased risk of atopy or respiratory It has been criticised because children might change between symptoms in the long term once they reach the age of 14.20 categories over time,2 but in that event pharmacological treatment should also change. This is analogous to the situation Can we prevent preschool wheeze in school age children with asthma; treatment is not left fixed over time but is increased or decreased depending on symptom progressing to school age asthma? pattern and severity. Unfortunately, few studies adopt this The clear cut evidence from good randomised controlled trials classification; most randomised controlled trials and genetic is that early use of inhaled corticosteroids, whether continuously and epidemiological studies combine children with both or intermittently with viral colds, does not affect progression symptom patterns. of disease.21-23 A trial of oral cetirizine in high risk children seemed to show benefit in preventing symptoms in subgroups Is it asthma? sensitised to particular aeroallergens,24 but a subsequent trial with L-cetirizine did not replicate these findings (J Warner, This question is commonly asked by parents who want to know personal communication, 2013). This means that we have no whether their child will continue to have symptoms and require disease modifying drug treatments, and treatment should solely drug treatment into school age and beyond. The answer, be focused on current symptoms. however, depends on what definition of asthma is being used by the questioner. If a purely symptomatic definition is used (symptoms of wheeze and breathlessness fluctuating over time and with treatment), then the answer is affirmative. If, however,

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CLINICAL REVIEW

What are the broad treatment strategies The Cochrane review identified use of intermittent inhaled corticosteroids as a partially effective strategy for episodic for children with preschool wheeze? 30 wheeze in preschool children. A proof of concept study in 129 Before any drugs are prescribed for either episodic viral wheeze children aged 1-6 years showed that the pre-emptive use of 750 or multiple trigger wheeze, it is essential to ensure that the home µg twice a day (compared with the maximum licensed dose of environment is optimal, particularly that the child is not exposed 200 µg twice daily in children aged 4 and above; not licensed to tobacco smoke; parental smoking “not in front of the children” in any dose below age 4) of fluticasone dipropionate for up to does not protect them from harm.25 A birth cohort study found 10 days, starting at the first sign of a viral upper respiratory tract that air pollution can increase vulnerability to preschool infection, led to a reduction in dose of rescue prednisolone (8% wheeze,26 but to date we have no specific advice based on of upper respiratory tract infections in the fluticasone group v individual exposure profiles. Drugs might reasonably be targeted 18% in the placebo group; odds ratio 0.49, 95% confidence at prevention of future complications such as airway remodelling interval 0.30 to 0.83).31 This huge dose, however, was and persistent airflow obstruction, and, additionally, to treat unsurprisingly associated with side effects and cannot be present symptoms. In practice, we have no drug strategies to recommended. Another study looked at regular twice daily reduce future risk of asthma; neither early use of continuous21 22 nebulised budesonide 0.5 mg compared with intermittent nor intermittent23 inhaled corticosteroids reduces the risk of nebulised budesonide 1 mg twice a day at the time of viral progression to school age asthma. If inhaled drugs are respiratory illnesses. This was a randomised double blind prescribed, repeated education of the parents in the correct use controlled trial in 278 children aged between 12 and 53 months of spacers is essential. If inhaled drugs in particular do not seem who had a positive modified asthma predictive index.32 There to be working, check that they are being properly administered was no difference in any respiratory outcome, but in the absence rather than escalate treatment. The use of a skilled respiratory of a placebo group it is not possible to state that either strategy nurse to help carers give inhaled drugs to children is invaluable. was beneficial. What this study definitely shows is that regular nebulised budesonide does not prevent viral exacerbations of How to treat episodic viral wheeze? wheeze. Smaller older trials of inhaled beclometasone also failed to show a preventive effect.33 There is currently no evidence to Intermittent symptoms should be treated with intermittent support the use of inhaled corticosteroids at licensed doses in therapy (and in practice this is likely to be what parents do children with episodic viral wheeze. As some studies suggest anyway). Failure to instigate regular inhaled treatment will not that intermittent inhaled corticosteroids might be a useful prejudice future respiratory health. It is important to consider approach in children with viral induced wheeze at higher than whether the child needs treatment at all. The use of inhaled licensed doses, further studies are required to clarify the dose therapy to treat mild respiratory noises with minimal respiratory and duration that might be beneficial in this setting. In practice, distress might be more problematic than the disease. If treatment however, it would be unwise to go above a fluticasone dose of is required, then initial treatment should be with an intermittent 150 µg twice a day, given the number and duration of viral colds bronchodilator (either short acting β2 agonist or anticholinergic). in normal preschool children and the risk of side effects

