Current Guidelines For The Management of Asthma in Young Children
Current Guidelines For The Management of Asthma in Young Children
Current Guidelines For The Management of Asthma in Young Children
Allergy Diagnostic & Clinical Research Unit, University of Cape Town Lung Institute, Cape Town, South Africa
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits
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The diagnosis and management of asthma in young children is difficult, since there are many different wheezy phenotypes with varying underlying
aetiologies and outcomes. This review discusses the different approaches to managing young children with wheezy illnesses presented in recently
published global guidelines. Four major guidelines published since 2007 are considered. Helpful approaches are presented to assist the clinician to
decide whether a clinical diagnosis of asthma can, or should be made in a young child with a recurrent wheezy illness and which treatments would
be appropriate, dependent on risk factors, age of presentation, response to initial treatment and safety considerations. Each of the guidelines pro-
vide useful information for clinicians assessing young children with recurrent wheezy illnesses. There are differences in classification of the disease
and treatment protocols. Although a firm diagnosis of asthma may only be made retrospectively in some cases and there are several effective guide-
lines to initiating treatment. Consistent review of the need for ongoing treatment with a particular pharmacological modality is essential, since
many children with recurrent wheezing in infancy go into spontaneous remission. It is probable that newer biomarkers of airway inflammation will
assist the clinician as to when to initiate and when to continue pharmacological treatment in the future.
Key Words: Asthma; preschool child; guideline
Copyright The Korean Academy of Asthma, Allergy and Clinical Immunology The Korean Academy of Pediatric Allergy and Respiratory Disease http://e-aair.org 1
Potter Volume 2, Number 1, January 2010
sis of asthma in young children, paucity of published studies on The applicability of any guideline for asthma rests on access to
different treatments for asthma and wheezy illnesses in the un- medications recommended in such guidelines. Khalied et al.11
der 5s, a lack of published biopsy studies on the pathology of have stressed that access to inhaled corticosteroids is they key
wheezy illnesses in young children. There are also differences to improving quality care for asthma in developing countries.
in different regions of the world in resources for treatment, In developed countries a high cost of essential medications can
modes of communication and availability of different treat- be a major obstacle for patients who need such treatment and
ments. in many developing countries many essential drugs are un-
Some have considered that with a lack of hard evidence, as available for asthma treatment and literacy and language barri-
would be obtained by large double blind placebo controlled ers are significant obstacles to implementation of guidelines.12
studies, a consensus approach based on evidence in older chil- It is difficult to apply current new guidelines for the manage-
dren and clinical experience is more appropriate.7 Even when ment of children under 5 years, if the only asthma medications
stricter criteria for recommendations are upheld according to on the World Health Organization essential drug list includes
published evidence only,8 the dilemma of whether asthma can Beclomethazone, Epinephrine, Ipratropium bromide and Sal-
be diagnosed with confidence in the under five aged group aris- butamol (WHO Essential Drug List, March 2007). Even when
es.9 It is more difficult to formulate guidelines for asthma in the optimal treatment available, only 30-40% of patients are totally
younger children firstly because the diagnosis for asthma may controlled.13
not be sure and children express different patterns of wheezy Management goals for childhood asthma are fairly consistent
illnesses, but also because asthma itself is a syndrome com- between the different guidelines. The aims are for a normal
posed of heterogeneous diseases.10 life free of any symptoms (e.g., cough, wheeze and breathless-
It is thus believed that asthma is unlikely to be a single disease, ness), the ability to have a restful sleep, to grow and develop
but rather a series of complex overlapping individual diseases normally, to attend school or preschool regularly and partici-
or phenotypes, each defined by its unique interaction between pate in all school activities including sports, to minimise the
genetic and environmental factors. These conditions include number of attacks of acute asthma, to avoid hospitalisation and
syndromes exacerbated by exposure to allergens, and aspirin to avoid medication related side effects.
exacerbated, or non-allergic factors, along with syndromes best The impact of the disease needs to be weighed against the
distinguished by their pathological findings (neutrophilic, eo- possible impact of the therapy. In the case of asthma treatment
sinophilic, pauci granulocytic), their response to therapy (corti- for children there are issues which are also extremely important
costeroid resistant, or leukotriene receptor antagonist sensitive) to the parents, such as normal appetite, good academic perfor-
and natural history (intermittent or persistent or remittent) de- mance at school, social development and lack of irritability or
pending on the development of airway remodelling and other disruption of family life. Quality of life is difficult to assess in
factors such as exposure and genotype. young children and symptom scores may not correlate well
It is against this background of a clear heterogeneity in the with quality of life ratings. Quality of life may be also influenced
asthma phenotypes encountered in older children and adults, by differences in society and cultural needs.
