Should Inhaled Corticosteroids Be Used to Treat Recurrent Wheeze in Preschool Children?

Abstract

Wheeze in preschool children is common. In a small proportion of children, it can be very troublesome, requiring repeated visits for medical attention. Response to treatment is variable and often disappointing. Children with frequent wheeze, particularly if they have a family history of asthma, are likely to benefit from inhaled corticosteroids, in terms of both improved symptom control and reduced number and severity of exacerbations. Children with infrequent episodic wheeze do not benefit from regular inhaled corticosteroids, and their use should be avoided in children with this pattern of wheeze.

Introduction

Wheezy episodes in children under 6 years of age are common. In the Tuscon Children's Respiratory study, almost 50% of children had at least 1 episode of wheeze by the time they were 6 years old.¹ In most preschool children, wheeze is episodic, associated with viral infections, and resolves by school age. A smaller proportion of children with preschool wheeze go on to have more troublesome asthma in later life. On the other hand, among older children and adults with asthma, over 70% had their first episode of wheeze before 3 years of age² (Fig. 1). Although there are predictors of persistence of symptoms, such as having a parent with asthma, evidence of allergic sensitization, concurrent eczema, and frequency of wheeze, including wheezing without upper respiratory tract infection,^3,4 these predictors have a relatively low positive predictive value and sensitivity when applied to children who have already had at least 1 episode of wheeze.

FIG. 1.

Proportions of children with wheeze and asthma.

Treating preschool children with wheeze is challenging for several reasons:

Simply establishing that the problem is wheeze can be hard. Parents frequently describe any respiratory noise as wheeze.⁵ Cough and breathlessness often occur at the same time as wheeze and may be the dominant symptoms. Pathology other than viral infections and asthma can result in wheezy disorders and so other causes need to be considered.

There is no agreed term for children who wheeze in early life and this leads to uncertainty about both diagnosis and treatment. Although these children clearly have recurrent small airways obstruction, which, in most instances, shows at least partial response to bronchodilators, many pediatricians and general practitioners prefer not to call this condition asthma, possibly because asthma carries with it an implication of a life-long condition and also suggests allergic sensitization. The lack of an agreed term has resulted in the use of a wide variety of alternative terms, such as viral-associated wheeze, viral-induced wheeze, wheezy bronchitis, and episodic wheeze, and in attempts to describe specific wheeze phenotypes that are distinct from asthma.⁶

Longitudinal studies of children with particular wheeze phenotypes such as viral wheeze and multi-trigger wheeze, suggest that children frequently change from one phenotype to another,⁷ which makes the concept of treatment tailored to phenotype difficult to sustain.

Response to treatment, particularly during exacerbations, is variable and often disappointing; for example, many younger children may not appear to derive much benefit from inhaled bronchodilators.

There are concerns from parents and doctors about the long-term effects of inhaled corticosteroids (ICS), particularly on growth, especially when given to very young children.

Despite evidence to the contrary, dogmatic views about childhood wheeze remain widespread. These include “You can't diagnose asthma before 2 years of age” and “Beta-agonists don't work in children under 2 years because they don't have beta-agonist receptors.” The second belief (which is entirely without basis) is prevalent in many centers in the United Kingdom and explains the preference of some pediatricians for inhaled ipratropium bromide for exacerbations of preschool wheeze.

Can ICS Affect the Natural History of Wheezing Illness?

A further issue that needs to be considered is whether early treatment of wheeze can influence the longer-term outcome—more specifically, can early treatment with ICS, irrespective of their effects on immediate symptoms control, prevent the development of severe asthma in later childhood and adult life? Lung function data from the Tuscon Children's Respiratory suggests that the lung function of children who wheeze both before the age of 3 years and at the age of 6 years is not different from children who never wheeze when measured shortly after birth, but is significantly lower than those who never wheeze by the age of 6 years.⁸ This loss of lung function may predispose these children to longer-term respiratory problems (asthma and chronic obstructive pulmonary disease) in adult life. It is tempting to speculate that early intervention in these children could alter this outcome.