If treatment needs to be escalated beyond intermittent β2 agonist including growth suppression and adrenal failure with higher or anticholinergic because of failure to control symptoms, the doses. There are currently no studies that have combined next options are intermittent leucotriene receptor antagonist intermittent inhaled corticosteroids with intermittent montelukast (montelukast), intermittent inhaled corticosteroids, or both. to treat episodic viral wheeze. There have been important recent randomised controlled trials of intermittent therapy. Is there any role for prophylactic The PREEMPT study examined intermittent montelukast continuous inhaled corticosteroids in 27 compared with placebo in 220 children aged 2-14. Treatment episodic viral wheeze? was initiated at the onset of symptoms of a respiratory tract infection and continued for a minimum of a week or until There is no evidence to support the use of regular inhaled symptoms had disappeared for 48 hours. The montelukast group corticosteroids in preschool children who do not wheeze between had fewer unscheduled consultations for asthma (odds ratio viral colds. In those children with really severe episodic wheeze 0.65, 95% confidence interval 0.47 to 0.89) and fewer days who require repeated admission to hospital or have prolonged away from school or childcare and less time off work for parents disruptive symptoms managed at home, however, a trial of (37% and 33%, respectively; P<0.001 for both). In a predefined prophylactic inhaled corticosteroids can be given. In some cases subgroup analysis, the benefits were greater in children aged it might become apparent that in fact there were interval 2-5 (about 80% of the study group). These findings were not symptoms that were underappreciated. In any event, the clinical confirmed in a much larger three way comparison of intermittent trials of inhaled corticosteroids in episodic viral wheeze were montelukast, continuous montelukast, and placebo (nearly 600 carried out in relatively mildly affected children, so the evidence children in each group).28 A three way comparison between in severely affected children is less robust. Treatment should standard treatment, intermittent montelukast, and intermittent be reviewed and discontinued if there is no benefit; there is no nebulised budesonide (the only aerosolised steroid permitted evidence to suggest the optimal duration of the therapeutic trial, by the FDA in preschool children) in 238 children aged 12-59 but six to eight weeks would seem a reasonable time period. If months showed minor and equivalent benefits for the two active the viral wheezing improves on treatment, regular attempts treatments compared with standard treatment.29 Benefits were should still be made to reduce the dose. It should be noted that, greater in the subgroup with a modified asthma predictive index. in a small study, even really severe episodic viral wheeze was Taken together, these studies suggest that a trial of montelukast not associated with eosinophilic airway inflammation4 and that in preschool children with troublesome viral induced wheeze inhaled corticosteroids (fluticasone 100 µg twice a day) led to is worth attempting. We recommend starting treatment at the growth suppression in the PEAK trial,21 so trials of inhaled first sign of a viral cold and discontinuing it when the child is corticosteroids in this context should be deployed only clearly better, rather than for a fixed period of days. exceptionally. If there is a suspicion that the child might in fact