that the literature is deplete on information on the natural his- Treatment of the young child also differs from that of the old-
tory of the disease, which starts in infancy. It is not known which er child because in addition to lung functions being difficult
childhood phenotypes develop into any of the defined adult under the age of 5, there are challenges to adequate delivery of
type asthma phenotypes. inhaled drugs, safety issues and ethical issues. Furthermore,
Thus in developing guidelines it would appear that the cur- there are dosing issues. For many drugs used in young children
rent objectives and goals have been to recommend treatments, careful dose ranging studies have not been conducted and dos-
which are effective for current control of the disease, rather ing is extrapolated from adult doses.14 This dilemma results
than treatments which modify the natural history of the dis- from the difficulties experienced in conducting necessary dou-
ease. Other than allergen specific immunotherapy for asth- ble bind placebo controlled studies of asthma medications at
ma, caused by and precipitated by a single allergen, which in it- different ages in young children bearing in mind the rights of
self is rare, even in children, there are no other treatments the child, the fact that children are not mini adults, primary
known to modify the natural history of the disease. and secondary end points of paediatric and infant studies are
An important consideration in the development of guidelines not always fully objective due to second party reporting of
is that the ISAAC data1 clearly show that the increases noted in outcomes by parents and caregivers and the assessment of on-
childhood asthma have not been confined to the developed going inflammation is difficult. To address the deficiency in
countries, but that asthma also poses a huge burden to the un- paediatric studies the FDA modernization and best pharma-
derdeveloped world, where resources are scarce and there is ceuticals for childrens act has been promulgated, the Europe-
competition for resources to treat other diseases such as TB, an Medicines Evaluation Agency has published a note for
AIDS, malnutrition, malaria and other infectious diseases. guidance on clinical investigation for medical products in the
population and the Therapeutics Goods Administration (TGA) ence of airway inflammation to be central to the diagnosis of
of Australia has given priority to paediatric submissions to en- asthma, confirmation of this is not usually possible in younger
courage industry to study all new products in children. children, using available clinical tools in practice. However, ele-
In practice this will involve studies in which the dosages are vations in both inflammatory cells and mediators have been
weight related, patients are clearly phenotyped according to the demonstrated in broncho alveolar large specimens obtained
onset and type of wheezy illness, differences in the pharmaco- from preschool children who have recurrent wheezing.15 Thus in
kinetics of the drug are studied and measurable effects on in- children 0-4 years of age, in some cases a therapeutic trial with
flammation are also considered (e.g., PD20, eNo, urinary leu- medications may also aid in confirming a diagnosis, whereas in
kotrienes, sputum eosinophilic cationic protein and other im- children 5-11 years one has the advantage of a preceding history
munological markers), in addition to variables such as airway and also simple lung function tests for reversibility, to aid the di-
hyperresponsiveness, growth, height, quality of life and disease agnosis.
modification. In the under fives the most common cause of asthma symp-
Bearing in mind the variability of the triggers of wheeze in toms is viral respiratory infection. Some remit in the preschool
young children (viruses, allergens, irritants, emotional factors years and others persist throughout childhood. It appears that
exercise), it is thus difficult to standardise all these variables to children under 3 years of age who have more than four epi-
study the effects of a particular drug on a particular outcome, in sodes of wheezing in the past year, affecting sleep are signifi-
a sufficiently large number of children, including a placebo cantly more likely to develop persistent asthma after the age of
arm. Furthermore longer studies may be necessary to study 5 years, particularly if they have a parental history of asthma, a
whether a particular drug has a disease modifying capability, physician diagnosis of atopic dermatitis, sensitization to aeroal-
bearing in mind the tendency of wheezing illnesses to sponta- lergens, evidence of food sensitisation, a greater than 4 percent
neously remit in a significant number of young children. peripheral blood eosinophilia or wheezing apart from colds.
It is important to stress that a number of young children pre- The Expert Panel 3 concluded that early intervention with in-
senting with wheeze may not have asthma. The younger the haled corticosteroids continuously16 or intermittently17 did not
child, the greater the possibility of an alternative diagnosis, e.g., alter the underlying severity or progression of the disease and
gastroesophageal reflux, cystic fibrosis, aspiration syndrome, that inhaled corticosteroids should be used to control asthma
immune deficiency, congenital heart disease and bronchopul- symptoms and improve the childs quality of life, but not for the
monary dysplasia. purpose of changing the natural history of the disease (Evi-
Furthermore there are a number of risk factors which increase dence A).