The question of whether or not early use of ICS can affect the natural history of wheezing disorders has been addressed by 3 randomized, controlled trials, 2 using continuous ICS and 1 using ICS only when the child was wheezy.^9–11 The 2 studies using continuous ICS^9,10 were of similar design; a combined total of 485 children were enrolled at around 2 years of age and were selected on the basis of having had at least 2 episodes of wheeze and an increased risk of developing asthma (most often because of having a parent with asthma). The children were randomized to receive fluticasone 200 μg/day or placebo and were followed for 3 years. At the end of these 2 studies, there was no benefit from regular use of fluticasone either in terms of the proportion of children with wheeze or an asthma diagnosis or in lung function. The children using regular fluticasone were on average about 1 cm shorter. In the study by Bisgaard et al.,¹¹ ICS were started even earlier; 411 infants thought to be at increased risk of wheeze, because of a history of maternal asthma, were randomized to receive either 400 μg of budesonide or placebo, to be taken at the time of any wheezy episode associated with a coryzal illness for a duration of 2 weeks on each occasion, over a period of 3 years. Of the 411 infants recruited, 301 had at least 1 wheezy episode. At the end of the 3 years of intervention, there was no evidence of symptomatic benefit during the study, no benefit in the proportion that developed more persistent wheezing, and no difference in lung function between the 2 groups.

So, based on these 3 studies at least, there seems to be no long-term disease-modifying effect of ICS in preschool wheezers, and any benefit of ICS in this group of children should be evaluated only in terms of symptom control.

Evidence for the Benefit of ICS on Symptom Control

A meta-analysis of randomized, controlled trials designed to evaluate the efficacy of ICS in preschool children with wheeze has been recently published.¹² Twenty-nine studies (a total of 3,259 children) were included in the meta-analysis. For most of these 29 studies, children were eligible to take part if they had symptoms (cough, wheeze, or breathlessness) occurring on at least 3 days per week and were then randomized to receive at least 4 weeks of ICS or placebo. The conclusion of the meta-analysis was that there was a 40% reduction in exacerbations of wheeze in children taking ICS, with 7 children needing to be treated with ICS to prevent 1 exacerbation. This effect was independent age, type of ICS, and atopic status. Children taking ICS also had significant improvement in symptoms scores.

This apparently clear-cut result is helpful in clinical decision making, provided it is applied to the same group of children as those who took part in the studies, that is, those with frequent symptoms. It does not apply to the majority of preschool wheezers who have relatively infrequent episodic wheeze and no interval symptoms. This point has been well illustrated by one of the studies included in the meta-analysis. Roorda et al.¹³ enrolled 305 children (age: 1–5 years) from 67 centers in 15 countries who had wheeze on at least 7 days of the last 14 days of a 4-week run-in period before the trial started. Children were then randomized to 100 μg fluticasone twice daily or to placebo for 12 weeks. The main outcome measure was number of days free of cough or wheeze. The children were subdivided according to the frequency of their symptoms during the 4-week run-in period—those with symptoms on 3 or more days per week and those with symptoms on less than 3 days per week—and according to whether or not there was a family history of asthma. Children in the less frequent symptoms subgroup had no improvement in symptom control when given fluticasone, irrespective of the family history of asthma. In children in the more frequent symptom group, there was an improvement in symptoms in those taking fluticasone (almost twice as many symptom-free days), but this was only statistically significant in those who also had a family history of asthma. Another interesting aspect of this study was the size of the placebo effect—compared with the run-in period, children on placebo with frequent symptoms increased the number of symptom-free days from 0% of days to 25% of days. High placebo response rates have been seen in other studies of preschool wheeze, and it should be borne in mind when trying to assess the benefit of therapy for wheeze given to children in clinical practice.