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CLINICAL REVIEW

have symptoms between colds, which are underappreciated by (0.9%) saline, in each case combined with salbutamol twice 20 the carers, a trial of inhaled steroids can reveal that the child minutes apart in the emergency department and then, if the child was previously much more symptomatic than was thought. was admitted to hospital, four times a day thereafter.38 Admission Whatever the context of therapeutic trials in preschool children, rates and lengths of stay were significantly reduced in the they should be for a fixed time period (such as six to eight hypertonic saline group, but there was no significant change in weeks, see above) and discontinued at the end of the agreed severity score, possibly because of the small size of the study. period to see if symptoms recur or in fact have resolved and Further work in larger numbers of children is needed to define treatment has become unnecessary (see the three stage trial the role of hypertonic saline in acute preschool wheeze. Given proposal below). the possibility of bronchoconstriction being induced by hypertonic saline, this treatment should be given only in a Is there a role for oral prednisolone in hospital setting. Palivizumab has been used to prevent infection with respiratory primary care for preschool wheeze? syncytial virus in high risk infants—for example, survivors of Recent evidence has questioned the role of prednisolone in acute extreme prematurity. The cost and inconvenience of monthly episodes of episodic viral preschool wheeze. In a home based injections means this has never been, and is still not, a treatment study, 217 preschool children who had at least one admission strategy for all babies. A recent double blind study, however, to hospital were randomised to a parent initiated course of randomised 429 infants born at 33-35 weeks’ gestation to 39 prednisolone or placebo at the next wheezing episode. No benefit palivizumab or placebo. Palivizumab reduced the number of was observed in the treatment group.34 A hospital study that days with wheeze in the first year of life by 61% and the randomised 687 preschool children admitted with wheeze to proportion of infants with recurrent wheeze from 21% to 10%. prednisolone or placebo in addition to bronchodilator therapy The more interesting question, which this trial could answer, is found there was no benefit in the prednisolone group.35 the vexed one as to whether early respiratory syncytial virus infection causes asthma or is merely a sign that the child was The implication of these two studies, involving more than 900 previously predisposed to asthma, provided the infants are children, is that any preschool child with viral induced wheeze followed up to school age. The current position is that this is who is well enough to stay in the community should not be work in progress, rather than an indication for a change in public prescribed oral prednisolone, and many children admitted to 36 policy. hospital also should not be prescribed oral prednisolone. These studies, however, were undertaken in children with relatively mild symptoms and most were discharged from hospital in less What about treatment plans? than 24 hours, so what these studies do not tell us is whether Treatment plans outlining self management actions to be taken prednisolone is indicated in really severe preschool viral wheeze. depending on the severity of symptoms and peak flow In the absence of evidence, it is likely that prednisolone will measurements are widely recommended in school age children. continue to be prescribed in this small subgroup of children in In a randomised controlled trial in which 200 children age 18 hospital. months to 5 years who had an unscheduled hospital visit or admission with wheezing were allocated either to standard care How should I treat multiple trigger or to receive a package consisting of a booklet, a written guided wheeze? self management plan, and two structured educational sessions, there were no differences in any outcomes.40 Despite this, many Preschool children who have wheeze or cough responsive to will use educational sessions and plans, but there is no evidence bronchodilator treatment and breathlessness on most days even of efficacy. when they do not have a viral cold should be considered for a trial of preventive drug treatment, either inhaled corticosteroids What is the role of nebulised therapy? or a leucotriene receptor antagonist (montelukast). As airway inflammation cannot routinely be measured in this age group, There is no role for nebulised therapy to deliver bronchodilator and many children will become asymptomatic before school apart from in children too sick to use inhalers. For all other age, it would be incorrect to assume the pathophysiology of the purposes, the evidence is clear that metered dose inhalers and disease is the same as school age asthma. Furthermore, the spacers are at least as good as nebuliser. younger the child, the less likely there is to be any eosinophilic 37 inflammation and therefore more reluctance to use inhaled Contributors: AB wrote the initial draft of the manuscript and is guarantor. corticosteroids. The manuscript was reviewed and edited by SS and JG; all authors There is a dearth of evidence, but the box shows a pragmatic agreed the final version. three stage trial of treatment, which is recommended in our Competing interests: We have read and understood the BMJ Group practice. policy on declaration of interests and declare the following interests: AB The aim of this three step approach is to prevent children being was supported by the NIHR Respiratory Disease Biomedical Research falsely labelled and inappropriately treated because someone Unit at the Royal Brompton and Harefield NHS Foundation Trust and has started a drug when the child was about to get better Imperial College London. Provenance and peer review: Not commissioned; externally peer spontaneously. Long acting β2 agonists are not licensed for use in preschool children. reviewed.