the likelihood of the development of asthma in young children It appears that while the disease may in fact progress during
in addition to genetic factors. Risk factors for asthma attacks in- the first 5 years of life, the recent childhood management pro-
clude exercise, exposure to specific allergens, viral infections, gramme study (CAMP) indicated that children aged 5-12 years
tobacco smoke, certain foods and food additives such as sul- who have mild or moderate persistent asthma, do not on aver-
phur dioxide and emotional factors. In addition the choice of age have a progressive decline in lung function. In the subset of
treatment will be influenced by the history which should con- these who experienced progressive reductions in lung growth
sider the frequency of previous attacks, the severity of previous compared to predicted measures, this was not prevented by in-
attacks, previous hospitalisation, repeated use of oral steroids haled steroids.18
such as prednisolone, the level of treatment previously neces- Observational prospective data from Martinez et al. suggests
sary to obtain control, attendance at a crche, concurrent rhi- that most loss of lung function occurs during the first 3-5 years
nitis and rate of response to treatment. of life.19 Although this is the case, the studies by Guilbert et al.16
in 2006 showed that ICS clearly reduced the symptom burden
THE NAEPP EP3 GUIDELINES and frequency of exacerbations when administered daily for 2
years, but did not prevent the reappearance of symptoms in the
The first of the recently published guideline for the manage- year of follow up after discontinuing therapy.
ment of asthma in young children is the EP3 NAEPP report pub- The EP3 guidelines recommend a regular follow up of those
lished in 2007.6 These guidelines point out that 50-80 percent of children who have moderate a persistent asthma to assess im-
children who have asthma, develop symptoms before their fifth pairment and risk domains for the development of progressive
birthdays, but because the disease is frequently under diag- disease. These include requirements for intermittent short act-
nosed many young children do not receive adequate therapy. ing b2 stimulants, exacerbations requiring systemic steroids, ur-
On the other hand, since not all wheeze is caused by asthma, gent care visits and if possible pulmonary function measures.
one should exert caution to avoid infants and younger children The concept of reducing impairment refers to the mainte-
receiving inappropriate prolonged asthma therapy. nance of current well-being of the child as evidenced by reduc-
The diagnosis of asthma is difficult. If one considers the pres- tion of symptoms, maintaining near normal pulmonary func-
tion meeting family needs and expectations and maintaining be considered when the period of risk has passed.
current normal activity levels, exercise and school attendance. Once the child is on long term treatment with daily preventers
The concept of reducing risk outlined by the EP-3 attempts adjustments may be made by assessing both the impairment
to prevent recurrent exacerbations of asthma and the need for and risk domains. These must be complemented by adequate
emergency care visits or hospitalisations, prevention of pro- education of the child and care giver, with particular attention
gressive loss of lung function and minimization of adverse to the level of adherence, to assess whether treatment should
events. It is recommended that both domains are considered as be stepped up or down.
both affect quality of life, but that these domains respond dif- Consideration of referral to a specialist is essential if there are
ferently to treatment. Thus, low dose steroids may reduce im- difficulties in controlling the asthma, children who require step
pairment (symptoms, SABA use and lung function), but does 3 or higher or if an exacerbation requires hospitalisation. A spe-
not reduce exacerbations requiring corticosteroids. cialist would also assess a possible role for immunotherapy and
While most of the new guidelines emphasise the role of the consider the role of allergy.
clinician in assessing and maintaining control of asthma in Furthermore the EP3 panel is of the opinion that ICS may be
an established treatment regime, when young patients are seen reduced by 25-50% every 3 months to the lowest possible dose
for their first episode of wheezing and factors like severity, age to maintain control (Evidence D). Reduction should be gradual
of onset, family history and the presence of other risk factors and since guidelines for stepping down treatment have not
will influence the clinicians decision regarding appropriate been validated, and clinical judgement of the individuals re-
therapy. sponse to therapy is very important. ICS at low doses for ex-
The EPR-3 recommends that impairment and exacerba- tended periods are safe. The potential for adverse events on
tions may be reduced by regular controller treatment in chil- medium to high dose ICS is usually limited to a small reduction
dren who have four or more episodes of wheezing in the past in growth velocity of approximately 1 cm in the first year of
year persisting for more than a day, plus a parental history of treatment which is not progressive over time and can be mea-
asthma, atopic dermatitis, sensitization to aeroallergens, a >4% sured by a stadiometer.20, 21
peripheral eosinophilia and wheezing apart from colds. The In children who are required to receive high dose corticoste-
guideline recommends a stepwise approach to treatment start- roids, age appropriate dietary intake of calcium and vitamin D
ing with low dose inhaled corticosteroids, or Montelukast. should be reviewed with the childs care givers (Evidence D)
Doses for most inhaled steroids in the 0-4 years old group are and slit lamp eye examination and bone densitometry should
not published. The daily dose for Budesonide inhalation sus- be considered (Evidence D).