Post hoc subgroup analysis of the Prevention of Early Asthma in Kids (PEAK) trial also emphasizes the importance of wheeze frequency as a predictor of treatment response.¹⁴ The PEAK trial randomized 285 children at 2 and 3 years of age to either placebo or fluticasone (176 μg/day). Children were eligible to take part if they had a positive asthma predictive index defined as frequent wheezing (at least 4 episodes in the previous year) and either 1 major risk factor for asthma (parental history of asthma, personal history of atopic dermatitis, or aeroallergen sensitization) or 2 minor risk factors for asthma (peripheral blood eosinophilia ≥4%, wheezing without colds, or allergic sensitization to food). During the 2-year treatment period of the trial, children on fluticasone had significantly more days free of asthma symptoms (93.2% versus 88.4%) and fewer exacerbations treated with oral corticosteroids (57.4 per 100 child-years versus 89.4 per 100 child-years). The post hoc analysis showed that the benefits of ICS on symptom reduction were only seen in children with asthma symptoms on more than 20% of days in the month prior to randomization. This result, like that of Roorda et al.,¹³ suggests that children with infrequent symptoms, even when there is a family history of asthma, will not benefit from regular treatment with ICS.

Infrequent Episodic Wheeze

Children who have episodes of wheeze that last a few days at a time, with or without concurrent symptoms of a viral upper respiratory tract infection, and who are wheeze free at other times are a less well-studied group. Although most children have relatively minor symptoms, wheeze episodes can be severe and require hospital admission for oxygen therapy and frequent nebulized bronchodilators and can cause a great deal of anxiety to parents and their doctors. The aim of treatment in this group is to prevent, or to ameliorate, the episodes of wheeze.

Two studies of daily ICS for this group of children showed no benefit in preventing exacerbations.^15,16 There have been 5 studies of intermittent high-dose ICS, most often given at the first sign of a cold and then for a period of 7–14 days,^17–21 all of which show some benefit of treatment, with modest reductions in symptoms during wheezy episodes. The most recent study²¹ enrolled 129 children aged 1–6 years, who had at least 3 episodes of wheeze, seemingly triggered by upper respiratory tract infections, who had been given at least 1 course of oral corticosteroids, and who had no interval symptoms. These children were randomly assigned to receive either 1500 μg per day of fluticasone or placebo, to be taken at the onset of an upper respiratory tract infection and to continue for 10 days. Children were studied over a period of 12 months; during that time they had an average of 8 upper respiratory tract infections, which were treated with ICS, meaning that they received approximately 80 days of high-dose fluticasone. The study showed that use of high-dose fluticasone in this way was associated with a 50% reduction in the number of exacerbations treated with oral corticosteroids (43 courses of steroids in the fluticasone group compared with 93 in the placebo group). Children in the fluticasone group had significantly worse growth—equivalent to that seen after 12 months of 200 μg per day of fluticasone—compared with those in the placebo group. The potential for side-effects and the likelihood that this treatment would be used for children with milder wheezing episodes than those enrolled in the study led the authors to conclude that short-course high-dose fluticasone should not be recommended for use in clinical practice.

Bacharier et al.²⁰ studied 238 preschool children with episodic wheeze. In this study, children were randomized, at the first sign of a cold, to 7 days of either 2 mg nebulized budesonide or 4 mg oral montelukast or to placebo over a 12-month period. Each child had an average of 3.5 treated respiratory tract infections. There were no differences between the 3 groups in the number of wheezy exacerbations, total number of days with symptoms, use of oral corticosteroids, or linear growth (possibly because fewer episodes were treated than in the Ducharme study²¹). Symptom severity (cough, wheeze, difficulty breathing) in the 14 days after start of treatment for each episode was reduced by about 35% in the budesonide and montelukast groups compared with the group of children taking placebo. This result with respect to montelukast is similar to the findings in a previous study of 220 children aged 2–14 years with episodic wheeze, who were randomized to montelukast or placebo at the onset of an upper respiratory tract infection, taken for 7 days or until symptoms had resolved for 48 h.²² In this study, there were no differences between the 2 groups in duration of symptomatic episodes or use of oral corticosteroids, but in the montelukast group there was a significant 30% reduction in each of unscheduled healthcare visits (mostly GP visits), missed time at school or child care, and parent time off work.