1 Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Are there any other new treatments Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:1096-110. around? 2 Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souef PN, Brand PL. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger In a small double blind trial, a total of 41 children aged 1-6 wheeze. Acta Paediatr 2010;99:56-60. years were randomised to nebulised hypertonic (7%) or normal

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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 weeks Step 2: Stop treatment; either there has been no improvement, in which case further escalation is not valuable, or symptoms have disappeared; 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 and the symptoms are troublesome, referral for consideration of further investigation is recommended Step 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 to hospital? 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 to hospital? 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) promoter genotype (http://clinicaltrials.gov/show/NCT01142505). This is a randomised controlled trial of intermittent therapy with montelukast started at the first sign of a viral cold or wheeze by parents. Both phenotypes of wheeze were recruited and analysis is due January 2014

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 the family 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 as efficacious • If inhaled drugs in particular do not seem to be working, check that they are being properly administered (or better yet, get a respiratory nurse to do this) rather than escalating treatment • Although several predictive indices for future asthma risk have been proposed, negative predictive value is excellent but positive predictive value is poor

Additional educational resources Resources for healthcare professionals The 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.aspx World 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 patients Asthma UK webpage (free): www.asthma.org.uk/advice-children-and-asthma NHS 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. 14 Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study Symptom-pattern and pulmonary function in preschool wheezers. J Allergy Clin Immunol (MAS) group. Perennial allergen sensitisation early in life and chronic asthma in children: 2010;126:519-26. a birth cohort study. Lancet 2006;368:763-70. 4 Sonnappa S, Bastardo CM, Saglani S, Bush A, Aurora P. Relationship between past 15 Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and airway pathology and current lung function in preschool wheezers. Eur Respir J preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. 2011;38:1431-6. Pediatrics 2009;123:e519-25. 5 Cane RS, Ranganathan SC, McKenzie SA. What do parents of wheezy children understand 16 Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al. Early detection of by “wheeze”? Arch Dis Child 2000;82:327-32. airway wall remodelling and eosinophilic inflammation in preschool wheezers. Am J Respir 6 Elphick HE, Ritson S, Rodgers H, Everard ML. When a “wheeze” is not a wheeze: acoustic Crit Care Med 2007;176:858-64. analysis of breath sounds in infants. Eur Respir J 2000;16:593-7. 17 Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma 7 Saglani S, McKenzie SA, Bush A, Payne DN. A video questionnaire identifies upper airway at school age among preschool children. J Allergy Clin Immunol 2012;130:325-31. abnormalities in pre-school children with reported wheeze. Arch Dis Child 2005;90:961-4. 18 Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic 8 Levy ML, Godfrey S, Irving CS, Sheikh A, Hanekom W, Bush A, et al. Wheeze detection: characteristics of children with recurrent wheezing at high risk for the development of recordings vs assessment of physician and parent. J Asthma 2004;41:845-53. childhood asthma. J Allergy Clin Immunol 2004;114:1282-7. 9 Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, et al. Associations 19 Devulapalli CS, Carlsen KC, Håland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, et of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of responsiveness in mid-childhood. Thorax 2008;63:974-80. age. Thorax 2008;63:8-13. 10 Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance of 20 Harris JM, Bush A, Wilson N, Mills P, White C, Moffat S, et al. Preschool wheezing cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996;75:489-93. phenotypes in a representative school cohort. Thorax 2010;65(suppl 4):A37. 11 British Guideline on the Management of Asthma (2012 update). www.brit-thoracic.org.uk/ 21 Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term guidelines/asthma-guidelines.aspx. inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 12 Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007;335:1037-41. 2006;354:1985-97. 13 Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and 22 Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team. Secondary wheezing in the first six years of life: the Group Health Medical Associates. N Engl J Med prevention of asthma by the use of inhaled fluticasone dipropionate in wheezy infants 1995;332:133-8. (IWWIN): double-blind, randomised controlled study. Lancet 2006;368:754-62. 23 Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998-2005.