pension is recommended at 0.25-0.5 mg and of Fluticasone at In the USA only the following are approved by the FDA for
176 g/day, with no specific doses recommended for Budeso young children under 4 years: ICS Budesonide nebuliser solu-
nide, Beclomethazone, Fluinisolide, Mometasone or Triamcin- tion (1-8 years of age), ICS Fluticasone DPI (4 years and older),
olone for the under five year old asthmatics. Daily doses for the Salmeterol used in combination with Fluticasone for children 4
5-11 year old asthmatics are 80-160 g Beclomethazone, 180- years and older, Montelukast 4 mg as a chewable tablet 2-6 years
400 g Budesonide, 500-750 g Fluinisolide, 160 g Fluinisolide of age and as granules down to 1 year of age. Cromolyn nebulis-
HFA, 80-176 mg Fluticazone HFA MDI, 100-200 g Fluticasone er is approved for children 2 years of age. Appropriate delivery
DPI and 300-600 g Triamcinolone. devices are essential. Children under 4 should use a MDI with a
The above doses are regarded as low daily doses and can be valved holding chamber or nebuliser with a face mask. The step-
stepped up (usually doubled) to a medium dose in children 5- wise approach to treatment recommended by the EP3 is given
11 years and quadrupled as a high daily dose in severe child- in Fig. 1.6
hood asthmatics. In the absence of published studies the EP3 In this guideline both LABA or Montelukast is given as add on
guidelines are extremely cautious in recommending specific in the 0-4 years of age which differs from some of the other
doses of inhaled steroid for the 0-4 year old asthmatics. Monte- guidelines.
lukast 4 mg is recommended for under 5 year olds and 5 mg Theophylline is not recommended for children under 5 years.
from 6-11 year olds (Evidence A). Montelukast is recommended as a trial in children 2 years or
In addition, long term controller therapy with inhaled cortico- older, in situations where inhaled medication delivery is subop-
steroid should be considered to reduce impairment in infants timal due to poor technique. There is no data on the use of long
and young children who consistently require treatment more acting b2 agonist under the age of 4 years. Montelukast may also
than 2 days per week for more than 4 weeks (Evidence D), for be considered as add on therapy. Recommendations for treat-
reducing exacerbations requiring systemic corticosteroids ment according to components of severity, impairment and risk
within a 6 month period (Evidence D) or during a period of a according to the NAEPP EP3 guidelines are summarised in Fig.
previously documented risk for a child (e.g., Winter, Spring, 2 and a figure for assessment of control and adjusting therapy
specific exposure) (Evidence D), but that discontinuation must for children 0-4 years of age is given in Fig. 3. The EP3 guidelines
Step 6 Step up if
Preferred: needed
High-dose
Step 5 ICS + either (first check
Preferred: LABA or adherence,
High-dose Montelukast inhaler technique,
Step 4 ICS + either and environmental
LABA or Oral systemic control)
Preferred: corticosteroids
Medium-dose Montelukast
Step 3 ICS + either
Preferred: LABA or
Medium-dose Montelukast
Assess
Step 2 ICS
control
Preferred:
Low-dose ICS
Step 1
Preferred: Alternative:
SABA PRN Cromolyn or
Montelukast
Step down if
possible
Patient education and environmental control at each step (and asthma is
well controlled
at least 3 months)
Quick-relief medication for all patients
SABA as needed for symptoms, intensity of treatment depends on severity of symptoms
With viral respiratory infection: SABA q 4-6 hr up to 24 hr (longer with physician consult). Consider short course of oral systemic
corticosteroids if exacerbation is severe or patient has history of previous exacerbations.
Caution: Frequent use of SABA may indicate the need to step up treatment. See text for recommendations on initiating daily
long-term-control therapy.
are the most detailed for children under 5 years, but not all of guideline for practice in Europe as well as in North America.
the recommended steps for treatment are evidence based or Thus these guidelines were not intended for global usage (e.g.,
validated. in underdeveloped countries).
Symptoms 2 days/wk >2 days/wk but not daily Daily Throughout the day
Interference with normal activity None Minor limitation Some limitation Extremely limited
Fig. 2. Classifying asthma severity and initiating treatment in children 0-4 yr of age. Assessing severity and initiating therapy in children who are not currently tak-
ing long-term control medication.
EIB, exercise-induced bronchospasm.
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
Level of severity is determined by both impairment and risk. Assess impairment domain by patients/caregivers recall of previous 2-4 wk. Symptom assessment
for longer periods should reflect a global assessment such as inquiring whether the patients asthma is better or worse since the last visit. Assign severity to the
most severe category in which any feature occurs.
At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. For treatment purposes, patients who
had 2 exacerbations requiring oral systemic corticosteroids in the past 6 months, or 4 wheezing episodes in the past year, and who have risk factors for persis-
tent asthma may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma.
