Pre-school wheeze is a complicated clinical area where there are few absolutes
Wheeze is a common symptom in pre-school children. Population-based studies have suggested that a quarter of children have had at least one episode of wheeze by 18 months,1 a third of children by age three and up to 50 per cent by age six.2 The vast majority of these wheezing episodes have viral respiratory tract infections as their trigger. However, the precise reasons that some children wheeze, whereas others with the same viral illness do not, remain a mystery.
Confusion abounds in primary and secondary care in paediatrics about the diagnosis and treatment of wheezing illnesses in pre-school children. One of the main difficulties with the terminology used in pre-school wheeze is the question of what is and isn’t asthma. The symptoms of wheeze and irritative non-productive cough are those of asthma, and some children clearly respond to ‘asthma’ treatments. What asthma is itself remains poorly understood in this group and although some of these children may go on to be diagnosed with typical atopic asthma at a later stage, the pathophysiology of pre-school wheeze is likely very different. If healthcare professionals are confused, we can be sure that parents and the public are doubly so — usually, parents want a simple explanation and plan and just want to know: ‘Is it asthma?’
The Global Initiative for Asthma (GINA) in 2015 defines asthma as follows: “Asthma is a heterogeneous disease, usually characterised by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.”
The term ‘asthma’ is now deliberately used as an umbrella term, like ‘anaemia’, ‘arthritis’ and ‘cancer’. An overarching principle in the new GINA report is the importance of individualising patient management, particularly in the pre-school age group.
The above definition is vague at best, confirms that asthma is inherently heterogeneous and suggests that we should steer clear of applying pedantic rules to determining if children do or don’t have what we think is asthma (as we don’t know exactly what it is or isn’t).
In 1995, Martinez et al proposed a system based on the age of onset of wheeze.2 They described persistent, late-onset and transient wheezing.3 These classifications can only be described retrospectively, therefore they remain of epidemiological interest but of little clinical benefit. In a similar vein, in 2008, the European Respiratory Society task force proposed a classification for pre-school wheeze with two main phenotypes based on temporal patterns: Episodic viral wheeze and multiple-trigger wheeze. The aim of defining the phenotypes was to describe a set of common features that might assist in guiding treatment and improve our understanding of the underlying mechanism.4
There is lots of conflicting evidence available and the outcome of many trials suggests a need for further research. The major limitations of the research in this area are as follows:
When we can’t accurately define the disease (or the symptom), clear and meaningful clinical trial outcomes are difficult.
Even with the most restrictive definitions, significant clinical heterogeneity may persist in the study cohort, diluting the overall findings.
High-quality, strictly-phenotyped studies of heterogeneous populations often apply to only a minority of patients in the ‘real world’.5
A Cochrane review in 2000 found no evidence to support the use of low-dose inhaled corticosteroid for the prevention or management of mild episodic viral wheeze. Subsequent studies have shown that while there is no evidence to suggest that continuous or intermittent use of inhaled corticosteroids (ICS) reduces the risk of progression to school-age atopic asthma, treatment can help control current symptoms of wheeze and cough and reduce the need for oral steroids.6-8 A 2015 Cochrane review examining the evidence for use of leukotriene receptor antagonists (LTRA) on an intermittent or maintenance basis for episodic wheeze in children showed no significant difference between treatment and placebo.9 The authors noted heterogeneity of patient responses within this group.
It seems likely that within these large studies and meta-analyses that there are children with no response to treatment mixed up with children with a good response. It is likely that it is this variability which ensures that lots of these trials either have negative or weakly positive outcomes.
In the face of very confusing terminology and weak or contradictory data from randomised, controlled trials for this very heterogeneous group of children, perhaps the most sensible and useful quote for many years in this area was provided by Prof Paul Brand: “Until phenotypes can be described that are associated with different pathobiological process, are related to different longitudinal outcomes, or are clearly different in terms of response to therapy, clinicians are encouraged to take a trial-and-error approach of different therapeutic agents in pre-school children with troublesome, recurrent wheeze.”10
The aim of wheeze management in paediatrics should be to ensure that the child has a normal quality of life with minimal symptoms, using as little medication as necessary. We neither want to see children with significant symptoms denied potentially effective treatments, nor children with side-effects from medications that do not work and are not needed but are given in increasing doses. Decisions in relation to treatment should be determined by both the frequency and severity of presentations. The more significant the child’s symptoms the more likely we are to try different treatments.
The first question we always want to know about a wheezing child referred to us is, does the child clearly and reproducibly respond clinically to a bronchodilator? For significant wheeze in any age group, bronchodilators should always be tried. Although there is little evidence to support it, we feel that children with a clear bronchodilator response are more likely to respond to an inhaled corticosteroid and this will also have to be tested objectively.
Aside from the minor concerns of rashes and oral candidiasis with inhaled steroids, the main concern that parents will be aware of is surrounding linear growth. This has been examined in detail in several studies. With very large numbers, it can be seen that there is a statistically significant reduction in final adult height of approximately 1cm in those using ICS for >12 months in childhood.11 After the first year, there appears to be little further reduction in growth velocity. It should be noted that a 1c coin is 1.9cm in diameter, and the average adult height is 175cm for a male and 161cm for a female — in which context 1cm, although statistically significant, is largely irrelevant clinically.
As responsible practitioners, however, we should never be complacent in relation to the balance of beneficial and harmful effects of medications. We should avoid giving medication to children who do not need it, ensure that ICS are used only for as long as necessary and that efficient delivery is optimised (so we don’t get side-effects with no benefit).