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24 Pool J, Petrova N, Russell RR. Exposing children to secondhand smoke. Thorax 39 Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, et al; 2012;67:926. Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy 25 Warner JO; ETAC Study Group. Early treatment of the atopic child. A double-blinded, preterm infants. N Engl J Med 2013;368:1791-9. randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in 40 Stevens CA, Wesseldine LJ, Couriel JM, Dyer AJ, Osman LM, Silverman M. Parental children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment education and guided self-management of asthma and wheezing in the pre-school child: follow-up. J Allergy Clin Immunol 2001;108:929-37. a randomised controlled trial. Thorax 2002;57:39-44. 26 Andersen ZJ, Loft S, Ketzel M, Stage M, Scheike T, Hermansen MN, et al. Ambient air pollution 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-course Cite this as: BMJ 2014;348:g15 montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-9. 28 Valovirta E, Boza ML, Robertson CF, Verbruggen N, Smugar SS, Nelsen LM, et al. Related links Intermittent or daily montelukast versus placebo for episodic asthma in children. Ann Allergy Asthma Immunol 2011;106:518-26. 29 Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr; CARE bmj.com/videos Network. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in Watch a collection of videos on this topic at preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol • 2008;122:1127-35. bmj.com/content/348/bmj.g15 30 McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev 2000;2:CD001107. 31 Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive use bmj.com/ of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 2009;360:339-53. Previous articles in this series 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 intermittent • Erectile dysfunction (BMJ 2014;348:g129) budesonide in preschool children with recurrent wheezing. N Engl J Med 2011;365:1990-2001. • Acute haematogenous osteomyelitis in children (BMJ 2014; 33 Wilson N, Sloper K, Silverman M. Effect of continuous treatment with topical corticosteroid 348:g66) on 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 oral • Supporting smoking cessation (BMJ 2014;348:f7535) prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet 2003;362:1433-8. • Abortion (BMJ 2014;348:f7553) 35 Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med • Diagnosis, management, and prevention of rotavirus 2009;360:329-38. 36 Bush A. Practice imperfect—treatment for wheezing in preschoolers. N Engl J Med gastroenteritis in children (BMJ 2013;347:f7204) 2009;360:409-10. 37 Saglani S, Malmstrom K, Pelkonen AS, Malmberg LP, Lindahl H, Kajosaari M, et al. Airway • Tick bite prevention and tick removal (BMJ 2013;347: remodeling and inflammation in symptomatic infants with reversible airflow obstruction. f7123) 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 acute © BMJ Publishing Group Ltd 2014 wheezing in preschool children. Pediatrics 2012;129:e1397.

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Table

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

Wheeze category Suggestive features Suggested actions

Normal child—commonest and also the hardest Child well and thriving, with no other features on history or Reassurance diagnosis to make (includes those with postviral examination to raise concerns cough, pertussis, and parents who are overanxious about minor symptoms or do not appreciate the number of viral infections a normal preschooler will acquire) Serious condition (such as immunodeficiency)—rare Suspect if history of symptoms from first day of life, chronic wet Refer for investigation (by telephone if but essential to diagnose or refer cough, sudden onset of symptoms, continuous unremitting symptoms, sudden onset of signs suggesting systemic illness; physical examination shows digital clubbing, endobronchial foreign body) unusually severe chest deformity, stridor, fixed wheeze, or asymmetric signs on auscultation, anything to suggest systemic disease Minor conditions that might may exacerbate or mimic Otherwise well and thriving child with history of easy vomiting, arching Initial empirical trials of treatment; refer wheezing syndrome—for example, away from breast, poor feeder (gastro-oesophageal reflux), or if no response and symptoms gastro-oesophageal reflux, chronic rhinitis prominent upper airway disease, inflamed nose, adenotonsillar troublesome. hypertrophy Child with prominent snoring should be considered for referral for sleep study True wheezing syndrome: episodic viral wheeze An otherwise well and thriving child with wheeze only at time of viral Treatment options discussed in text. (EVW); multiple trigger wheeze (MTW) cold, often but not invariably with no personal or family history of Refer if child is not responding atopic disorders (EVW); wheeze with viral colds and also between colds with typical asthma triggers such as exertion and excitement, cold air, allergens (MTW). There is often but not invariably a personal or family history of atopic disorders

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