The PRACTALL guidelines are fairly easy for the clinician to asthma or different aetiologies (including irritant exposure).
follow. A key point to making a firm diagnosis of asthma in in- Using such an approach, asthma phenotypes are identified.
fants 0-2 years is the persistence of symptoms. In children 3-5 In order to obtain a confident diagnosis of atopy, the history
years persistence versus intermittent wheezing is more sugges- should focus on frequency of symptoms (including wheeze,
tive of asthma, whereas in children 6-12 years, allergen induced nocturnal cough, exercise induced wheeze and persistence of
symptoms and seasonality suggest a diagnosis of asthma. cough with colds) as well as more indirect assessments such as
These guidelines stress the importance of the history (family fatigue, poor school performance, avoidance of normal play
history, previous or current eczema, exacerbation rate, identifi- and specific triggers (e.g., exercise). The clinical examination
able triggers [e.g., exercise]) examination (evidence of atopy should look for evidence of eczema, dry skin, allergic shiners,
such as drug, skin, dermatitis, conjunctivitis and rhinitis). Tests irritated conjunctive and persistent oedema of the nasal muco-
such as skin prick tests and Immunocap RASTs are considered sa, allergic salute and allergic crease on the bridge of the nose.
important when assessing all children with recurrent wheeze Recommendations include avoidance of exposure to tobac-
and lung function and peak flow reversibility should be con- co-smoke, a balanced diet, avoidance of obesity and encour-
ducted in those old enough to perform such tests. agement of exercise. Allergen avoidance is recommended
The guidelines encourage the clinician to decide whether epi- when there is sensitisation and a clear association between al-
sodes are precipitated mainly by colds: virus induced asthma, lergen exposure and symptoms. The PRACTALL guidelines also
exercise: exercise induced asthma, allergens allergen induced provide a treatment algorithm for the treatment of asthma in
Short-acting b2-agonist
use for symptom control 2 days/wk >2 days/wk Several times per day
(not prevention of EIB)
Risk
Medication side effects can vary in intensity from none to very troublesome and worrisome.
Treatment-related adverse
The level of intensity does not correlate to specific levels of control but should be considered
effects
in the overall assessment of risk.
Fig. 3. Assessing asthma control and adjusting therapy in children 0-4 yr of age.
EIB, exercise-induced bronchospasm.
The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.
The level of control is based on the most severe impairment or risk category. Assess impairment domain by caregivers recall of previous 2-4 wk. Symptom as-
sessment for longer periods should reflect a global assessment such as inquiring whether the patients asthma is better or worse since the last visit.
At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense
exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who
had 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even
in the absence of impairment levels consistent with not-well-controlled asthma.
Before step up in therapy: Review adherence to medications, inhaler technique, and environmental control. If alternative treatment option was used in a step, dis-
continue it and use preferred treatment for that step.
children over 2 years of age.7 young children is still unclear26 and suggestions that children
The treatment algorithm is a step-up and step-down ap- using LABAs regularly27 may have an increased risk of exacerba-
proach, but is not graded by level of impairment or risk as is tions and hospitalisations, the PRACTALL guidelines only rec-
suggested in the EP3 guidelines. For acute attacks, Ipratropium ommend their use in severe asthmatics unresponsive to inhaled
bromide combined with b2 agonists may result in favourable corticosteroids at high doses, or in those in whom the addition
outcomes in children.22 Inhaled corticosteroids are recom- of LTRAs have not improved the patients symptoms. LABAs
mended as a first line treatment for persistent asthma with leu- should never be used without concomitant inhaled corticoste-
kotriene receptor antagonists as an alternative.23 roids.
Evidence for the anti-inflammatory effects of Montelukast on The PRACTALL guidelines also address asthma treatment in
nitric oxide exhalation is cited24 and its usefulness as add on children 0-2 years. Intermittent b2 agonists are the first choice
treatment to inhaled corticosteroids25 justifies its place in step and LTRAs are recommended for long or short term treatment
up treatment. Because efficacy of LABA in the management of of viral wheezing. Nebulised or MDI plus spacer delivered in-
haled corticosteroids are recommended for persistent asthma, Furthermore the guidelines stress that the descriptions of
especially when severe episodes requiring frequent oral corti- wheeze used in epidemiological studies (transient versus per-
costeroids have occurred. Evidence of atopy should lower the sistent wheeze) can only be applied retrospectively.19 It was
threshold for inhaled corticosteroid therapy, which should be thus suggested that definitions of temporal patterns of a wheeze
first line in such cases. There are very few studies of the efficacy would be more useful to clinicians, than retrospective defini-
and safety of allergen immunotherapy for asthmatics under the tions of wheeze which would be more useful for epidemiologi-
age of 5 years. cal studies.
