Definition, assessment and treatment of wheezing disorders in

Transcription

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 Souëf, S. McKenzie, P.J.F.M. Merkus,
F. Midulla, J.Y. Paton, G. Piacentini, P. Pohunek, G.A. Rossi, P. Seddon,
M. Silverman, P.D. Sly, S. Stick, A. Valiulis, W.M.C. van Aalderen, J.H. Wildhaber,
G. Wennergren, N. Wilson, Z. Zivkovic and A. Bush
ABSTRACT: There is poor agreement on definitions of different phenotypes of preschool
wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to
describe children who wheeze intermittently and are well between episodes, and multiple-trigger
wheeze for children who wheeze both during and outside discrete episodes. Investigations are
only needed when in doubt about the diagnosis.
Based on the limited evidence available, inhaled short-acting b2-agonists by metered-dose
inhaler/spacer combination are recommended for symptomatic relief. Educating parents
regarding causative factors and treatment is useful. Exposure to tobacco smoke should be
avoided; allergen avoidance may be considered when sensitisation has been established.
Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze;
benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze
and can be started when symptoms of a viral cold develop.
Given the large overlap in phenotypes, and the fact that patients can move from one phenotype
to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost
any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical
benefit.
Large well-designed randomised controlled trials with clear descriptions of patients are needed
to improve the present recommendations on the treatment of these common syndromes.
KEYWORDS: Asthma, episodic viral wheeze, inhaled corticosteroids, montelukast, multipletrigger wheeze
CONTENTS
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Definitions of temporal pattern of wheeze . . . . . . . . . . . . . . . . . . . . . . . . .
Retrospective epidemiological description of duration of wheeze . . . . . . . . .
Long-term outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations: definitions of phenotypes (based on low-level evidence)
Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
History and physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Recommendations: assessment (based on very low-level evidence) . . . . . .
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AFFILIATIONS
For affiliation details, please see the
Acknowledgements section.
CORRESPONDENCE
P.L.P. Brand
Princess Amalia Children’s Clinic
Isala klinieken
P.O. Box 10400
8000 K Zwolle
The Netherlands
Fax: 31 384247660
E-mail: [email protected]
Received:
January 06 2008
Accepted after revision:
May 26 2008
STATEMENT OF INTEREST
Statements of interest for
P.L.P. Brand, E. Baraldi, H. Bisgaard,
A.L. Boner, J.A. Castro-Rodriguez,
A. Custovic, J.C. de Jongste, E. Eber,
M.L. Everard, U. Frey, M. Gappa,
L. Garcia-Marcos, W. Lenney,
S. McKenzie, G. Piacentini,
G.A. Rossi, P. Seddon, M. Silverman,
A. Valiulis, W.M.C. van Aalderen,
J.H. Wildhaber, G. Wennergren and
A. Bush can be found at
www.erj.ersjournals.com/misc/
statements.shtml
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
EUROPEAN RESPIRATORY JOURNAL
P.L.P. BRAND ET AL.
Treatment . . . . . . . . . . . . . . .
Environmental manipulation .
Parent and patient education
Pharmacological therapy . . .
Delivery devices . . . . . . . . . .
WHEEZING DISORDERS IN PRESCHOOL CHILDREN
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1101
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1102
1104
Methodological considerations . . . . . . . . . . . . . . . . . 1104
Recommendations for treatment (based on low-level evidence
unless otherwise specified) . . . . . . . . . . . . . . . . . . . . 1104
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106
opulation studies have shown that approximately one
in three children has at least one episode of wheezing
prior to their third birthday, and the cumulative
prevalence of wheeze is almost 50% at the age of 6 yrs [1, 2].
Most wheeze in preschool children is associated with viral
upper respiratory tract infections, which recur frequently in
this age group. As a result, recurrent wheeze is a very common
clinical problem facing practitioners throughout the world. It
has been estimated that the problem of preschool wheeze
utilises 0.15% of the total healthcare budget in the UK [3].
Despite its high prevalence, there is a lack of evidence
regarding the pathophysiology and treatment of preschool
wheeze.
The details of the search strategies are available on request.
In most cases, the results were limited to English language
material. No date limits were applied.
P
The understanding of preschool wheezing illness has been
enhanced by a number of birth cohort studies, in particular by
highlighting the existence of different phenotypes [1, 4, 5].
However, the possible implications of these different phenotypes for treatment are poorly acknowledged in current
international guidelines on the diagnosis and management of
asthma [6–8]. Indeed, although two paediatric societies recently
published guidelines on preschool wheezing disorders [9, 10],
comprehensive evidence-based guidelines on the diagnosis and
management of wheezing disorders in preschool children have
not been published to date. The present ERS Task Force was
instituted for exactly that purpose. The Task Force defined a
phenotype as a cluster of associated features that are useful in
some way, such as in managing the child or understanding the
mechanisms of disease. Given the multifactorial nature of all
wheezing disorders (including asthma) in general, and preschool wheezing disorders in particular, it is highly likely that
clinical phenotypes described in the literature are the extremes
of a broad spectrum of wheezing disorders [11, 12]. The Task
Force therefore realises that the phenotypes defined in the
present report are not exhaustive, and that many individual
patients may not fit into the categories described. There may be
overlap between phenotypes and they may change over time.
Each subgroup, consisting of at least three people, reviewed the
retrieved references for relevant papers, adding additional
papers from personal files if required. The evidence from the
retrieved relevant papers was graded, according to recent
recommendations [13], as high-, moderate-, low- or very lowgrade evidence based on the following criteria: study design
and quality (systematic reviews and randomised controlled
trials: high quality; observational studies: low quality; any other
type of article: very low quality), consistency of the data and
relevance. A draft report was prepared by each subgroup. This
was submitted to the whole Task Force for comments. The
individual reports were then combined by the Task Force chairs
(P.L.P. Brand and A. Bush), and the present manuscript was
organised into three main sections: Definitions, Assessment and
Treatment. Based on the evidence reviewed and graded by each
subgroup, the Task Force chairs put together a list of
recommendations that were graded according to the Grading
of Recommendations Assessment, Development and Evaluation
(GRADE) methodology [13]. Instead of the usual system of
grading the strength of recommendations as A, B, C or D, the
GRADE working group proposal to use a different, and more
readily interpretable, system of categorising recommendations
in four groups was followed: should (or should not) be done, or
possibly should (or should not) be done. Recommendations
could only be categorised as should (or should not) be done
when the entire Task Force unanimously endorsed this
recommendation.
The purpose of the present Task Force was to produce
guidelines for the treatment of wheezing in children aged
,6 yrs based on all of the available evidence.
RESULTS
One of the main findings of the present Task Force was that the
evidence on which to base recommendations is limited in this
age group. When no evidence was available from original
studies, narrative reviews and published expert opinions were
considered for inclusion in the present report. All of the
evidence presented is of low quality unless specifically stated
otherwise. The present recommendations are likely to change
when more evidence becomes available.
METHODS
Literature searches were performed in order to identify
material relating to preschool wheeze. Eleven relevant study
areas were identified, and, for each area, a literature search
was carried out based on a predefined series of key clinical
questions and keywords by a single clinical librarian. Search
strategies were constructed by the clinical librarian in
collaboration with a representative of each group in the Task
Force. Searching included the Cochrane library, PubMed and
EMBASE, and the strategies included filters to limit the results
by study type (reviews, randomised controlled trials and other
types of experimental research) and age range (0–5 yrs).
DEFINITIONS
Definitions used in children aged ,6 yrs are often confusing.
Although many individuals later diagnosed with asthma
exhibit their first symptoms during the preschool age period,
making a diagnosis of asthma in preschool children is difficult.
According to the latest edition of the Global Initiative for
Asthma (GINA) guidelines, asthma is a syndrome with a
highly variable clinical spectrum, characterised by airway
inflammation [6]. Inflammation, however, has been poorly
studied in preschool children, and may be absent in very
young children who wheeze [14]. Therefore, a symptoms-only
descriptive approach, outlined in table 1, was adopted.
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The majority of the Task Force agreed not to use the term
asthma to describe preschool wheezing illness since there is
insufficient evidence showing that the pathophysiology of
preschool wheezing illness is similar to that of asthma in older
children and adults.
Wheeze is defined as a continuous high-pitched sound with
musical quality emitting from the chest during expiration. It is
one of a number of forms of noisy breathing in preschool
children [15]. Parents differ widely in their understanding and
definition of wheeze; some think it is a sound such as
whistling, squeaking or gasping, whereas others define it as
a different rate or style of breathing, or think it is the same as
cough [15–19]. If based on parental report alone, therefore,
children may be labelled as having wheeze when they do not.
If possible, therefore, wheeze should be confirmed by a health
professional, bearing in mind that not all healthcare workers
are equally accurate in estimating the severity of wheeze [20].
By definition, the present Task Force has not addressed the
clinical problem of isolated cough without wheeze. Guidelines
on the diagnosis and management of chronic cough in
childhood are available elsewhere [21]. Since wheeze is the
end result of narrowing of intrathoracic airways and expiratory flow limitation, irrespective of the underlying mechanism,
there are numerous reasons for a child to wheeze, including
anatomical abnormalities of the airways, cystic fibrosis and
bronchomalacia. The Task Force unanimously agreed that the
differential diagnosis of wheeze in preschool children should
not be discussed in detail in the present report for a number of
reasons. First, there is very little, if any, evidence to support
recommendations regarding the diagnostic approach to a
wheezing infant. Secondly, the differential diagnosis of wheeze
in preschool children has been discussed in detail in textbooks
[22, 23]. Thirdly, it was felt that most clinicians and researchers
would recognise the clinical problem of recurrent wheezing in
preschool children without an in-depth discussion of its
differential diagnosis.
TABLE 1
P.L.P. BRAND ET AL.
Causative factors for recurrent wheeze may vary from child to
child and within a child over time, due to a large number of
interactions between genetic factors and the environment [24]. As
in adults [25], specific combinations of genetic and environmental
factors determine the individual patient’s phenotype. In clinical
practice, however, most of these factors are unknown.
The phenotypes used in epidemiological studies (transient
versus persistent wheeze) can only be applied retrospectively
[1, 4, 5]. Although the use of these phenotypes has improved
mechanistic understanding, they are of little use to the
clinician. Although the epidemiological phenotype of transient
wheeze is often assumed to be equivalent to the clinical
phenotype of episodic wheeze, this has never been demonstrated. Therefore, definitions of temporal pattern of wheeze
(which are useful to clinicians) were distinguished from the
retrospective definitions of duration of wheeze (which are
used in epidemiological studies; table 1).
Definitions of temporal pattern of wheeze
Episodic (viral) wheeze
Episodic (viral) wheeze is defined as wheeze in discrete
episodes, with the child being well between episodes.
Although not unique to the preschool age group [26, 27], this
phenotype appears to be most common in preschool children
[1, 4, 5]. It is usually associated with clinical evidence of a viral
respiratory tract infection, although microbiological diagnostic
studies are rarely performed in clinical practice. The most
common causative agents include rhinovirus, respiratory
syncytial virus (RSV), coronavirus, human metapneumovirus,
parainfluenza virus and adenovirus [28]. Repeated episodes
tend to occur seasonally.
Factors underlying the frequency and severity of episodes are
only partially understood, but the severity of the first episode
(which is, in turn, related to pre-existent impaired lung
function and younger age), atopy, prematurity and exposure
to tobacco smoke have been implicated [29–35]. Whether or not
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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P.L.P. BRAND ET AL.
the initial episode is classified as bronchiolitis is irrelevant.
Similarly, it is not known whether or not the causative agent of
the initial episode plays a major role in determining long-term
outcome. Both RSV and rhinovirus have been linked to an
increased risk of persistent wheezing over time [36–38]. In the
case of RSV, most studies show that this has disappeared by
the age of 11 yrs, and is not associated with an increased risk of
atopy [37]. For rhinovirus, such long-term data are lacking.
Episodic (viral) wheeze most commonly declines over time,
disappearing by the age of 6 yrs, but can continue as episodic
wheeze into school age, change into multiple-trigger wheeze or
disappear at an older age [1, 26].