A Pragmatic Approach

How should the available evidence influence clinical practice? In this section, I outline my personal approach to the wheezy preschool child. When faced with a child who is having episodes of wheeze, there are 3 key questions to address:

Is this really wheeze, and if so what is the reason for the wheeze?

What is the pattern of wheezing?

Is there a personal or family history of atopic disease?

The treating physician must first satisfy themselves that the child's symptoms are related either to viral respiratory tract infection or early asthma and are not, for example, due to aspiration lung disease (with or without gastro-oesophageal reflux) or structural airway abnormalities. Careful history and examination are usually sufficient for this purpose. Thereafter, identifying the pattern of wheeze (frequency, severity, and precipitants) and the personal and family history of atopic disease are the critical determinants of whether or not it is worth using ICS.

Children with infrequent episodes of wheeze (less than once per month), who do not wheeze at other times, will not derive benefit from regular ICS. Intermittent high-dose ICS have a modest effect in reducing severity of wheeze exacerbation, but at the cost of unacceptable side effects. Treatment options for these children include beta-agonists when they are wheezy, intermittent or continuous montelukast,^20,22 and possibly oral prednisolone for severe episodes. Three randomized, placebo-controlled trials of oral prednisolone for mild-to-moderate episodic wheeze have failed to show benefit.^23–25 The temptation to add additional therapies in children who have severe (requiring hospital admission) but infrequent episodic wheeze should be resisted.

Children who wheeze or cough on at least 3 days per week and who have a parent with asthma or a personal history of eczema or hay fever are likely to benefit from regular ICS, in terms of both day-to-day symptom control and reduction in exacerbations, and regular ICS should be started.

Children who fall in-between these 2 categories can be given a 3-month trial of ICS treatment evaluated by symptom diary. Benefit is most likely to be seen in children with a family history of asthma or a personal history of eczema or hay fever. If no benefit is seen, ICS should be discontinued.

Children may switch between categories, so regular follow-up is needed, either to start ICS or to reduce and then stop them.

Conclusion

Most asthma starts in early childhood. There is a genetic predisposition, but other triggers appear to be needed for the disease to become manifest. One of these triggers may be viral respiratory infection. The process by which early intermittent wheeze progresses to more persistent wheeze with atopic sensitization is not understood. The currently available treatments provide incomplete relief from symptoms in preschool children and do not affect disease progression. The Holy Grail of early asthma pathophysiology remains undiscovered.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Martinez

, Wright

, Taussig

, Holberg

, Halonen

, Morgan

. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med, 1995; 332:133–138.

Stern

, Morgan

, Halonen

, Wright

, Martinez

. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet, 2008; 372:1058–1064.

Castro-Rodríguez

, Holberg

, Wright

, Martinez

. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med, 2000; 162:1403–1406.

Caudri

, Wijga

, A Schipper

, Hoekstra

, Postma

, Koppelman

, Brunekreef

, Smit

, de Jongste

. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol, 2009; 124:903–910.

Cane

, Ranganathan

, McKenzie

. What do parents of wheezy children understand by “wheeze”? Arch Dis Child, 2000; 82:327–332.

Brand

, Baraldi

, Bisgaard

, Boner

, Castro-Rodriguez

, Custovic

, de Blic

, de Jongste

, Eber

, Everard

, Frey

, Gappa

, Garcia-Marcos

, Grigg

, Lenney

, Le Souëf

, McKenzie

, Merkus

, Midulla

, Paton

, Piacentini

, Pohunek

, Rossi

, Seddon

, Silverman

, Sly

, Stick

, Valiulis

, van Aalderen

, Wildhaber

, Wennergren

, Wilson

, Zivkovic

, Bush

. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J, 2008; 32:1096–1110.