Sublingual immunotherapy (SLIT) may be a safe and effective A temporal pattern of wheeze is thus suggested. Wheeze may
alternative to subcutaneous injections in children with asthma28 be an episodic viral wheeze, with the child being well between
and the effects may be long lasting,29 but immunotherapy is not episodes. These episodes are caused by rhinovirus, respiratory
recommended when asthma is unstable. Patients should have syncytial virus, human meta pneumo virus, para influenza vi-
few, if any, symptoms and a FEV1 of at least 80% of predicted val- rus and adenovirus.
ue. Age is not an absolute contraindication and therapy can be Whether or not the initial episode is classified as bronchiol-
given from 3 years of age, with caution by well trained staff in itis is irrelevant. Episodic viral wheeze disappears by the age of
specialist centres. six years, but may continue into school age or change into
Children under 5 years should be given practical instructions multiple-trigger wheeze. Multiple-trigger wheeze describes
on inhaler use while their parents require training in inhaler children who also respond with wheezing to other triggers.
devices and strategies for managing episodes. They should be These include tobacco, crying, laughter or exercise.36 Many be-
provided with theoretical and practical education including a lieve that multiple-trigger wheeze reflects chronic allergic air-
written action plan. Asthma education is an integral part of way disease and could be classified as asthma. This classifica-
asthma management and must be offered to all parties in- tion differs from the retrospective epidemiological classifica-
volved. The asthma quiz for kids30 and the paediatric asthma tion of wheezing reported from the Tucson birth cohort19 of
control tests31 are patient based tools for identifying children transient and persistent wheezing. Children with transient
with uncontrolled asthma. wheezing, wheezed during the first 3 years of life and do not
have a personal history of eczema or a family history of asthma.
THE ERS TASK FORCE GUIDELINES The group of late onset wheezers who started wheezing after
3 years often had associated maternal asthma, male sex and a
These guidelines were developed as evidence based guide- history of rhinitis.
lines while recognising that there is limited evidence available The diagnosis of wheezing is made by history taking alone and
for the treatment of wheezing disorders in preschool children. investigations are justified when symptoms are present from
The cumulative prevalence of wheeze is almost 50% by the time birth, airway obstruction is abnormally severe and recovery is
children are 6 years old.32 It is proposed that given the multifac- slow, or incomplete, or associated with repeated admissions.
torial nature of all wheezing disorders in childhood, the clinical Sensitisation to hens egg at the age of 1 year is a reasonable
phenotypes described in the literature are extremes of a broad marker for allergic sensitisation to aeroallergens at age 3 years
spectrum of wheezing disorders.33 These guidelines utilised the with a specificity of >90% and sensitivity of 30%.37
Cochrane Library, Pubmed and EMBASE to search for evi- There appear to be no studies supporting the usefulness of
dence based treatments and graded the evidence into high, pulmonary function tests in children with non-specific symp-
moderate or low grade evidence based on study design and toms, or in distinguishing between episodic and multiple trig-
quality and also applied the GRADE methodology.34 ger wheeze, but a bronchodilator response in young children
They concluded that almost all of the evidence available was may assist in discriminating common wheezing disorders from
of low quality. In quoting the GINA definition that asthma is a other conditions. Reference values for FeNo are only available
syndrome with a highly variable clinical spectrum character- for children over 4 years.38
ised by airway inflammation,35 they point out that inflamma- Biopsy evidence of inflammation of the airways in young chil-
tion has been poorly studied in preschool children and may be dren is scarce and the only consistent biopsy finding in wheezy
absent in very young children who wheeze. Thus, the majority children is thickening of the basement membrane,39 but not in
of the task force agreed not to use the term asthma to describe infants at median age of 12 months, whereas a study done at
preschool wheezing since there is insufficient evidence show- mean age 29 months in wheezy children40 reported eosinophilic
ing that the pathophysiology of preschool wheezing is similar airway inflammation and reticular basement membrane thick-
to that of asthma in older children or adults. ening, implying an age window during when inflammation
It is believed that specific combinations of genetic and envi- develops.
ronmental factors determine the patients phenotype, but that Treatment guidelines stress the importance of allergen avoid-
in clinical practice most of these factors are as yet unknown. ance but it is unclear whether the required reduction in allergen
exposure can be achieved in normal life and there are no stud- dence that anti-house dust measures prevent the onset of asth-
ies or allergen avoidance in preschool children with wheeze.41 ma. Unless the child is sensitised to a pet species, there is insuf-
Studies on the effectiveness of parental education are disap- ficient data to recommend for or against the presence of a pet
pointing.42 in the house. Sensitization to cockroaches is associated with an
Treatment guidelines of the ERS task force recommend in- increased risk of developing asthma45 and sensitization to Al-
haled b2 agonists as the most effective bronchodilators available; ternaria is a risk factor for more severe asthma.46 There is no ev-
suggesting that single isomer R-albuterol is preferable. There are idence that diet in pregnancy or breast feeding or probiotics in-
no published randomised placebo controlled trials in preschool fluences the development of asthma, but some evidence that a
children on the addition of long acting b2 agonists to inhaled farming environment may be protective.