Multiple-trigger wheeze
Although a viral respiratory tract infection is the most common
trigger factor for wheeze in preschool children, some young
children also wheeze in response to other triggers (multipletrigger wheeze; table 1). Others have used the term persistent
wheeze for this syndrome, but this is confusing because this
term is also used to describe the long-term temporal outcome
of wheeze (discussed further later).
Systematic studies of other such triggers are lacking. A textbook,
written by two experts in the field, suggests that tobacco smoke
and allergen exposure are important triggers, and that some
children may also wheeze in response to mist, crying, laughter or
exercise [23]. Although many believe that multiple-trigger
wheeze in preschool children reflects chronic allergic airway
inflammation (and could, therefore, be classified as asthma),
there is little evidence to support this (see Investigations section).
Retrospective epidemiological description of duration of
wheeze
The outcome and related characteristics of preschool wheeze
have been determined by prospective birth cohort studies;
however, in individuals, these categories can only be recognised retrospectively [1, 4, 5]. Therefore, these phenotypes can
only be used in epidemiological studies and are of no value in
clinical practice. Three groups have been recognised (table 1)
but it should be stressed that the overlap between these groups
is considerable and that the age limits applied are arbitrary.
In the Tucson birth cohort, 34% of children wheezed during the
first 3 yrs of life but 60% of these had ceased to wheeze by the
age of 6 yrs. As a group, these infants with transient wheeze
show reduced lung function prior to the first respiratory
illness, are exposed to maternal smoking, and are not
characterised by a personal history of eczema or a family
history of asthma [1]. In an attempt to predict which preschool
wheezers continue to wheeze beyond the age of 6 yrs, these
history data have been combined with characteristics such as
blood eosinophilia into an asthma predictive index [39].
Although groups of children with a positive asthma predictive
index respond to inhaled corticosteroid (ICS) therapy [40, 41],
the predictive value of this index for the disappearance or
persistence of wheeze over time in individual patients is of
only modest clinical value [39].
to be atopic and show normal lung function at birth and through
the teenage years [42].
Children who wheezed in the first 3 yrs and continued beyond
the age of 6 yrs were termed persistent wheezers [1]. This was
associated with normal lung function during the first year of
life, but reduced lung function from the preschool age period
and through adulthood (in most but not all cohort studies),
with atopy and a family history of asthma [1, 4, 5].
Long-term outcome
Long-term studies have shown that ,25% of children with
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
the long-term outcome of asthma in school-age children has
been extensively studied, both at the general population level
and in patients with more severe disease, little evidence
regarding the outcome of preschool wheezing into adulthood
is available. Ongoing birth cohort studies should be able to
provide information on the outcome in general populations
during the 2010s. Considering more severe early wheeze, half
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
10 yrs, but only 57% by 17–20 yrs [44–46], illustrating the
tendency for relapse during adolescence. Female sex, passive
smoking during infancy and early sensitisation to allergens
were risk factors for symptoms continuing into early adulthood, but type of virus and premature birth were not.
Recommendations: definitions of phenotypes (based on
low-level evidence)
1) For clinical purposes, wheeze should be described in terms
of its temporal pattern and classified as episodic (viral) or
multiple-trigger wheeze.
2) Use of the terms transient, late-onset and persistent wheeze
should probably be limited to population-based cohort studies
and should not be used clinically.
3) The term asthma should probably not be used in preschool
children because data regarding underlying inflammation are
lacking.
ASSESSMENT
History and physical examination
The purpose of history-taking and physical examination is to
confirm that the preschool child has a wheezing disorder, to
identify the pattern of symptoms, the severity of the condition
and any possible trigger factors, and to look for features
suggestive of another diagnosis or associated condition. The
detailed diagnostic tests for these conditions are beyond the scope
of the present report and have been discussed by others [23].
The 15% of children who started wheezing after the age of 3 yrs
and were still wheezing at the age of 6 yrs were defined as
having late-onset wheeze. This was associated with maternal
asthma, male sex and a history of rhinitis [1]. This group tended
History
History-taking is the main diagnostic instrument in the
assessment of preschool wheeze in those who are not
wheezing during the consultation. Accurately identifying
wheeze from the history can be difficult since the term is used
by parents and healthcare workers to describe a variety of
symptoms [15, 17–19]. Children with doctor-confirmed wheeze
exhibit greater airways resistance than children with only
reported wheeze [47], even though interobserver agreement
between doctors is poor [48]. A video questionnaire may help
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parents to distinguish wheeze from upper airway noises [49].
Symptom scoring systems have been insufficiently validated to
justify general use, and validated questionnaires for this
purpose in this particular age group are needed. Noisy
breathing is common among infants aged ,6 months but only
a small proportion have wheeze [15]. Reported noisy breathing
that responds to bronchodilator therapy is likely to be genuine
wheeze and to be caused, at least in part, by constriction of
airway smooth muscle [50].
Physical examination
No evidence is available regarding the usefulness of physical
examination in wheeze assessment. A textbook states that the
degree of airway narrowing can only be estimated crudely and
indirectly, by assessing work of breathing (chest retractions,
nasal flaring and use of accessory respiratory muscles) and by
auscultation of the chest to assess the ratio of expiration to
inspiration and the degree of wheeze [23]. Upper airway
obstruction (in particular, nasal congestion) can contribute to
respiratory distress. The aim of further physical examination is
the identification of unusual or atypical features that would
suggest another underlying condition [23].
Investigations
The diagnosis of a preschool wheezing disorder can be made
by history-taking alone. The type, invasiveness and number of
any investigation largely depends upon the degree of
morbidity and the doubt about the diagnosis [23]. This is a
matter of clinical judgement. Most clinicians would agree that
investigations are only justified when symptoms are present
from birth, airway obstruction is abnormally severe, recovery
is very slow or incomplete (resulting in prolonged or repeated
hospital admission in the first few years of life), episodes
continue in the absence of a viral infection or, sometimes, in
cases when parents are very anxious [22, 23]. There is little
research evidence to guide the choice of investigations. Among
infants and preschool children with severe persistent symptoms who were investigated according to a fixed diagnostic
protocol, a considerable number of pathological findings were
observed suggesting that invasive investigations are justified
in this category [51, 52].
Microbiological investigations
With current viral culture and PCR technology, a wide range of
respiratory viruses can be identified, including the most
common causative viruses [28]. There is no evidence, however,
that this contributes to management, either in the short term
(the acute episode) or in the long term, and it is recommended
only for research purposes.
Tests of sensitisation to allergens
The reported prevalence of sensitisation in preschool children
with wheeze in population studies varies widely [1, 4, 5].
Limited evidence is available regarding the prevalence of
sensitisation in preschool children presenting to healthcare
workers with wheeze. One study comparing children aged 2–
5 yrs with doctor-confirmed wheeze who were responding
favourably to a bronchodilator to healthy non-wheezing
children found that 32% of wheezy children gave positive
skin-prick test results to one or more aeroallergens, compared
to 11% of healthy children (likelihood ratio 2.9) [53].
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Sensitisation to inhalant allergens in 1–4-yr-old children from
general practice increases the likelihood of the presence of
asthma at the age of 6 yrs by a factor of two to three [54].
Sensitisation to hen’s egg at the age of 1 yr is a reasonable
marker for allergic sensitisation to aeroallergens at the age of
3 yrs, with a specificity of .90% and sensitivity of .30% [55].
Total serum immunoglobulin E measurements in early life are
not predictive of outcome [56]. Although elevated eosinophilic
cationic protein levels in preschool wheezers are associated
with symptom persistence [57], the degree of overlap between
groups renders such measurements useless for clinical
purposes. Blood eosinophilia can be used as part of an asthma
predictive index, but the predictive value of this index (in
particular, that of a positive result) is low [39].
Radiological examinations
There is no evidence that chest radiographs help in the
diagnosis or treatment of preschool children with acute or
recurrent wheezing [58]. Improvements in diagnostic imaging
techniques may improve understanding of the mechanisms
and long-term outcome of early childhood wheezing disorders
by providing details about airway structure, airway wall
thickness and airway calibre. At present, however, specialised
imaging should be restricted to unusual or severe disease [22].
Measurement of gastro-oesophageal reflux
Although gastro-oesophageal reflux is common among infants
and preschool children with chronic or recurrent respiratory
symptoms [59], a beneficial effect of demonstrating and
treating gastro-oesophageal reflux in infants with wheeze has
not been shown.
Lung function tests
Studies have shown reduced forced expiratory flows associated with wheeze [50, 52, 60, 61]. Low lung function in
school-age children [62–64] and infants [65] appears to track
into early adulthood. It is not known, therefore, whether lung
function deficits in school-age children with wheezing reflect
developmental characteristics of the lung and airways in
wheezy children, disease activity while symptomatic or
remodelling secondary to airway inflammation. The presence
of airway reactivity in infancy is associated with lower
childhood lung function and increased risk of asthma in later
childhood [66], but the mechanisms of airway reactivity in this
age group are poorly understood and probably include factors
other than inflammation [67].
There are no studies supporting the usefulness of pulmonary
function tests in children with nonspecific symptoms, or in
distinguishing between episodic and multiple-trigger wheeze.
In the individual patient, however, determination of lung
function (and bronchodilator response) in preschool children
can help in the discrimination of common wheezing disorders
from other conditions [68, 69].
Exhaled nitric oxide and other assessments of airways
inflammation
Elevated exhaled nitric oxide fractions (FeNO) have been found in
wheezing infants, especially when they are atopic [70, 71], and
these normalise during treatment with ICSs [72] and montelukast
[73, 74]. FeNO in infants are affected by environmental exposures
P.L.P. BRAND ET AL.
and genetic predisposition to atopy [75]. Reference values for
FeNO are only available for children aged o4 yrs [76]. For
uncooperative children aged ,4 yrs, measurement of FeNO has
not been standardised and there is no evidence supporting the
usefulness of measuring or monitoring FeNO in this age group.
Other tests of inflammation, such as analysis of induced sputum,
have not been studied at all in preschool children.
Airway wall biopsy and bronchoalveolar lavage
Few studies have applied bronchoalveolar lavage or bronchial
biopsy in preschool wheezing disorders. Most such investigations have been performed in children with severe or unusual
clinical features, limiting the generalisability of findings. Both
the degree of inflammation and the composition of the infiltrate
have been variable, with neutrophils dominating in some
studies, eosinophils in others and no evidence of either in
others [77]. The only consistent finding was thickening of the
reticular basement membrane in wheezy children [77], but not
in infants (median age 12 months), even when reversible airflow
obstruction and atopy were demonstrated [14]. A recent study
showed that, by a median age of 29 months, some children with
confirmed wheeze exhibit eosinophilic airway inflammation
and reticular basement membrane thickening, implying an age
window at 12–30 months during which interventions aimed at
preventing established airway inflammation might be possible
[78]. Further studies of airway inflammation using bronchoalveolar lavage and bronchial biopsy in large groups of
representative patients with episodic and multiple-trigger
wheeze are urgently needed in order to improve understanding
of the pathophysiology of preschool wheezing disorders.
Unfortunately, such studies are hindered by ethical and
practical constraints. At present, such invasive investigations
should only be used in unusual cases in specialised centres.
Recommendations: assessment (based on very low-level
evidence)
1) The pattern and triggers of wheeze, personal and family
history of atopy, and household smoking should be assessed
by history-taking.
2) Parentally reported wheeze should be confirmed by a health
professional whenever possible.
3) Tests of allergic sensitisation should be performed in
patients requiring long-term treatment and follow-up.
4) Other investigations should probably not be carried out
unless wheeze is unusually severe, therapy-resistant or
accompanied by unusual clinical features.
using environmental control in the treatment of preschool age
wheezing to reduce existing symptoms (secondary prevention)
is the notion that allergen exposure contributes to the severity of
symptoms [80]. There is some evidence that exposure to
allergens in early life increases the risk of wheezing, but this is
dependent upon the allergen, the population and other
environmental factors [81]. The combination of sensitisation
and high exposure to sensitising allergen in early life is
associated with significantly poorer lung function at the age of
3 yrs [82]. Sensitisation to perennial allergens during the first
3 yrs of life is associated with reduced lung function at school
age, with concomitant high exposure to perennial allergens
early in life aggravating this [83]. High allergen exposure during
preschool age enhances the development of airway hyperresponsiveness in sensitised children with wheeze (with later-life
sensitisation and exposure having much weaker effects) [83].