We are trained as doctors to very carefully establish a definitive diagnosis before prescribing treatments to a patient. In a scenario such as this, however, we must view treatments differently in the short-to-medium term as trials of treatment can be very helpful diagnostic aids to assist us to establish what something is, or isn’t, as the case may be. We must enter this sphere with openness and honesty: If we knew before we started who would respond to treatment, we wouldn’t need to do this. We must be objective, clearly communicate with our patients and parents why we are doing what we are doing, engage them thoroughly in the process, and use their eyes and ears to establish for us what effect trials of medications have. There are no tests other than a good history in most cases.
Parents are usually worried and frustrated (not least because they are hearing a different version from several different sources) when they present to us. They want what we want: To know that nothing serious is going on, to try to reduce symptoms and improve quality of life and to ensure we are not doing harm to their child with treatments that are more harmful than beneficial.
The first step is to clarify a history of recurrent wheeze
Pre-school children experience many forms of noisy breathing and clarifying parental perception of the term ‘wheeze’ is crucial in assessment of the child.12 Clinicians are encouraged to demonstrate wheeze to parents.
A trial of a short-acting bronchodilator
Parents need a clear brief instruction on inhaler and spacer technique and when medications should be used. Follow-up should assess if there is a clinical response to bronchodilator:
‘Fifteen minutes after you give the blue inhaler, is there any difference in your child’s breathing?’
As required, short-acting bronchodilators may suffice in many cases. Scheduled use of bronchodilators should be avoided as tachyphylaxis occurs with salbutamol.
If symptoms continue to be problematic, consider a trial of inhaled corticosteroids
Assessment after an agreed window of treatment is vital to see if there has been an improvement and also to evaluate if the symptoms recur off-treatment.4 If the wheezing is predominantly in winter time with viral infections, there is little benefit in a trial of ICS in the summer, when the trigger for wheeze is unlikely to occur and therefore there should be seasonal consideration for the timing of a trial. The duration of a trial will depend on the frequency of symptoms and the trigger. For daily symptoms, one would expect a good response in weeks, whereas for a child getting severe episodes every two months or so with colds, a trial of four-to-six months may be needed to see if there is clearly a benefit.
If symptoms were significant and the ICS is deemed to be successful, consider continuing throughout the winter months and try stopping in the summer in those where there is a clear pattern of wheeze with colds and in the winter more than summer.
For children with winter wheeze who do well in the summer, we would always advise that the parents try each year to not restart the ICS — in which case, we will ensure that treatment is discontinued when no longer needed.
If there is a clear failure to respond, return to first principles and ensure there is good understanding and appropriate medication use. Trials of inhaled corticosteroids are of use both from a symptomatic point of view and diagnostic, with the proviso that they are discontinued if they are ineffective. If a trial of treatment is successful, children should be followed up six-monthly on a scheduled basis. Medications should be weaned as tolerated, with the aim of using minimal medications and good symptom control.
The evidence overall would suggest a lower likelihood of benefit from montelukast than ICS for non-atopic wheeze and this would not be our first choice of preventer agent. However, in individuals where there are significant symptoms and other agents have not worked, montelukast can be trialled in the same way as ICS and with the same caveats. Some authors suggest that there may be some benefit from montelukast used on an as-needed basis with exacerbations. Again, this would need to be done on a trial-and-error basis and the medication discontinued if it is not helpful.
In pre-school children, a phenotype we see commonly is the child with excessive coughing at night during colds and for a number of weeks afterwards. Some of these children also cough with exercise, particularly when unwell. Children who present with an incessant, irritant cough (particularly nocturnal symptoms) should be considered for a trial of inhaled corticosteroids.
As a rule of thumb, in children, significant bacterial infection and wheeze almost never coexist and unlike in adults, steroids and antibiotics are rarely needed in combination for children with a wheezing illness. Chest auscultation and radiographs are of very little value in determining if a child needs an antibiotic (they rarely do) during a wheezing episode, given the very poor specificity of both. A clinical history is usually far superior.
When to reconsider the diagnosis
Wheeze that is associated with a daily wet cough.
Daily wheeze in an infant.
Respiratory symptoms of very early onset (from early infancy).
Failure to respond to standard therapies, despite good compliance.
Pre-school wheeze is a complicated area where there are few absolutes. There is likely significant clinical heterogeneity between patients with a similar phenotype. Our goal for assessment and management should be to ensure that the child has a normal quality of life, using as little medication as necessary. We should keep an open mind, take a comprehensive history and employ appropriate trials of medication to help us to figure out whether we can help the child and family to control symptoms.
Henderson J, Granell R, Heron J, et al. Associations of wheezing phenotypes in the first six years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008;63:974-80.
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133-8.
Stein RT, Martinez FD. Asthma phenotypes in childhood: Lessons from an epidemiological approach. Paediatr Respir Rev 2004;5:155-61.
Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: An evidence-based approach. Eur Respir J 2008;32:1096-110.
Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: To whom do the results of the trials apply? Thorax 2007;62:219-23.
Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in pre-school children at high risk for asthma. N Engl J Med 2006;354:1985-97.
Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A, team Is. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): 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.
Brodlie M, Gupta A, Rodriguez-Martinez CE, Castro-Rodriguez JA, Ducharme FM, McKean MC. Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane Database Syst Rev 2015;10:CD008202.
Schultz A, Brand PL. Episodic viral wheeze and multiple trigger wheeze in preschool children: A useful distinction for clinicians? Paediatric respiratory reviews 2011;12:160-4.
Loke YK, Blanco P, Thavarajah M, Wilson AM. Impact of inhaled corticosteroids on growth in children with asthma: Systematic review and meta-analysis. PLoS One 2015;10:e0133428.
Elphick HE, Sherlock P, Foxall G, et al. Survey of respiratory sounds in infants. Arch Dis Child 2001;84:35-9.