corticosteroids. Inhaled corticosteroids are effective for symp- A diagnosis of asthma should be considered when a young
tom control, reduction of exacerbations, lung function and air- child presents a symptom pattern of wheeze/cough occurring
way responsiveness in children with multiple-trigger wheeze.43 recurrently, during sleep, with activity, laughing or crying in the
Doses recommended in preschool children up to 400 g Be- presence of a positive family history and evidence of allergic
clomethazone equivalent may be used with metered dose in- sensitisation. Although no tests diagnose asthma with certainty
haler plus a spacer, without benefit from higher doses. Those in young children, a therapeutic trial with short acting bron-
with a positive family history, over 2 years and frequent symp- chodilators and inhaled glucocorticosteroids for at least 8-12
toms show the best response to inhaled steroids. However one weeks may provide some guidance as to the presence of asth-
study using inhaled Fluticazone to wheezy infants showed no ma (Evidence D). Lung function, bronchial challenge and other
improvement in lung function.44 It is suggested that after a trial physiological tests do not have a major role in the diagnosis of
of 3 months of inhaled corticosteroids, treatment should be asthma in children 5 years and younger. To aid early identifica-
withdrawn in those who become almost completely free of tion of asthma in the clinical setting, a number of risk profiles
wheeze to assess the need for ongoing therapy. and predictive assessments have been published. The Asthma
For episodic viral wheeze the clinical benefits of inhaled corti- Predictive Index (API)47 based on the Tuscan study showed that
costeroids are controversial and maintenance treatment up to a child with a positive API has a 4-10 fold greater chance of de-
400 g/day does not reduce the severity or frequency of attacks veloping asthma between ages 6 and 13 while 95% of children
in these children. Nasal steroids have not been demonstrated with a negative API remained free of asthma (Evidence C).
to be of benefit in preschool children with recurrent wheeze For children under 5, asthma management plans based on
with allergic rhinitis. Furthermore there is no evidence that par- the level of respiratory symptoms are just as effective as plans
ent initiated oral steroids are associated with benefit, in terms based on self monitoring of lung function (Evidence B).48 The
of hospital admissions, symptom scores, or bronchodilator use. relationship between current control and future risk de-
A study of Montelukast in 689 young children with multiple- scribed in the NAEPP guidelines6 have not yet been carefully
trigger wheeze achieved an improvement in symptom and a studied in small children. The importance of good daily asthma
30% reduction in exacerbations.23 Cromones and Xanthenes control is stressed. The guidelines warn against excessive or
are not recommended and neither is allergen immunotherapy prolonged unnecessary use of inhaled, or systemic corticoste-
outside the setting of a randomised controlled trial. roids, since many children with wheezing go into remission. No
objective measures to assess clinical control have been validat-
THE NEW GINA GUIDELINES ed in children younger than 4 years. It appears that asthma is
rare in the transient wheeze groups, but there are other pheno-
A comprehensive strategy for asthma management and pre- types.
vention in children 5 years and younger has recently been pub- Inhaled glucocorticosteroids are effective in the management
lished.9 It addresses risk factors associated with the develop- of asthma in young children (Evidence A), but do not induce a
ment of asthma, the diagnosis of asthma and management and remission. Low doses have not been associated with any clini-
pharmacological treatment (education, control, pharmacother- cally serious adverse systemic effects.
apy and the management of acute exacerbations). These guide- Table 1 lists the low doses which have not been associated
lines are evidence based using Categories A-D in which Cate- with clinically adverse effects in trials including measures of
gory A is derived from a rich body of data of randomised con- safety. Table 2 presents the GINA management approach based
trolled trials, Category B from a limited body of controlled trial on asthma control for children 5 years and younger.
data, post hoc analysis or meta analysis of RCT, Category C for Anti leukotrienes improve asthma outcomes in young chil-
non-randomised or observational studies and Category D for dren (Evidence A), however the role of leukotrienes as add on
panel consensus judgment. therapy in children under 5 years whose asthma is uncon-
For risk factors of asthma the guidelines recognise that there trolled on inhaled glucocorticosteroids has not yet been specif-
is mixed evidence for house dust mite avoidance and no evi- ically evaluated. Leukotriene receptor antagonists are safe.