Moving school-age atopic asthmatic children from their homes
to the low-allergen environment of high-altitude sanatoria
temporarily improves levels of markers of airway inflammation and asthma severity [84]. Some studies suggest that
allergen avoidance at home may also be of some benefit
amongst children of this age range [85, 86]. It remains unclear,
however, whether the required major reduction in exposure
can be achieved in normal life and whether it would be of
beneficial effect in young children since no studies on the
effects of allergen avoidance have been performed in preschool
children with wheeze [87].
Parent and patient education
Parental knowledge and understanding of wheezing disorders
in preschool children and their treatment is often inadequate
(especially with respect to medication and the preceding signs
and preventive actions) [88]; however, few educational studies
in wheezy children have explicitly focused on the preschool
age group.
Many educational studies have included children aged as
young as 2 yrs, but the age range of the study group is
frequently not described, and there is rarely an analysis of
whether outcomes are different in younger children. For
example, the Cochrane Review on educational interventions in
children and adolescents aged 2–18 yrs with asthma included
no separate analysis of outcomes in younger children [89].
Indeed, of the 32 studies included in the review, only one
studied preschool children exclusively [90]; two other studies
that included children aged ,2 yrs were excluded.
Allergen avoidance
Allergen avoidance to prevent the development of symptoms, in
either the population as a whole or high-risk subgroups
(primary prevention), is not discussed here. The rationale for
Of the few studies in preschool children, those that have
utilised multiple teaching sessions have shown improvements
in morbidity, with more symptom-free days and better
caregiver quality of life [90, 91], as well as improved knowledge and improved self-efficacy [92], and outcomes similar to
those in older children. These studies all used different
formats: reading of a home booklet followed by practitioner
review on next consultation [92], small group teaching by
nurses [90] and home-based education [91]. One other large
randomised controlled trial in preschool children with acute
wheeze found no effect of an education programme upon
subsequent healthcare utilisation, disability score, parent’s
quality of life and parental knowledge of asthma [93]. This
study included two structured 20-min one-to-one sessions, the
VOLUME 32 NUMBER 4
TREATMENT
Environmental manipulation
Reducing tobacco smoke exposure
There is consistent strong evidence that passive exposure to
environmental tobacco smoke is harmful, in terms of both
induction and exacerbation of preschool wheeze [79], and
should be firmly discouraged.
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c
first during hospital attendance and the other 1 month later.
This raises the possibility that multiple educational sessions of
longer duration might be more effective in preschool children.
Virtually all studies in preschool children have targeted
education at parents or carers. However, young children
themselves may benefit from asthma education and practical
training in skills. One study found that children aged 2–5 yrs
who were exposed to a developmentally appropriate educational intervention that included a picture book and video tape
showed improved asthma knowledge, as well as better
compliance and health, compared to controls [94].
Therefore, although educating parents of preschool children
with wheeze (and perhaps also the children themselves)
appears effective, and is advised, more work is needed before
specific educational approaches can be recommended.
Pharmacological therapy
Short-acting b2-agonists
Inhaled rapidly acting b2-agonists are the most effective
bronchodilators available, and, therefore, the drugs of choice
for acute symptoms of wheeze. Double-blind placebo-controlled studies have demonstrated significant bronchodilatory
effects [95–98] and protective effects against bronchoconstrictor agents [99, 100] in infants and preschool children treated
with rapidly acting inhaled b2-agonist. Thus, infants possess
functional b2-receptors from birth, and stimulation of these
receptors can produce the same effects as in older children,
although paradoxical responses to inhaled b2-agonists have
been reported in infants [50, 101]. Oral administration of b2agonist is also effective but is limited by systemic side-effects
[102]. Intravenous infusion of b2-agonists has only shown an
advantage over hourly inhaled treatment in very severe acute
wheeze in young children [103].
After inhalation, b2-agonists are usually well tolerated. Sideeffects, such as muscle tremor, headache, palpitations, agitation and hypokalaemia, are only seen when high doses are
used [104].
Single-isomer R-albuterol is theoretically preferable (although
much more expensive) to the racemic mixture of albuterol
since the S-isomer is therapeutically inactive [104]. There is,
however, no evidence regarding the clinical effectiveness or
superiority of the use of R-albuterol compared to the racemic
mixture in this age group.
Long-acting inhaled b2-agonists
Formoterol and salmeterol have shown long-lasting bronchodilatory and bronchoprotective effects in preschool children
[99, 105]. There are no published double-blind randomised
placebo-controlled trials in preschool children on the addition
of long-acting inhaled b2-adrenergic agents to ICSs.
Inhaled corticosteroids
Treatment with ICSs may be considered for the treatment of
current symptoms, or possibly for the prevention of progression of symptoms (disease modification). Each is considered in
turn, as follows.
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P.L.P. BRAND ET AL.
Inhaled corticosteroids in treatment of symptoms of multipletrigger wheeze
A systematic review of randomised double-blind controlled
trials of inhaled glucocorticosteroids in preschool children with
multiple-trigger wheeze has shown significant improvements in
important health outcomes, including symptoms, exacerbation
rates, lung function and airway hyperresponsiveness [106]. The
treatment effect appears to be smaller than that seen in schoolage children and adults. For example, studies of ICSs in
preschool children with multiple-trigger wheeze have reported
a reduction in exacerbations by ,50% [107, 108]. Compared to
placebo, children using 200 mg?day-1 fluticasone exhibit a mean
of 5% fewer days with symptoms [106].
The dose–response relationship of ICSs in preschool children is
not entirely clear. Dose-related effects have been shown for
exacerbation rate on treatment with daily ICS doses of up to
400 mg?day-1 beclometasone equivalent (or 200 mg?day-1 fluticasone) via pressurised metered-dose inhaler (pMDI) with spacer
(pMDI-S) [107], without any further benefit from higher doses.
Comparison of 0.25, 0.5 and 1.0 mg nebulised budesonide daily,
however, showed similar improvement to that with placebo in
one study [109], whereas another suggested a dose relation in
the range 0.25–1.0 mg nebulised budesonide b.i.d. [110]. Marked
individual variations in response are seen between patients. In a
post hoc analysis of two large randomised controlled trials in
young children (aged 12–47 months), those with frequent
symptoms, aged .2 yrs and/or with a family history of asthma
showed the best response to treatment with fluticasone
(200 mg?day-1), whereas those with less frequent symptoms,
without a family history of asthma and aged ,2 yrs showed no
significant treatment effect [111]. Two recent studies using
inhaled fluticasone to treat wheezy infants and preschool
children failed to find any improvement in lung function [112,
113]. Atopic markers, such as a history of atopic dermatitis or
allergic rhinitis, did not improve the chance of responding to
ICSs [111]. However, preschool children with wheeze, selected
based on the asthma predictive index for the prediction of
persistent wheeze (including atopic dermatitis, allergic rhinitis
and eosinophilia), respond to ICSs as a group [40, 41].
Local side-effects, such as hoarseness and candidiasis, are rare
in preschool children [114], probably because medication is
usually delivered by metered-dose inhaler with spacer (MDI-S)
combination. Studies on the systemic side-effects of inhaled
steroids have yielded inconsistent results. In a 1-yr study of
200 mg?day-1 fluticasone in preschool children, height growth
was similar in the fluticasone-treated children to that in the
cromoglycate-treated children [114]. In another study, however, height growth was reduced by 1.1 cm after 2 yrs of
inhaled 200 mg?day-1 fluticasone compared with placebo [41].
The long-term consequences of inhaled steroid therapy on
growth in preschool children have not been studied. Clinically
relevant effects on adrenal function have only been observed in
children receiving high doses of ICSs (.400 mg?day-1 beclometasone equivalent) [106]. The risk of cataract was not
increased in a study of 358 children aged 1–3 yrs receiving
daily treatment with ICSs for o1 yr [114]. No other potential
systemic side-effects have been studied in preschool children.
Thus ICSs are effective in preschool children with multipletrigger wheeze, but the effect is smaller than that in older
P.L.P. BRAND ET AL.
children, and there is some concern about the effect on height.
This justifies a more critical approach to long-term ICS use in
preschool children with multiple-trigger wheeze than in older
children and adults with asthma. Many clinicians tend first to
give a trial of ICS for a period of ,3 months. If there is no
improvement, the treatment should not be stepped up but
stopped, and further investigations should be carried out in
order to identify the cause of symptoms. If preschool children
with multiple-trigger wheeze respond well to ICS therapy, it is
unclear whether this is due to treatment or the natural
resolution of symptoms. It is recommended, therefore, that
treatment be withdrawn in children who become (almost)
completely free of wheeze after ICS therapy. There are also
clinicians who only continue treatment with ICSs in multipletrigger wheeze if symptoms recur after withdrawal, and
respond to reintroduction of the medication.
Inhaled corticosteroids in treatment of symptoms of episodic
(viral) wheeze
The clinical benefits of ICSs for episodic (viral) wheeze are
controversial [106]. Systematic reviews have concluded that
episodic high-dose inhaled glucocorticosteroids (1,600–
3,200 mg?day-1 budesonide) provide some benefit in episodic
(viral) wheeze (with a 50% reduction in the requirement for oral
steroids, but no effect on hospitalisation rates or duration of
symptoms), but that maintenance treatment with 400 mg?day-1
beclometasone equivalent does not reduce the number or the
severity of wheezing episodes in episodic (viral) wheeze [106,
115]. It should be emphasised that the available evidence is
based on a few small trials that may be underpowered for the
detection of a treatment effect. For example, the study on the
effect of maintenance treatment with ICSs in episodic (viral)
wheeze analysed only 41 patients [116]. The most recent study,
published only in abstract form, showed that intermittent
treatment with 1.5 mg?day-1 fluticasone for f10 days for
episodic (viral) wheeze reduced the severity and duration of
symptoms but at a cost of slightly reduced height [117]. Thus,
the use of high-dose intermittent steroids in this age group
requires careful consideration.
Nasal corticosteroids to reduce episodic (viral) wheeze
Although treatment of allergic rhinitis may help to ameliorate
asthma in school-age children and adolescents, a randomised
controlled trial of nasal corticosteroids in preschool children
with recurrent wheeze failed to demonstrate any benefit [118].
Treatment of episodic (viral) wheeze in preschool children to
reduce risk of persistent wheeze during later childhood
Three randomised controlled trials (two on daily ICSs and one
on intermittent use when the child was wheezy) have shown
that use of ICSs in preschool children with episodic (viral)
wheeze does not reduce the risk of persistent wheeze at the age
of 6 yrs, and that symptoms return when steroid therapy is
discontinued [41, 119, 120].
needed to treat 3) [121]. Although that review included several
studies in preschool children, they were not analysed
separately. A systematic review of two studies found no
evidence that parent-initiated oral corticosteroids are associated with a benefit in terms of hospital admissions,
unscheduled medical reviews, symptoms scores, bronchodilator use, parent and patient impressions, physician assessment, or days lost from work or school [122].
Leukotriene modifiers
Montelukast is the only cysteinyl leukotriene receptor antagonist licensed for the treatment of young children, at a dosage of
4 mg orally once daily. No clinically relevant side-effects have
been reported [123].
Montelukast in multiple-trigger wheeze
In two studies, montelukast provided protection against
bronchoconstriction induced by hyperventilation with cold
dry air, and improved airways hyperresponsiveness by one
doubling dose after 4 weeks, compared to placebo [124, 125].
The bronchoprotective effect was independent of concurrent
steroid treatment. In a multicentric study of 689 young children
with multiple-trigger wheeze, montelukast improved symptoms and achieved a 30% reduction in exacerbations [123]. One
recent study showed that nebulised budesonide was more
effective at reducing exacerbation rates in 2–8-yr-old children
with multiple-trigger wheeze than oral montelukast [126]. Since
preschool children were not analysed separately, it is not known
whether this difference in efficacy also applies to this age range.