Schultz

, Devadason

, Savenije

, Sly

, Le Souëf

, Brand

. The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr, 2010; 99:56–60.

Morgan

, Stern

, Sherrill

, Guerra

, Holberg

, Guilbert

, Taussig

, Wright

, Martinez

. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med, 2005; 172:1253–1258.

Guilbert

, Morgan

, Zeiger

, Mauger

, Boehmer

, Szefler

, Bacharier

, Lemanske

Jr. , Strunk

, Allen

, Bloomberg

, Heldt

, Krawiec

, Larsen

, Liu

, Chinchilli

, Sorkness

, Taussig

, Martinez

. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med, 2006; 354:1985–1997.

10.

Murray

, Woodcock

, Langley

, Morris

, Custovic

. IFWIN study team. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet, 2006; 368:754–762.

11.

Bisgaard

, Hermansen

, Loland

, Halkjaer

, Buchvald

. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med, 2006; 354:1998–2005.

12.

Castro-Rodriguez

, Rodrigo

. Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics, 2009; 123:519–525.

13.

Roorda

, Mezei

, Bisgaard

, Maden

. Response of preschool children with asthma symptoms to fluticasone propionate. J Allergy Clin Immunol, 2001; 108:540–546.

14.

Bacharier

, Guilbert

, Zeiger

, Strunk

, Morgan

, Lemanske

Jr. , Moss

, Szefler

, Krawiec

, Boehmer

, Mauger

, Taussig

, Martinez

. Childhood Asthma Research Education Network of the National Heart Lung, Blood Institute. Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol, 2009; 123:1077–1082.

15.

Wilson

, Sloper

, Silverman

. Effect of continuous treatment with topical corticosteroid on episodic viral wheeze in preschool children. Arch Dis Child, 1995; 2:17–20.

16.

Doull

, Lampe

, Smith

, Schreiber

, Freezer

, Holgate

. Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial. BMJ, 1997; 315:858–862.

17.

Wilson

, Silverman

. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child, 1990; 65:407–410.

18.

Connett

, Lenney

. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child, 1993; 68:85–87.

19.

Svedmyr

, Nyberg

, Thunqvist

, Asbrink-Nilsson

, Hedlin

. Prophylactic intermittent treatment with inhaled corticosteroids of asthma exacerbations due to airway infections in toddlers. Acta Paediatr, 1999; 88:42–47.

20.

Bacharier

, Phillips

, Zeiger

, Szefler

, Martinez

, Lemanske

Jr. , Sorkness

, Bloomberg

, Morgan

, Paul

, Guilbert

, Krawiec

, Covar

, Larsen

, Mellon

, Moss

, Chinchilli

, Taussig

, Strunk

. CARE Network. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol, 2008; 122:1127–1135.

21.

Ducharme

, Lemire

, Noya

, Davis

, Alos

, Leblond

, Savdie

, Collet

, Khomenko

, Rivard

, Platt

. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med, 2009; 360:339–353.

22.

Robertson

, Price

, Henry

, Mellis

, Glasgow

, Fitzgerald

, Lee

, Turner

, Sant

. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med, 2007; 175:323–329.

23.

Grant

, Duggan

, DeAngelis

. Independent parental administration of prednisone in acute asthma: a double-blind, placebo-controlled, crossover study. Pediatrics, 1995; 96:224–229.

24.

Oommen

, Lambert

, Grigg

. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1–5 years: randomised controlled trial. Lancet, 2003; 362:1433–1438.

25.

Panickar

, Lakhanpaul

, Lambert

, Kenia

, Stephenson

, Smyth

, Grigg

. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med, 2009; 360:329–338.