Table 1. Low daily doses* of inhaled glucocorticosteroids for children 5 yr and Table 2. Asthma management approach based on control for children 5 yr and
younger younger
Drug Low daily dose (g) Asthma education
Beclomethasone dipropionate 100 Environmental control
Budesonide MDI + spacer As needed rapid-acting b2-agonists
Budesonide nebulized 200
Uncontrolled or only
500 Controlled on as Partly controlled on as
partly controlled
Mometasone furoate NS
Triamcinolone acetonide NS y y y
*A low dose is defined as the dose which has not been associated with clini-
cally adverse effects in trials including measures of safety. This is not a table of Controller options
clinical equivalence.
NS = not studied in this age group. Continue as needed Low-dose inhaled Double low-dose inhaled
rapid-acting b2-agonists glucocorticosteroid glucocorticosteroid
Long acting bronchodilators are not recommended for chil- Low-dose inhaled
dren under 5 years (Evidence D) and cromolyn cannot be rec- Leukotriene modifier glucocorticosteroid plus
ommended (Evidence A). Suggested levels of control are pro- leukotriene modifier
vided in Table 3 for children 5 years and younger with asthma.
*Oral glucocorticosteroids should be used only for treatment of acute severe ex-
The treatment of intermittent wheezing remains controversial acerbations of asthma. Shaded boxes represent the preferred treatment options.
where a diagnosis of asthma seems unlikely. Evidence for effi-
cacy of short term controllers (e.g., inhaled glucocorticoste-
roids, leukotriene modifiers and oral glucocorticosteroids) is it has been estimated that over 10% of doctors ignore the exis-
lacking. The initial treatment is a dose of rapidly acting inhaled tence of 78% of available guidelines.49 Guidelines may not be
b2 agonist every 4-6 hours as needed for a day or more until followed if they are considered to be based on opinion, poor
symptoms disappear (Evidence A). Regular controller treat- evidence, or do not consider patients values and preferences.
ment may be indicated in a child with less frequent but more Thus for the under 5s we have a lot of information through ex-
severe episodes of viral induced wheeze (Evidence D). The new tensive reviews of the available literature on studies of asthma
GINA guidelines also provide detailed management plans for aetiology, phenotypes, natural history and pharmacotherapy
acute exacerbations. which is consolidated in the available guidelines.
In the future new guidelines are expected to be published us-
CONCLUSIONS ing the GRADE system (Grading of Recommendations, Assess-
ment, Development and Evaluation) whose activity is endorsed
All the recent guidelines have stressed the difficulties in mak- by the WHO34 and an attempt has been made to include as-
ing a firm diagnosis of asthma in children under 5 and several pects of the GRADE recommendation in the ERS guidelines.8
wheezy phenotypes have been identified. Each of the guide- This new method will not only assess the quality of the evi-
lines provides a unique perspective and important insights into dence across studies for each important outcome but the bal-
the problems facing clinicians treating young children with ance between benefits, harm and strengths of recommenda-
asthma and there are a number of recommendations which are tions, bringing scientific evidence near to real life situations
clear and are repeated in each of the guidelines. which will make guidelines easier to apply.
However, following guidelines depend on factors within the The available guidelines do not adequately address the man-
guidelines themselves, social-cultural context of the strategies agement of asthma or wheezing phenotypes for children under
used to spread them and organizational, economic and political the age of 5 in the underdeveloped world where there is a lack
context for the implementation of guideline strategies.49 Knowl- of resources, but also because there is an absence of studies on
edge, attitude, skills, experiences, beliefs and values play a fun- asthma management in practice in the under 5s in these re-
damental role both for the physician, the parent and the patient. gions.
Lack of consensus among different new guidelines can be a ma- It would be prudent for regions and countries to consider all
jor obstacle to doctors adopting a particular guideline and com- the available guidelines and to adapt then so that they are un-
plex guidelines are not practical for busy doctors to follow. derstandable in regional contexts and that the recommenda-
Lack of familiarity with guidelines is a common problem and tions are in line with available resources in a particular region
Uncontrolled
Controlled Partly controlled
Characteristic (3 or more of features of partly
(All of the following) (Any measure present in any week)
controlled asthma in any week)
*Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate. Although patients with current clinical control are less likely to ex-
perience exacerbations, they are still at risk during viral upper respiratory tract infections and may still have one or more exacerbations per year.
to facilitate their implementation and thus improve the man- 6. NIH. National Asthma Education and Prevention Program. Expert
agement of asthma in young children around the world. Panel Report III: Guidelines for the Diagnosis and Management of
Asthma. Bethesda, MD: National Institutes of Health; National
Heart, Lung, and Blood Institute; 2007. NIH Publication No. 07-4051.
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