Montelukast in episodic (viral) wheeze
Daily use of montelukast over a 1-yr period reduced the rate of
wheezing episodes in 549 children with episodic (viral) wheeze
by 32% compared to placebo (number needed to treat 12) [127].
A trial of intermittent montelukast, started when patients
developed signs of a common cold, compared with placebo in
220 children with episodic wheeze showed a 30% reduction in
unscheduled health visits (number needed to treat 11), but no
effect on hospitalisations, duration of episode, and b-agonist
and prednisolone use [128].
Cromones
Clinical documentation regarding sodium cromoglycate use in
preschool children is sparse and there are no reports on
infants. The Cochrane Review concluded that a beneficial effect
of cromolyn therapy in preschool children with multipletrigger wheeze could not be proven [129]. Most studies were of
poor quality, but one well-designed randomised controlled
trial found no effect on symptom scores or exacerbation
frequency in children aged 1–4 yrs with multiple-trigger
wheeze [130]. No studies have been performed with nedocromil in preschool children.
Systemic glucocorticosteroids
A systematic review of systemic corticosteroids in hospitalised
children with acute asthma found that corticosteroid-treated
children were seven times more likely to be discharged early
than placebo-treated children, and five times less likely to
relapse within 1–3 months following discharge (number
Xanthines
The Cochrane Review on the effects of xanthines (theophylline
and aminophylline) in the chronic treatment of children with
asthma, the effects on symptoms and exacerbations of wheeze
in preschool children were small and mostly nonsignificant
[131]. The studies were all small however. There have been no
good studies comparing xanthines to other medications in
preschool wheeze.
VOLUME 32 NUMBER 4
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Anticholinergic agents
In the Cochrane Review it was concluded that inhaled
ipratropium may be beneficial in older children [132], but
there is no good evidence in preschool children [133]. There are
no important side-effects when ipratropium is inhaled by
MDI-S combination.
Antihistamines
The antihistamines ketotifen and cetirizine have been studied
in preschool wheeze. In the Cochrane Review it was concluded
that children treated with ketotifen were 2.4 times as likely to
be able to reduce or stop bronchodilator treatment than those
treated with placebo. There were also less consistent benefits
with respect to asthma symptoms and exacerbations [134]. The
interpretation of these studies, however, is hampered by the
fact that the description of patients is insufficient to classify
them as having episodic (viral) wheeze or multiple-trigger
wheeze. In addition, the initial favourable reports in the 1980s
were never confirmed in later studies. There are no good
studies comparing ketotifen to other asthma medications.
Cetirizine was compared to placebo in a randomised trial in
infants with atopic dermatitis, with the aim of preventing the
development of asthma. At the age of 3 yrs, there was no
difference in wheeze prevalence between the two groups. In a
post-hoc analysis in a subgroup of patients radioallergosorbent
test-positive for cat, house dust mite or grass pollen, there
appeared to be a protective effect of cetirizine [135]. This needs
to be confirmed in further studies. There are no studies of
cetirizine in preschool children with wheeze.
Other treatment options
No studies have been performed on the effects of immunotherapy or influenza immunisation in preschool children
with wheeze.
Delivery devices
As a general principle, inhaled drug delivery is preferable to
the oral and parenteral routes, in order to provide rapid relief
of symptoms and minimise systemic side-effects. Inhalation
therapy in preschool children is hampered by numerous
factors, including narrower airways, increased turbulence,
deposition high in the respiratory tree, and lack of cooperation
and coordination. Although there is anecdotal evidence
suggesting that some preschool children may be able to use
dry powder inhalers effectively and reliably [136], there is
consensus among experts that these devices should not be
used in preschool children because they lack the ability to
generate sufficiently high inspiratory flows [137]. Similarly,
pMDIs cannot be used by preschool children without the use
of a spacer device because of difficulties in the appropriate
timing of the inspiratory effort. The two inhalation systems to
be considered, therefore, are pMDI-S and nebuliser.
A systematic review has shown that the delivery of inhaled b2agonists by pMDI-S in acutely wheezy infants and preschool
children is more effective than by nebuliser; recovery was
quicker and the risk of hospital admission was reduced by 60%
[138]. There are no studies comparing the two delivery devices
for long-term management. The economic, practical and
hygienic advantages of pMDI-S over nebulisers support the
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VOLUME 32 NUMBER 4
P.L.P. BRAND ET AL.
use of pMDI-S as the preferred means of delivery of inhaled
drugs in preschool children.
Although there is no formal evidence to support this, there is
consensus that cooperative children should use a spacer device
with a mouthpiece wherever possible [137]. Noncooperative
children aged ,3 yrs should use a spacer with a face mask; a
tight face mask seal is considered important for optimal drug
delivery. Crying children are unlikely to receive any drug to
the lower airways [139].
Filter studies have shown high day-to-day variability in
delivered doses in preschool children [140]. This should be
borne in mind when prescribing therapy and judging its effects.
If a spacer is used, it should be noted that electrostatic charge
reduces MDI-S delivery. New unwashed and unprimed plastic
spacers are electrostatically charged, and, therefore, yield
reduced drug delivery [141]. This can be overcome by washing
the plastic spacer in detergent and allowing it to drip dry,
priming it with 5–10 puffs of aerosol or using a metal spacer.
There are no data on the safety of the detergent washing method
however. Since priming with aerosol is the most expensive and
wasteful method of the three, it is not recommended.
Methodological considerations
In accordance with others [106], the Task Force found it
difficult to synthesise the evidence on the efficacy of treatment
in preschool wheeze for a number of reasons. First, inclusion
criteria were commonly unclear. Studies have included
children with asthma or wheeze without further specification.
Even when inclusion criteria were specified, pooling such
studies was frequently impossible because of clinical heterogeneity or the lack of distinction of different phenotypes.
Secondly, treatment (agents, dosages and delivery devices)
differed considerably between studies. Thirdly, different outcome parameters have been studied, most of which were
neither standardised nor validated. Fourthly, the number of
studies and the number of patients enrolled was generally
quite low, especially for studies on ICSs in episodic wheeze.
Fifthly, given the fact that symptoms of wheeze in preschool
children tend to resolve spontaneously and that the most
troublesome symptoms occur episodically, adherence to
treatment by parents and caregivers is probably low, although
few studies have examined this. The one study specifically
addressing this found that parents of preschool children with
troublesome wheeze would not give their child a bronchodilator on 40% of the occasions when the child was wheezy,
even though they knew their adherence was monitored and
even though they were instructed to administer inhaled
bronchodilator when their child was wheezing [142]. Finally,
age appears to be an important effect modifier, in that the
younger the child is, the poorer the response to any treatment.
Recommendations for treatment (based on low-level
evidence unless otherwise specified)
1) Passive smoking is deleterious to preschool children with
wheeze, as at all ages (high-level evidence), and should be
firmly discouraged.
2) There is insufficient evidence on which to base recommendations for the reduction of exposure to environmental allergens
in the treatment of preschool wheezing.
P.L.P. BRAND ET AL.
3) An educational programme using multiple teaching sessions
on causes of wheeze, recognising warning signals and
treatment should be provided to parents of wheezy preschool
children.
4) A pMDI-S combination should be used as the preferred
delivery device for inhalation therapy in preschool children
(high-level evidence).
5) In cooperative children, spacers with a mouthpiece should
probably be used.
6) In uncooperative young children, spacers with a tight-fitting
face mask should probably be used.
7) Plastic spacers should be treated with detergent before use
in order to reduce their electrostatic charge.
Acute wheezing episode
1) Inhaled short-acting b2-agonists on an as-needed basis
should be used for the symptomatic treatment of acute
wheezing in preschool children. These drugs should be used
cautiously in infants since paradoxical responses have been
reported in this age group.
7) A trial of montelukast may be considered in preschool
children with multiple-trigger wheeze.
8) Cromones, ketotifen and xanthines are not recommended
for use in preschool children with wheeze.
9) Immunotherapy is not recommended for preschool children
with wheeze outside the setting of a randomised controlled
trial.
10) Influenza immunisation is not recommended for preschool
children with wheeze.
Maintenance treatment of episodic (viral) wheeze
1) Montelukast 4 mg once daily should probably be given for
the treatment of episodic (viral) wheeze.
2) A trial of inhaled corticosteroids may be considered in
preschool children with episodic (viral) wheeze, in particular
when episodes occur frequently or if the family history of
asthma is positive.
6) Infants aged 1–2 yrs should only be prescribed ICSs if their
symptoms are troublesome and they show a clear-cut response
to treatment.
ACKNOWLEDGEMENTS
The affiliation details of the present study’s authors are as
follows. P.L.P. Brand: Princess Amalia Children’s Clinic, Isala
Clinics, Zwolle; J.C. de Jongste: Dept of Paediatric Respiratory
Medicine, Erasmus Medical Centre/Sophia Children’s
Hospital, Rotterdam; P.J.F.M. Merkus: Dept of Paediatrics,
Division of Respiratory Medicine, Children’s Hospital,
Radboud Medical Centre Nijmegen, Nijmegen; and W.M.C.
van Aalderen: Dept of Paediatric Pulmonology, Emma
Children’s Hospital, Academic Medical Centre, Amsterdam
(all the Netherlands). E. Baraldi: Dept of Paediatrics, Unit of
Respiratory Medicine and Allergy, Unit of Neonatal Intensive
Care, University of Padua School of Medicine, Padua; A.L.
Boner and G. Piacentini: Dept of Paediatrics, G.B. Rossi
Polyclinic, Verona; F. Midulla: Dept of Paediatric Emergency,
University of Rome La Sapienza, Rome; and G.A. Rossi:
Pulmonary Disease Unit, G. Gaslini Institute, Genoa (all Italy).
H. Bisgaard: Danish Paediatric Asthma Centre, Copenhagen
University Hospital, Copenhagen, Denmark. J.A. CastroRodriguez: School of Medicine, Pontifical Catholic University
of Chile, Santiago, Chile. A. Custovic: North West Lung
Research Centre, Wythenshawe Hospital, Manchester; M.L.
Everard: University Division of Child Health, Sheffield
Children’s Hospital, Sheffield; J. Grigg: Academic Unit of
Paediatrics, Institute of Cell and Molecular Science, Barts and
The London Medical School, London; S. McKenzie: Fielden
House, Royal London Hospital, Barts and The London NHS
Trust, London; N. Wilson: Dept of Paediatrics, Royal
Brompton Hospital, London; A. Bush: Dept of Paediatric
Respirology, National Heart and Lung Institute, Royal
Brompton Hospital and Imperial College, London; W.
Lenney: Academic Dept of Child Health, University Hospital
of North Staffordshire, Stoke-on-Trent; J.Y. Paton: University
Division of Developmental Medicine, Yorkhill Hospitals,
Glasgow; P. Seddon: Royal Alexandra Children’s Hospital,
Brighton; and M. Silverman: Dept of Infection, Inflammation
and Immunology, University of Leicester, Leicester (all UK).
J. de Blic: Paediatric Pneumology and Allergology Service,
Paris Public Assistance Hospitals, Necker Hospital for Sick
Children, Paris, France. E. Eber: Respiratory and Allergic
Disease Division, Dept of Paediatrics and Adolescent
VOLUME 32 NUMBER 4
2) Alternative routes of administration (oral and intravenous)
should not be used.
3) Single-isomer salbutamol should not be used.
4) Addition of ipratropium bromide to short-acting b2-agonists
may be considered in patients with severe wheeze.
5) A trial of oral corticosteroids should probably be given to
preschool children with acute wheeze of such severity that
they need to be admitted to hospital.
6) Parent-initiated treatment with a short course of oral
corticosteroids should not be given.
7) Although high-dose ICS therapy appears to have a small
beneficial effect in the treatment of acute wheezing in
preschool children, this treatment is not recommended because
of high cost and lack of comparison to bronchodilator therapy.
Maintenance treatment of multiple-trigger wheeze
1) ICSs at a daily dose of up to 400 mg?day-1 beclometasone
equivalent should be given for the treatment of preschool
children with multiple-trigger wheeze.
2) When the response to this treatment is poor, patients should
not be treated with higher doses but should probably be referred
to a specialist for further evaluation and investigations.
3) If response to inhaled steroids is favourable, treatment
should probably be discontinued after several weeks or
months, in order to judge whether symptoms have resolved
or whether ongoing treatment is needed.
4) Linear growth should be measured in preschool children
using ICSs.
5) Infants younger than 1 yr should probably not be prescribed
ICSs.
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Medicine, Medical University of Graz, Graz, Austria. U. Frey:
Paediatric Respiratory Medicine, Inselspital, Berne University
Hospital and University of Berne, Berne; and J.H. Wildhaber:
Dept of Paediatrics, Fribourg Bertigny Hospital, Fribourg (all
Switzerland). M. Gappa: Dept of Paediatric Pulmonology and
Neonatology, Medical University of Hanover, Hanover,
Germany. L. Garcia-Marcos: Institute of Respiratory Health,
University of Murcia, Murcia, Spain. P. Le Souëf: School of
Paediatrics and Child Health; P.D. Sly: Division of Clinical
Sciences, Telethon Institute for Child Health Research, Centre
for Child Health Research; and S. Stick: Centre for Asthma,
Allergy and Respiratory Research (all University of Western
Australia, Perth, Australia). P. Pohunek: Motol University
Hospital, Prague, Czech Republic. A. Valiulis: Vilnius City
University Hospital, Vilnius, Lithuania. G. Wennergren: Dept
of Paediatrics, Gothenburg University, Queen Silvia Children’s
Hospital, Gothenburg, Sweden. Z. Zivkovic: Centre for
Paediatric Pulmonology, Dr Dragisa Misovic Medical Centre,
Belgrade, Serbia.
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and 18 months’ posttreatment follow-up. J Allergy Clin
Immunol 2001; 108: 929–937.
Agertoft L, Pedersen S. Importance of training for correct
Turbuhaler use in preschool children. Acta Paediatr 1998;
87: 842–847.
O’Callaghan C, Barry PW. How to choose delivery
devices for asthma. Arch Dis Child 2000; 82: 185–187.
Castro-Rodriguez JA, Rodrigo GJ. b-agonists through
metered-dose inhaler with valved holding chamber
versus nebulizer for acute exacerbation of wheezing or
asthma in children under 5 years of age: a systematic
review with meta-analysis. J Pediatr 2004; 145: 172–177.
Iles R, Lister P, Edmunds AT. Crying significantly
reduces absorption of aerosolized drug in infants. Arch
Dis Child 1999; 81: 163–165.
Janssens HM, Devadason SG, Hop WCJ, Le Souëf PN, de
Jongste JC, Tiddens HAWM. Variability of aerosol
delivery via spacer devices in young asthmatic children
in daily life. Eur Respir J 1999; 13: 787–791.
Janssens HM, Heijnen EMEW, de Jong VM, et al. Aerosol
delivery from spacers in wheezy infants: a daily life
study. Eur Respir J 2000; 16: 850–856.
Ferguson AE, Gibson NA, Aitchison TC, Paton JY.
Measured bronchodilator use in preschool children with
asthma. BMJ 1995; 310: 1161–1164.
Copyright PCRS-UK - reproduction prohibited
Primary Care Respiratory Journal (2010); 19(1): 75-83
DISCUSSION PAPER
Setting the standard for routine asthma consultations:
a discussion of the aims, process and outcomes of 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
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Senior Clinical Research Fellow, Allergy and Respiratory Research Group, Centre of Population Health Sciences: GP Section, University of
Edinburgh, Scotland, UK
Chief Executive, Education for Health, The Athenaeum, Warwick, UK
General Practitioner, The Park Medical Practice, Shepton Mallet, UK
General Practitioner, The Rycote Practice, East Street, Thame, UK
Team Leader: Respiratory & Asthma, Education for Health, The Athenaeum, Warwick, UK
Professor of Primary Care Respiratory Medicine, Centre of Academic Primary Care, University of Aberdeen; Foresterhill Health Centre,
Westburn Road, Aberdeen, Scotland, UK
Honorary Clinical Senior Lecturer at the National Heart and Lung Institute, Imperial College, London, UK
Executive Director of Research and Policy, Asthma UK, London, UK
Policy Advisor, Primary Care Respiratory Society UK, Lockerbie, UK
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Originally submitted 31st December 2008; resubmitted 15th July 2009; revised version received 8th November 2009;
accepted 18th November 2009; online 29th January 2010
Abstract
Globally, asthma morbidity remains unacceptably high. If outcomes are to be improved, it is crucial that routine review consultations in
primary care are performed to a high standard. Key components of a review include:
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• Assessment of control using specific morbidity questions to elucidate the presence of symptoms, in conjunction with the frequency of
use of short-acting bronchodilators and any recent history of acute attacks
• After consideration of the diagnosis, and an assessment of compliance, inhaler technique, smoking status, triggers, and rhinitis,
identification of poor control should result in a step-up of treatment in accordance with evidence-based guideline recommendations
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• Discussion should address understanding of the condition, patient-centred management goals and attitudes to regular treatment, and
should include personalised self-management education
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Regular review of people with asthma coupled with provision of self-management education improves outcomes. Underpinned by a
theoretical framework integrating professional reviews and patient self-care we discuss the practical barriers to implementing guided selfmanagement 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
Worldwide, asthma is an important cause of morbidity,
economic cost, and mortality. It is estimated that about 300
million people have asthma, with the highest prevalence in the
UK, Australasia and North America.1 In England, data from
general practice suggest that 5.8% of the population have
‘active asthma’ (defined as a diagnosis of asthma and a
prescription for asthma treatment in the previous 12 months).2
Despite the focus in international guidelines on assessing
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
www.thepcrj.org
doi:10.4104/pcrj.2010.00006
75
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H Pinnock et al.
conditions.23-27 The widely cited Long-Term Conditions
pyramid of care (LTC pyramid) emphases the importance of
self-management to “ensure patients and carers have the
skills and knowledge they need to understand how to best
handle their condition, including how to deal with flare-ups,
to adjust medicines, improve their life-styles and access health
care services”26. Routine reviews operate in the boundary
between patient self-care and professional management,28,29
not only offering opportunities specifically to reinforce and
refine self-management skills, but also more generally to
build the trusted relationship valued by patients (see Figure
2).29
Asthma reviews
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Asthma reviews in primary care should incorporate three key
steps:
1. Assessing control in order to target care appropriately
2. Responding to that assessment by identifying reasons for
poor control and adjusting management strategy
accordingly
3. Exploring patients’ ideas, concerns and expectations, and
guiding self-management to facilitate on-going control
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guidelines,3 surveys have consistently shown unacceptable
morbidity associated with low expectations on the part of
patients.4-8 It has been estimated that up to three-quarters of
the 80,000 admissions for asthma in the UK in 2004 might
have been prevented with improved long-term care.9 A key
strategy for reducing the burden of asthma is a shift in
emphasis from acute management to long-term care and
supported self-management, in order to reduce chronic
morbidity and impairment of quality of life, as well as
reducing exacerbations, admissions and mortality.3,10 Proactive
care, with structured reviews provided by clinicians with
training in asthma care, improves outcomes.11-15
After describing the policy and theoretical framework
linking regular reviews and guided self-management, this
discussion paper sets out the evidence base supporting the
recommended content of good asthma reviews in primary
care. It then discusses the role of ‘pay-for-performance’ –
exemplified by the UK Quality and Outcomes Framework16 –
as a driver for improving treatment outcomes. An Opinion
sheet providing practical guidance for clinicians is available
from www.pcrs-uk.org.
Policy and theoretical framework
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The framework for monitoring chronic disease described by
Glasziou et al. emphasises the inter-relationship between
professional review and patient self-management,17 using
asthma as an exemplar condition (see Figure 1). Cochrane
reviews provide support for this concept, concluding that
improved outcomes are the result of training in asthma selfmanagement coupled with regular review.18-20 This dual
approach is summarised in the GINA asthma guideline as
‘guided self-management’,9 is explicitly recommended (Grade
A) in the 2008 update of the BTS/SIGN asthma guideline,10
and is a core strategy of national programmes to improve
asthma care in Finland and Australia.21,22
Self care is a ‘key pillar’ of the policy approach to meeting
the challenge of providing care for people with long-term
Maintenance
Exacerbation
regaining
control
Maintenance
Figure 2. The long-term condition pyramid with the
boundary between professional and self care (adapted
from Degeling et al.28).
Level 1
At risk of a longterm condition
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Co
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Bo
an
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na
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Pre
Initial treatment,
treatment gaining control
Asthma control reflects the degree to which symptoms are
reduced, exacerbations are prevented and normal lung
function is maintained by treatment,30 with current guidelines
defining ‘control’ as no symptoms, no exacerbations and
normal lung function9 (see Table 1). Occasional daytime
symptoms (defined as less than twice a week) may be
consistent with good control, but disturbed sleep due to
asthma signals loss of control. Challenge tests for assessment
Stepping
down
Best
peak
flow
Level 2
With a long-term condition
80%
60%
Level 3
Complex co-morbidities
Arrows are professional reviews
Line is patient self-management
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Selfmanagement
for health
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Figure 1. The inter-relationship between professional
and self-monitoring (adapted from Glaziou et al.17 to
illustrate the management and self-management of
asthma).
1. Assessing control
Care
management
Case
management
Routine asthma reviews
Table 1. Levels of Asthma Control (reproduced from GINA guidelines9).
Characteristic
Controlled (All of
the following)
Partly Controlled (Any measure
present in any week)
Uncontrolled
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
Lung function (PEF or FEV1)iii
Normal
< 80% predicted or personal best(if known)
Exacerbations
None
One or more/yeari
One in any weekii
i.Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate
ii.By definition, an exacerbation in any week makes that an uncontrolled asthma week.
iii.In adults and older children.
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suitable for use in clinical practice, which can facilitate
detection of poor control. A review of some asthma control
tools is available on the web-site of the International Primary
Care Respiratory Group.38,39 Common to all these tools is
specific enquiry about the presence of symptoms,
interference with activities and disturbance at night.
There are two short, well-validated questionnaires widely
used in research which may be suitable for use in clinical
practice.10,30 The Asthma Control Questionnaire40,41 uses five
morbidity questions plus an optional measure of the forced
expiratory volume in one second (FEV1), has been tested for
use in clinical practice, and a score of more than 1.5 indicates
poor control.42 The Asthma Control Test uses similar morbidity
questions but also includes a rating of overall control, with a
score of 20 or more indicating good control.43,44 Both are
available in a number of languages and have been validated
for self-administration.
However, validity of questionnaires is determined under
carefully controlled conditions, since the mode, circumstances
and place of administration may affect the responses.45 By
contrast, conditions of administration in routine clinical
practice are likely to be very variable, with some practices
arranging completion prior to the asthma review at home or
in the waiting room, whilst others administer them formally in
the consultation. Some clinicians may explain or paraphrase
the questions to assist with completion. There is, therefore, a
need to establish the value of such scores for assessing
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of bronchial hyper-responsiveness are unlikely to be practical
measures of control in primary care settings, though
estimation of exhaled nitric oxide as a measure of
inflammation may have a place in clinical care in the future.30
In primary care, asthma control is normally assessed on
the basis of symptoms, supplemented by examination of the
clinical records. Frequent use of reliever inhalers implies poor
control, and intermittent requests for preventer treatment
signals the need to address patients’ perception of, and fears
about, regular treatment.10 The occurrence of an acute
exacerbation is evidence of poor control over a longer timeframe than the duration of current symptoms.31 A primary
care clinician with access to patient records can easily check
the number of courses of oral steroid required over the
previous year. A ‘one-off’ peak expiratory flow (PEF) or
spirometry reading taken in clinic is of limited value in
assessing the control of a variable condition, though if the
patient is well-controlled it can provide an up-to-date ‘best’
reading for use in action plans. Although few patients will
maintain an accurate paper-based PEF diary on a daily
basis,32,33 use of mobile technology may engage some patients
with on-going PEF and symptom monitoring.34,35
Surveys have consistently shown unacceptably high levels of
asthma morbidity.4-8 Trials demonstrate that by adopting a policy
of ‘zero tolerance’ to symptoms, patients with asthma can
achieve good control;36 however, it remains unclear to what
extent good control as defined by guidelines can be achieved in
real-life practice.37 Patients will wish to balance the benefits of
stepping up therapy until control is achieved against perceptions
of, and preferences for, long-term treatment, and the
practicalities of short consultations may restrict the time available
to address all the diverse factors which result in poor control.37
• Measures of morbidity
Patients’ perception of control may differ markedly from that
based on objective assessment of symptoms,5,8 and clinicians
over-estimate improvements in asthma control.6 This has
given impetus to the development of morbidity scores,
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Table 2. The Royal College of Physicians three questions46.
In the last month
1.
Have you had difficulty sleeping because of asthma symptoms
(including cough)?
2.
Have you had your usual asthma symptoms during the day
(cough, wheeze, chest tightness or breathlessness)?
3.
Has your asthma interfered with your usual activities
(eg housework, work, school, etc)?
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Adherence with regular preventative medication is known to
be poor, and under-use should be considered when there is a
failure to control asthma symptoms.59,60 Patients self-reporting
and health care professional assessment both overestimate
regular use of prophylactic medication.59,61,62 In primary care,
repeat prescribing records provide an indication of adherence
with prescribed asthma regimens.10
Simple, verbal and written instructions and information on
asthma and its treatment for patients and carers may help to
overcome unintentional non-adherence.10 Patents balance
their perceived need for treatment against their concerns
about taking a medication.51 Enquiry, based on a nonjudgemental assumption of non-adherence, can facilitate an
open discussion of the rationale and potential benefits of
regular therapy versus the disadvantages of taking a drug
with (perceived or real) side effects, thus enabling the patient
to reach an informed decision about concordance with
clinical advice on the use of inhaled steroids.
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If control is good, a reminder of action to be taken if asthma
deteriorates may be all that is necessary. However, if
assessment of symptoms, taken in conjunction with the
reported and recorded use of short-acting bronchodilators
and any recent history of any acute attacks, suggests that
control is not ideal, the reasons for this should be considered
and addressed appropriately before increasing asthma
therapy.10 A recent primary care review has considered the
causes for poor control in detail.51 Here, we present a
summary of the key implications for routine practice:
• Assessing adherence
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2. Response to assessment and adjustment of
management
training is required to maintain good technique.55,56 Those
unable to master or maintain good technique with one device
should be offered an alternative.51 This has been specifically
highlighted in children, where inadequate technique –
resulting either from poor training or from choosing a device
poorly suited to the child – significantly reduces drug delivery
to the lungs and results in poor asthma control.58
Practical training when a device is first prescribed,
supported by review of inhaler technique at every asthma
consultation (whether with a nurse, doctor, pharmacist or
other healthcare professional) is good practice.3,10,55,56,58
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control in a range of normal clinical scenarios.
The ‘Royal College of Physicians (RCP) three questions’
represent a consensus UK view on a short symptom
questionnaire,46 which correlates with the Asthma Control
Questionnaire and is responsive to change.47 A refinement of
the RCP three questions which scores the number of days in
the previous week affected by symptoms has been suggested
to improve discriminatory power. The questions (or very
similar precursors of the ‘RCP three questions’) have been
used successfully to target care,48 including use by postal
questionnaire49 and during telephone reviews.50 Whilst
occasional symptoms (e.g. on two or less days a week) may
be acceptable, any nocturnal waking or activity limitation
should be considered as less than well-controlled disease, and
management should be adjusted accordingly.3,10
• Reviewing the diagnosis
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An increase in symptoms, or failure to respond to treatment,
should lead to reconsideration of the diagnosis.10,52 An
unrecognised diagnosis (for example chronic obstructive
pulmonary disease (COPD) in a smoker, gastro-oesophageal
reflux as a trigger for cough, obesity as a cause of
breathlessness), or the development of a co-morbid
condition, may be responsible for apparent poor control.52 A
wide range of rare conditions in childhood may be initially
misdiagnosed as asthma.53
• Checking and correcting inhaler technique
Poor inhaler technique is a well documented problem which
results in ineffective and wasteful use of therapy, and is an
important cause of poor control.51-56 As few as a quarter of
patients make no mistakes when using a pressurised
metered-dose inhaler (pMDI), while just over a half can use
dry powder inhalers, breath-actuated pMDI or pMDI with a
spacer without errors.57 Provision of a spacer for use in an
acute situation may improve effectiveness at a time when
breathlessness makes usual pMDI technique more difficult.
Meta-analysis of the effect of teaching inhaler technique
shows significant improvement after an educational
intervention with a ‘number needed to teach’ (to achieve an
‘ideal’ technique) of 2.6 patients.57 However, repeated
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• Asking about, and treating rhinitis
Rhinitis and asthma are common diseases which co-exist in
75-80% of patients52 and are associated with substantial cost
to patients, employers and health care systems. The
relationship between rhinitis and asthma is strongly
supported by epidemiological, pathophysiological and clinical
evidence.63-71 Patients with co-existent asthma and rhinitis
incur greater prescription drug costs and experience more
general practitioner (GP) visits and hospitalisations for asthma
than those with asthma alone.72,73
Treatment of concomitant allergic rhinitis, particularly with
intranasal steroids and/or leukotriene receptor antagonists, is
associated with significant reductions in risk of emergency
room treatment and hospitalisation for asthma.74-76 Rhinitis
(including seasonal rhinitis) should therefore be sought as a
co-morbidity in all patients with uncontrolled asthma and
treated appropriately.52
• Assessing smoking status and offering cessation advice
Smoking adversely affects asthma control. This may signal a
diagnosis of COPD, either as a co-morbidity or because the COPD
has been incorrectly diagnosed as asthma. Smoking also reduces
78
the effectiveness of inhaled steroids.63,77,78 It is therefore important
to enquire about smoking status and to offer cessation advice to
patients with poorly controlled asthma. Persistent smokers may
need relatively high doses of inhaled steroids.10
preference (e.g. preferred degree of autonomy versus
frequency of professional review; peak flow versus symptom
monitoring) as well as the severity of asthma, risk of very
severe attacks and the maintenance treatment plan.19
• Adjusting therapy according to evidence-based
guidelines
• Implementation in primary care
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The challenge for primary care is that of implementing these
evidence-based recommendations. Studies have shown
consistently that provision of self-management education is
poorly implemented in practice.8,83,84 Some of the recognised
barriers, such as time and resources, are practical issues which
need to be addressed when planning routine care for people
with asthma.85,86 Confusion about details of action plans (such
as the relevance of increasing inhaled steroids) are a further
barrier.87 Despite the growing body of evidence from primary
care,88-92 there is scepticism about whether the evidence
applies to the relatively low risk mild patients in whom benefit
is harder to demonstrate.84 More fundamentally, provision of
asthma action plans is often perceived as an optional task
delegated to a nurse educator.80 Recognition that self-care
and professional care are inextricably linked as
complementary aspects of the management of all people
with long-term conditions – as illustrated in the framework
for monitoring and self-monitoring (see Figure 2)17 – may be
the conceptual key that will help unlock implementation.
A systematic review of the implementation of asthma
action plans highlighted the importance of this interrelationship between the facilitation of regular, structured
review and the provision of self-management education.93 All
three primary care studies in this review demonstrated
increased ownership of asthma action plans,92,94,95 and showed
a consistent trend to improved clinical outcomes, though the
only significant benefits were a reduction in episodes of
‘speech limiting wheeze’,92 and night time waking.94 Similarly,
within managed care programmes, nurse-led telephonebased reviews incorporating self-management education
supported by written information can increase the use of
inhaled steroids.96,97 This inter-relationship is encompassed in
international guidelines as the concept of ‘guided selfmanagement’.3
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After consideration of diagnosis, compliance, inhaler
technique, smoking status, triggers and rhinitis, the
identification of poor control should result in a step-up of
treatment in accordance with the evidence-based advice of
international or national guidelines.3,10 Discussion of the
advantages and disadvantages of treatment options, and
acknowledgement of patient preferences – i.e. whether to
accept symptoms, or whether to accept a change or an
increase in treatment such as a higher dose of inhaled
steroids, an additional therapy, a combination inhaler instead
of separate inhalers, an inhaled long-acting bronchodilator or
an oral leukotriene receptor antagonist – is good consulting
practice and would seem likely to optimise future
concordance.79
Control should be maintained on the lowest possible dose
and stepping down treatment is an important and frequentlyoverlooked step for patients who are consistently well
controlled, especially in children who often ‘grow out’ of their
asthma.3,10
3. Exploring perceptions and supporting
self-management
• Guideline recommendations
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International guidelines emphasise that “Patient education is
the key to success of every aspect of asthma management and
prevention”,3 as many of the obstacles to achieving best
control relate to misunderstanding of the condition, underestimation of the potential benefits of regular treatment, and
exaggerated fears about side effects of asthma treatment. The
UK national guideline includes the Grade A recommendation
that “Patients with asthma should be offered selfmanagement education that should focus on individual needs,
and be reinforced by a written action plan”.10
The provision of self-management education,
incorporating a written asthma action plan, can reduce
hospitalisation,80 unscheduled consultations, time lost from
work and nocturnal asthma, as well as improving self-efficacy
and asthma-related quality of life.16,81 Similar benefits have
been shown in school age children,20 though an innovative
approach may be required for pre-school children.81
Clear advice from a systematic review on the components
of effective asthma action plans – i.e. written instructions, 23 action points triggered by symptoms or based on best peak
flow, advice on increasing inhaled steroids and commencing
oral steroids – is now available.82 Health professionals should
tailor the self-management intervention to allow for patient
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Ensuring access to professional advice
Patients value flexible access to professional advice in order to
support self-care,29,98 but not all patients are willing to attend
a pre-arranged appointment for a regular review.83,99 Repeat
prescribing arrangements should aim to be sufficiently flexible
to enable patients to order more inhalers promptly when
needed, but should include checks to ensure that those
patients requesting reliever inhalers frequently are reminded
to arrange a review.
There is now evidence to inform the appropriate role of
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
•
Set up a register and devise a recall system using a range of reminders (verbal, postal, telephone, e-mail, SMS). Consider opportunistic
•
Ask standard morbidity questions to enable objective assessment of control and tailor the review (both in content and mode of
•
Adopt a policy of ‘zero tolerance’ of symptoms, addressing the potential reasons for poor control and recommending stepping up
•
Prioritise guided self-management and the provision of personal asthma action plans, using every opportunity to review, revise, and
•
Audit the asthma review service, ideally focusing not only on process, but also on patient outcomes.
patients will make a choice appropriate to the severity of their asthma.
phone calls to non-attenders.
delivery) appropriate to the needs of the patient.
treatment as appropriate.
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spanning a range of countries, professionals and disease
areas concluded that audit and feedback can be moderately
effective at improving professional practice.105 The process of
asthma reviews, particularly when the consultations are
recorded on computer templates, offers ready opportunities
for repeated audit cycles. However, detailing and auditing all
the possible functions of an asthma review, whilst potentially
improving process, risks automating the consultation and
making it less responsive to individual patient needs. The UK
Quality and Outcomes Framework (QOF) – a ‘pay for
performance’ scheme which was introduced as part of the UK
General Medical Services Contract in 2004 and which
rewards practices for achieving pre-determined standards of
care for a range of long-term conditions16 – recognised this
potential risk, and the approach adopted was to reward the
‘provision of an asthma review’ recorded as a single coded
entry in the computerised clinical records.106 Concerns remain
about the quality of the review represented by this ‘tick box’,
though serial detailed audits in 60 representative practices
showed significant progress in assessing control by the
recording of specific symptoms, and checking inhaler
technique as part of the review.107 Disappointingly, despite
uniformly high achievement in the process measures for
QOF,108 the proportion of well-controlled patients varies
considerably between practices.109
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increase the proportion of patients reviewed without loss of
clinical effectiveness,100 though patients whose asthma is
causing concern prefer a face-to-face review.101 Asking
standard morbidity questions by telephone can identify those
who should be invited for a face-to-face review whilst
offering a convenient telephone option to those currently
under good control.50 The provision of a telephone asthma
review option within routine practice showed that
opportunistic telephone calls could provide consultations to
non-responders who would otherwise not have had a
review.102 A suggested model of care incorporating this
evidence is given in Table 3.
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refine the plan with the patient.
Ensuring quality
Appropriate training
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Asthma reviews should be undertaken by healthcare
professionals with appropriate training to enable them not only
to assess control but also to adjust treatment as necessary.20 In
the UK, this is frequently an experienced practice nurse,
though a survey published in 2007 highlighted that 20% of
nurses did not have any specialist asthma training.103 Whilst
guidelines (and clinical governance) might recommend that at
least one member of the primary care team has specialist
respiratory training, this raises concerns about the potential
deskilling of other members of the team.84 Poorly defined interprofessional roles and inadequate communication between
colleagues can act as barriers to the implementation of
guideline recommendations,86 an issue of particular importance
in the context of guided self-management. Although a
specialist clinician may initiate education, it is incumbent on all
members of the team to provide the on-going, consistent
support for guided self-management.104 Multi-disciplinary
education and support for professionals was a core component
of the successful Finnish programme.21
Audit and standards
A systematic review of 118 randomised controlled trials
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Conclusion
Too many of the 300 million people around the world living
with asthma are coping on a daily basis with a variable
condition that significantly affects their quality of life, despite
the existence of treatment which could substantially improve
their symptoms. At the core of a routine review is the
opportunity to identify patients with sub-optimal control and
(for both patients and professionals) the need to adopt an
approach of ‘zero tolerance’ to symptoms. Recognition of the
inter-relationship of professional reviews and patient self-
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management underpins the partnership
management strategies are negotiated.
as
future
15. Griffiths C, Foster G, Barnes N, et al. Specialist nurse intervention to reduce
unscheduled asthma care in a deprived multiethnic area: the east London
randomised control trial for high risk asthma.
BMJ 2004;328:144-7.
http://dx.doi.org/10.1136/bmj.37950.784444.EE
Funding
No direct funding. HP is supported by a Primary Care Research Career Award from
the Chief Scientist’s Office, Scottish Government.
16. NHS Confederation, British Medical Association
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BMJ 2014;348:g15 doi: 10.1136/bmj.g15 (Published 4 February 2014)
Page 1 of 7
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
35
and environmental medicine , Sejal Saglani reader in paediatric respiratory medicine
Imperial 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
1
Lower respiratory tract illnesses with wheeze are common,
occurring in around a third of all preschool children (here
defined as aged between 1 and 5 years). They are a major source
of morbidity and healthcare costs, including time off work for
carers, and are often difficult to treat. This review focuses on
the two areas in which there have been recent developments.
The first is the classification of these children by symptom
pattern into “episodic viral” and “multiple trigger” wheezers.1
These phenotypes can change within an individual over time,2
but they are a useful guide to current treatment, and there are
also physiological and pathological rationales for their use.3 4
The second area is the recent series of large randomised
controlled trials of treatment, specifically related to the roles of
intermittent montelukast and inhaled and oral corticosteroids.
These trials have shown clearly that inhaled corticosteroids and
prednisolone in particular have been misused and overused in
the past, mandating a reappraisal of treatment algorithms.
What is wheeze?
Wheeze is a term that is often used imprecisely, as has been
shown in studies with a video questionnaire and direct
quantification of wheeze.5-8 Indeed, some European languages
do not even have a word for wheeze. Our definition is high
pitched whistling sounds usually in expiration and associated
with increased work of breathing, but which can also sometimes
be heard in inspiration. In research studies, wheeze can be
quantified directly by using surface microphones, which is the
ideal. With this technique, it was shown that physicians
auscultating the chest accurately identify wheeze8; parents and
nurses were much less reliable.
How common is wheeze in preschool
children?
Preschool wheeze is common. In the Avon Longitudinal Study
of Parents and Children (ALSPAC) study, a prospective
longitudinal observational study, 26% of 6265 infants reported
on had had at least one episode of wheeze by the age of 18
months.9
What is the best clinical approach to the
preschool wheezer?
Once it is established that the child has actual wheeze, history
and a careful physical examination should be used to place the
child in one of four categories (table⇓). History and physical
examination are used to categorise the child and to decide
whether further investigation is needed. In general, there are
three reasons for a referral: if diagnosis is in doubt, if treatment
is not working, and if any party (general practitioner, parent) is
unhappy with progress. A report of two cross sectional,
community based observational studies found that isolated dry
cough in a community setting, without wheeze or breathlessness,
is most unlikely to be caused by any form of asthma.9 Most
preschool wheezers do not require any additional tests.
Confusion arises from the different uses of the term
“bronchiolitis.” In the United Kingdom, this is an illness
characterised by respiratory distress and showers of fine crackles
in a child aged under 1 year; though wheeze can be present as
well, it is the crackles that define the illness. It should be
emphasised that any rigid definitions based on age are likely,
to some extent, to be artificial. In the United States and
elsewhere, “bronchiolitis” is used synonymously with wheezing
illness. We have not discussed the approach to bronchiolitis as
defined in the UK; interested readers are referred elsewhere.10-12
Should preschool wheezers be subdivided
(phenotyped)?
Several approaches have been used to categorise preschool
wheezers. The first two are mentioned because they are of
scientific importance and are widely quoted in the literature,
but they are not useful in guiding treatment.
Correspondence to: A Bush, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK [email protected]
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
Page 2 of 7
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Summary points
Preschool wheeze should be divided into “episodic viral” and “multiple trigger” according to the history, and these categories, which 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
only in the first three years of life) and persistent (wheeze
throughout the first six years of life).9 13 These studies have
led to many insights into the evolution of symptoms and
lung function, but the categories can be determined only
retrospectively and give no guide to treatment, so are not
useful for the clinician
• Atopic versus non-atopic: early aeroallergen sensitisation
is certainly predictive of ongoing symptoms and loss of
lung function at school age,14 but does not predict the
response to treatment with inhaled corticosteroids15
• Symptom pattern: the European Respiratory Society Task
Force1 suggested that preschool wheezers should be placed
into one of two pragmatic categories. This is our favoured
categorisation for planning treatment:
– Episodic viral wheeze (EVW): the child wheezes only
with usually clinically diagnosed viral upper respiratory
infections and is otherwise totally symptom free
– Multiple trigger wheeze (MTW): the child wheezes with
clinically diagnosed upper respiratory infections but also
with other triggers, such as exercise and smoke and
allergen exposure.
This last classification is used to guide treatment (see below).
It has been criticised because children might change between
categories over time,2 but in that event pharmacological
treatment should also change. This is analogous to the situation
in school age children with asthma; treatment is not left fixed
over time but is increased or decreased depending on symptom
pattern and severity. Unfortunately, few studies adopt this
classification; most randomised controlled trials and genetic
and epidemiological studies combine children with both
symptom patterns.
Is it asthma?
This question is commonly asked by parents who want to know
whether their child will continue to have symptoms and require
drug treatment into school age and beyond. The answer,
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,
the definition includes evidence of airway eosinophilic
inflammation, the answer is more difficult as few if any have
the ability to measure this in preschool children. What most
parents actually want to know is whether their child will go on
with symptoms and the need for treatment into school age and
beyond. The evidence from cross sectional physiological work
and studies of endobronchial biopsies in children with severe
preschool wheeze is that multiple trigger wheeze is associated
with more airflow obstruction than episodic viral wheeze, and
the airway pathology (eosinophilic inflammation and
remodelling) is similar to childhood and adult asthma.16 By
contrast, episodic viral wheeze is not associated with evidence
of eosinophilic inflammation, so the use of inhaled
corticosteroids in this group is questionable.
Does preschool wheeze lead to asthma?
Several clinical predictive indices for future risk of asthma have
been developed based on combinations of the presence of atopic
manifestations, indirect evidence of airway inflammation, such
as peripheral blood eosinophil count, and severity of preschool
wheeze.17-19 They all have a high negative predictive value and
a poor positive predictive value (typically positive predictive
values 44-54, negative 81-8817-19). Children who have episodic
viral wheeze only have no increased risk of atopy or respiratory
symptoms in the long term once they reach the age of 14.20
Can we prevent preschool wheeze
progressing to school age asthma?
The clear cut evidence from good randomised controlled trials
is that early use of inhaled corticosteroids, whether continuously
or intermittently with viral colds, does not affect progression
of disease.21-23 A trial of oral cetirizine in high risk children
seemed to show benefit in preventing symptoms in subgroups
sensitised to particular aeroallergens,24 but a subsequent trial
with L-cetirizine did not replicate these findings (J Warner,
personal communication, 2013). This means that we have no
disease modifying drug treatments, and treatment should solely
be focused on current symptoms.
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What are the broad treatment strategies
for children with preschool wheeze?
Before any drugs are prescribed for either episodic viral wheeze
or multiple trigger wheeze, it is essential to ensure that the home
environment is optimal, particularly that the child is not exposed
to tobacco smoke; parental smoking “not in front of the children”
does not protect them from harm.25 A birth cohort study found
that air pollution can increase vulnerability to preschool
wheeze,26 but to date we have no specific advice based on
individual exposure profiles. Drugs might reasonably be targeted
at prevention of future complications such as airway remodelling
and persistent airflow obstruction, and, additionally, to treat
present symptoms. In practice, we have no drug strategies to
reduce future risk of asthma; neither early use of continuous21 22
nor intermittent23 inhaled corticosteroids reduces the risk of
progression to school age asthma. If inhaled drugs are
prescribed, repeated education of the parents in the correct use
of spacers is essential. If inhaled drugs in particular do not seem
to be working, check that they are being properly administered
rather than escalate treatment. The use of a skilled respiratory
nurse to help carers give inhaled drugs to children is invaluable.
How to treat episodic viral wheeze?
Intermittent symptoms should be treated with intermittent
therapy (and in practice this is likely to be what parents do
anyway). Failure to instigate regular inhaled treatment will not
prejudice future respiratory health. It is important to consider
whether the child needs treatment at all. The use of inhaled
therapy to treat mild respiratory noises with minimal respiratory
distress might be more problematic than the disease. If treatment
is required, then initial treatment should be with an intermittent
bronchodilator (either short acting β2 agonist or anticholinergic).
If treatment needs to be escalated beyond intermittent β2 agonist
or anticholinergic because of failure to control symptoms, the
next options are intermittent leucotriene receptor antagonist
(montelukast), intermittent inhaled corticosteroids, or both.
There have been important recent randomised controlled trials
of intermittent therapy.
The PREEMPT study examined intermittent montelukast
compared with placebo in 220 children aged 2-14.27 Treatment
was initiated at the onset of symptoms of a respiratory tract
infection and continued for a minimum of a week or until
symptoms had disappeared for 48 hours. The montelukast group
had fewer unscheduled consultations for asthma (odds ratio
0.65, 95% confidence interval 0.47 to 0.89) and fewer days
away from school or childcare and less time off work for parents
(37% and 33%, respectively; P<0.001 for both). In a predefined
subgroup analysis, the benefits were greater in children aged
2-5 (about 80% of the study group). These findings were not
confirmed in a much larger three way comparison of intermittent
montelukast, continuous montelukast, and placebo (nearly 600
children in each group).28 A three way comparison between
standard treatment, intermittent montelukast, and intermittent
nebulised budesonide (the only aerosolised steroid permitted
by the FDA in preschool children) in 238 children aged 12-59
months showed minor and equivalent benefits for the two active
treatments compared with standard treatment.29 Benefits were
greater in the subgroup with a modified asthma predictive index.
Taken together, these studies suggest that a trial of montelukast
in preschool children with troublesome viral induced wheeze
is worth attempting. We recommend starting treatment at the
first sign of a viral cold and discontinuing it when the child is
clearly better, rather than for a fixed period of days.
The Cochrane review identified use of intermittent inhaled
corticosteroids as a partially effective strategy for episodic
wheeze in preschool children.30 A proof of concept study in 129
children aged 1-6 years showed that the pre-emptive use of 750
µg twice a day (compared with the maximum licensed dose of
200 µg twice daily in children aged 4 and above; not licensed
in any dose below age 4) of fluticasone dipropionate for up to
10 days, starting at the first sign of a viral upper respiratory tract
infection, led to a reduction in dose of rescue prednisolone (8%
of upper respiratory tract infections in the fluticasone group v
18% in the placebo group; odds ratio 0.49, 95% confidence
interval 0.30 to 0.83).31 This huge dose, however, was
unsurprisingly associated with side effects and cannot be
recommended. Another study looked at regular twice daily
nebulised budesonide 0.5 mg compared with intermittent
nebulised budesonide 1 mg twice a day at the time of viral
respiratory illnesses. This was a randomised double blind
controlled trial in 278 children aged between 12 and 53 months
who had a positive modified asthma predictive index.32 There
was no difference in any respiratory outcome, but in the absence
of a placebo group it is not possible to state that either strategy
was beneficial. What this study definitely shows is that regular
nebulised budesonide does not prevent viral exacerbations of
wheeze. Smaller older trials of inhaled beclometasone also failed
to show a preventive effect.33 There is currently no evidence to
support the use of inhaled corticosteroids at licensed doses in
children with episodic viral wheeze. As some studies suggest
that intermittent inhaled corticosteroids might be a useful
approach in children with viral induced wheeze at higher than
licensed doses, further studies are required to clarify the dose
and duration that might be beneficial in this setting. In practice,
however, it would be unwise to go above a fluticasone dose of
150 µg twice a day, given the number and duration of viral colds
in normal preschool children and the risk of side effects
including growth suppression and adrenal failure with higher
doses. There are currently no studies that have combined
intermittent inhaled corticosteroids with intermittent montelukast
to treat episodic viral wheeze.
Is there any role for prophylactic
continuous inhaled corticosteroids in
episodic viral wheeze?
There is no evidence to support the use of regular inhaled
corticosteroids in preschool children who do not wheeze between
viral colds. In those children with really severe episodic wheeze
who require repeated admission to hospital or have prolonged
disruptive symptoms managed at home, however, a trial of
prophylactic inhaled corticosteroids can be given. In some cases
it might become apparent that in fact there were interval
symptoms that were underappreciated. In any event, the clinical
trials of inhaled corticosteroids in episodic viral wheeze were
carried out in relatively mildly affected children, so the evidence
in severely affected children is less robust. Treatment should
be reviewed and discontinued if there is no benefit; there is no
evidence to suggest the optimal duration of the therapeutic trial,
but six to eight weeks would seem a reasonable time period. If
the viral wheezing improves on treatment, regular attempts
should still be made to reduce the dose. It should be noted that,
in a small study, even really severe episodic viral wheeze was
not associated with eosinophilic airway inflammation4 and that
inhaled corticosteroids (fluticasone 100 µg twice a day) led to
growth suppression in the PEAK trial,21 so trials of inhaled
corticosteroids in this context should be deployed only
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
the carers, a trial of inhaled steroids can reveal that the child
was previously much more symptomatic than was thought.
Whatever the context of therapeutic trials in preschool children,
they should be for a fixed time period (such as six to eight
weeks, see above) and discontinued at the end of the agreed
period to see if symptoms recur or in fact have resolved and
treatment has become unnecessary (see the three stage trial
proposal below).
Is there a role for oral prednisolone in
primary care for preschool wheeze?
Recent evidence has questioned the role of prednisolone in acute
episodes of episodic viral preschool wheeze. In a home based
study, 217 preschool children who had at least one admission
to hospital were randomised to a parent initiated course of
prednisolone or placebo at the next wheezing episode. No benefit
was observed in the treatment group.34 A hospital study that
randomised 687 preschool children admitted with wheeze to
prednisolone or placebo in addition to bronchodilator therapy
found there was no benefit in the prednisolone group.35
The implication of these two studies, involving more than 900
children, is that any preschool child with viral induced wheeze
who is well enough to stay in the community should not be
prescribed oral prednisolone, and many children admitted to
hospital also should not be prescribed oral prednisolone.36 These
studies, however, were undertaken in children with relatively
mild symptoms and most were discharged from hospital in less
than 24 hours, so what these studies do not tell us is whether
prednisolone is indicated in really severe preschool viral wheeze.
In the absence of evidence, it is likely that prednisolone will
continue to be prescribed in this small subgroup of children in
hospital.
How should I treat multiple trigger
wheeze?
Preschool children who have wheeze or cough responsive to
bronchodilator treatment and breathlessness on most days even
when they do not have a viral cold should be considered for a
trial of preventive drug treatment, either inhaled corticosteroids
or a leucotriene receptor antagonist (montelukast). As airway
inflammation cannot routinely be measured in this age group,
and many children will become asymptomatic before school
age, it would be incorrect to assume the pathophysiology of the
disease is the same as school age asthma. Furthermore, the
younger the child, the less likely there is to be any eosinophilic
inflammation37 and therefore more reluctance to use inhaled
corticosteroids.
There is a dearth of evidence, but the box shows a pragmatic
three stage trial of treatment, which is recommended in our
practice.
The aim of this three step approach is to prevent children being
falsely labelled and inappropriately treated because someone
has started a drug when the child was about to get better
spontaneously. Long acting β2 agonists are not licensed for use
in preschool children.
Are there any other new treatments
around?
In a small double blind trial, a total of 41 children aged 1-6
years were randomised to nebulised hypertonic (7%) or normal
(0.9%) saline, in each case combined with salbutamol twice 20
minutes apart in the emergency department and then, if the child
was admitted to hospital, four times a day thereafter.38 Admission
rates and lengths of stay were significantly reduced in the
hypertonic saline group, but there was no significant change in
severity score, possibly because of the small size of the study.
Further work in larger numbers of children is needed to define
the role of hypertonic saline in acute preschool wheeze. Given
the possibility of bronchoconstriction being induced by
hypertonic saline, this treatment should be given only in a
hospital setting.
Palivizumab has been used to prevent infection with respiratory
syncytial virus in high risk infants—for example, survivors of
extreme prematurity. The cost and inconvenience of monthly
injections means this has never been, and is still not, a treatment
strategy for all babies. A recent double blind study, however,
randomised 429 infants born at 33-35 weeks’ gestation to
palivizumab or placebo.39 Palivizumab reduced the number of
days with wheeze in the first year of life by 61% and the
proportion of infants with recurrent wheeze from 21% to 10%.
The more interesting question, which this trial could answer, is
the vexed one as to whether early respiratory syncytial virus
infection causes asthma or is merely a sign that the child was
previously predisposed to asthma, provided the infants are
followed up to school age. The current position is that this is
work in progress, rather than an indication for a change in public
policy.
What about treatment plans?
Treatment plans outlining self management actions to be taken
depending on the severity of symptoms and peak flow
measurements are widely recommended in school age children.
In a randomised controlled trial in which 200 children age 18
months to 5 years who had an unscheduled hospital visit or
admission with wheezing were allocated either to standard care
or to receive a package consisting of a booklet, a written guided
self management plan, and two structured educational sessions,
there were no differences in any outcomes.40 Despite this, many
will use educational sessions and plans, but there is no evidence
of efficacy.
What is the role of nebulised therapy?
There is no role for nebulised therapy to deliver bronchodilator
apart from in children too sick to use inhalers. For all other
purposes, the evidence is clear that metered dose inhalers and
spacers are at least as good as nebuliser.
Contributors: AB wrote the initial draft of the manuscript and is guarantor.
The manuscript was reviewed and edited by SS and JG; all authors
agreed the final version.
Competing interests: We have read and understood the BMJ Group
policy on declaration of interests and declare the following interests: AB
was supported by the NIHR Respiratory Disease Biomedical Research
Unit at the Royal Brompton and Harefield NHS Foundation Trust and
Imperial College London.
Provenance and peer review: Not commissioned; externally peer
reviewed.
1
2
Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al.
Definition, assessment and treatment of wheezing disorders in preschool children: an
evidence-based approach. Eur Respir J 2008;32:1096-110.
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
wheeze. Acta Paediatr 2010;99:56-60.
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Pragmatic regimen for trial of treatment
Step 1: Trial of inhaled corticosteroids or montelukast in standard dose for a defined period, usually four to eight 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.erseducation.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
4
5
6
7
8
9
10
11
12
13
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Symptom-pattern and pulmonary function in preschool wheezers. J Allergy Clin Immunol
2010;126:519-26.
Sonnappa S, Bastardo CM, Saglani S, Bush A, Aurora P. Relationship between past
airway pathology and current lung function in preschool wheezers. Eur Respir J
2011;38:1431-6.
Cane RS, Ranganathan SC, McKenzie SA. What do parents of wheezy children understand
by “wheeze”? Arch Dis Child 2000;82:327-32.
Elphick HE, Ritson S, Rodgers H, Everard ML. When a “wheeze” is not a wheeze: acoustic
analysis of breath sounds in infants. Eur Respir J 2000;16:593-7.
Saglani S, McKenzie SA, Bush A, Payne DN. A video questionnaire identifies upper airway
abnormalities in pre-school children with reported wheeze. Arch Dis Child 2005;90:961-4.
Levy ML, Godfrey S, Irving CS, Sheikh A, Hanekom W, Bush A, et al. Wheeze detection:
recordings vs assessment of physician and parent. J Asthma 2004;41:845-53.
Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, et al. Associations
of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway
responsiveness in mid-childhood. Thorax 2008;63:974-80.
Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance of
cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996;75:489-93.
British Guideline on the Management of Asthma (2012 update). www.brit-thoracic.org.uk/
guidelines/asthma-guidelines.aspx.
Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007;335:1037-41.
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and
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14
15
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23
Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study
(MAS) group. Perennial allergen sensitisation early in life and chronic asthma in children:
a birth cohort study. Lancet 2006;368:763-70.
Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and
preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis.
Pediatrics 2009;123:e519-25.
Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al. Early detection of
airway wall remodelling and eosinophilic inflammation in preschool wheezers. Am J Respir
Crit Care Med 2007;176:858-64.
Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthma
at school age among preschool children. J Allergy Clin Immunol 2012;130:325-31.
Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopic
characteristics of children with recurrent wheezing at high risk for the development of
childhood asthma. J Allergy Clin Immunol 2004;114:1282-7.
Devulapalli CS, Carlsen KC, Håland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, et
al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of
age. Thorax 2008;63:8-13.
Harris JM, Bush A, Wilson N, Mills P, White C, Moffat S, et al. Preschool wheezing
phenotypes in a representative school cohort. Thorax 2010;65(suppl 4):A37.
Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term
inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med
2006;354:1985-97.
Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team. Secondary
prevention of asthma by the use of inhaled fluticasone dipropionate in wheezy infants
(IWWIN): double-blind, randomised controlled study. Lancet 2006;368:754-62.
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
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Pool J, Petrova N, Russell RR. Exposing children to secondhand smoke. Thorax
2012;67:926.
Warner JO; ETAC Study Group. Early treatment of the atopic child. A double-blinded,
randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in
children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment
follow-up. J Allergy Clin Immunol 2001;108:929-37.
Andersen ZJ, Loft S, Ketzel M, Stage M, Scheike T, Hermansen MN, et al. Ambient air
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Cite this as: BMJ 2014;348:g15
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• Erectile dysfunction (BMJ 2014;348:g129)
• Acute haematogenous osteomyelitis in children (BMJ 2014;
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• Supporting smoking cessation (BMJ 2014;348:f7535)
• Abortion (BMJ 2014;348:f7553)
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Page 7 of 7
CLINICAL REVIEW
Table
Table 1| Four groups of childhood wheezing disorders, based on personal practice
Wheeze category
Suggestive features
Normal child—commonest and also the hardest
Child well and thriving, with no other features on history or
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)
Suggested actions
Reassurance
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
wheezing syndrome—for example,
away from breast, poor feeder (gastro-oesophageal reflux), or
gastro-oesophageal reflux, chronic rhinitis
prominent upper airway disease, inflamed nose, adenotonsillar
hypertrophy
True wheezing syndrome: episodic viral wheeze
(EVW); multiple trigger wheeze (MTW)
Initial empirical trials of treatment; refer
if no response and symptoms
troublesome.
Child with prominent snoring should be
considered for referral for sleep study
An otherwise well and thriving child with wheeze only at time of viral Treatment options discussed in text.
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

Definition, assessment and treatment of wheezing disorders in

Transcription

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