Paediatric asthma

What is paediatric asthma?
Can Pulmicort be used in children with asthma? 
What doses of Pulmicort are normally used by children? 
Efficacy of Pulmicort on exercise-induced bronchoconstriction in children with asthma 
At what age can children start to use Pulmicort Turbuhaler? 
How can Pulmicort be administered to children with asthma? 
Is treatment with Pulmicort safe in children? 
Does Pulmicort treatment affect growth in children? 
What is the influence of asthma on growth? 
Can Pulmicort affect the symptoms of croup?

What is paediatric asthma?

Several studies have shown that in most cases of chronic, persistent asthma, the initial manifestations of disease have occurred during the first five years of life. In some cases asthma seems to disappear already at the preschool age, in other children during the prepubertal age, while some children develop a disease which will continue into adulthood. Three different distinct types of children with asthma or asthma-like symptoms have been identified (1,2):

a) Transient wheezing of infancy. These children start to wheeze during the first 1-2 years of life during viral infections, especially those caused by respiratory syncytial virus (RSV). Many of these children will have only one or a few episodes of wheezing, with no further symptoms beyond the age of 2-3 years.

b) Nonatopic wheezers. These children wheeze during viral infections in early life and continue to have recurrent airway obstruction during the early school years, but no sensitization to allergens has occurred.

c) IgE-associated wheeze/asthma. These children who develop atopy-related asthma start to have symptoms during the second and third years of life. They tend to develop chronic asthma that continues into adulthood in many cases.

Wheezing types in childhood
 

Fig. 1. Hypothetical yearly peak prevalence of wheezing for the three phenotypes in childhood. Prevalence for each age interval should be the sum of the areas under each curve. The dashed curves suggest wheezing can present different curve shapes due to many different factors, including overlap of groups. (Modified from Ref. 1)

Reference:
1. Stein RT, Holberg CJ, Morgan WJ et al.: Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997; 52: 946-952.

2. Martinez FD, Helms PJ. Types of asthma and wheezing. Eur Respir J 1998; 27: 3s-8s.

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Can Pulmicort be used in children with asthma? Several studies with Pulmicort Turbuhaler and Pulmicort Respules have been performed in children with asthma.

As an example, the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study (1) included 7241 patients. Of them 27% were 6-10 years old, and 17% 11-17 years old. Treatment with Pulmicort Turbuhaler, 200 µg once daily for children under 11 years, and 400 µg once daily for the older, was found very effective.

Several studies in young children (from 6 months of age) have been performed with the suspension for nebulisation of budesonide (Pulmicort Respules). Clear efficacy vs placebo nebulisation has been shown (2,3).

In general, children under 2 years of age can be treated with Pulmicort Respules for nebulisation, children 2-5 years of age can use Pulmicort delivered via a pMDI attached to a large volume spacer, and children aged
6 years and older can use Pulmicort Turbuhaler.

These are also the age limits generally approved by regulatory agencies in most countries for the use of Pulmicort in children.

Reference:
1. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind study. Lancet 2003; 361:1071-76 and Eur Respir J 2002; 20, suppl 38: 305s.

2. Baker JW, Mellon M, Wald J et al. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103: 414-421.

3. Kemp JP, Skoner DP, Szefler SJ et al.: Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children. Ann Allergy Asthma Immunol 1999; 83: 231-239.

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What doses of Pulmicort are normally used by children?

In general, asthma in children is mild, and doses 100 µg to 200 µg daily are mostly very effective. Very few children need 400 µg daily or higher doses. If higher doses are required the benefit/risk ratio for these doses is still better than that of oral corticosteroid doses giving the same degree of asthma control.

When Pulmicort Respules is used daily doses of 0.25 mg, 0.5 mg and 1.0 mg can be used depending on disease severity. These doses can be administered once daily or in divided doses over the day.

Reference:
1. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report. NIH Publication number 02-3659, 2002.

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Efficacy of Pulmicort on exercise-induced bronchoconstriction in children with asthma

A large proportion of children with asthma experience exercise-induced symptoms and bronchoconstriction. Exercise-induced bronchoconstriction (EIB) correlates well with the degree of nonspecific airway hyperresponsiveness measured with e.g. histamine or methacholine. Rapid-acting bronchodilators inhaled before exercise protect against airway narrowing but do not affect the underlying bronchial hyperresponsiveness. Treatment with anti-inflammatory medication should therefore be considered.

In children with mild asthma treatment with Pulmicort once daily or twice daily (see Fig.1.) significantly reduced the post-exercise fall in FEV ₁ (1).

Exercise-induced asthma

Fig.1. Mean fall in FEV 1 after treatment with budesonide once or twice daily vs placebo (from Ref. 1.)

In children with moderate-tosevere asthma and exercise-induced bronchoconstriction 100, 200 and 400 µg of Pulmicort given via a large volume spacer per day were tested. A dose-responce relationship for protection against EIB was found (Fig 2) (2). The fall in FEV1 after exercise was 55%, 26%, 20% and 10% at the end of run-in (no anti.inflammatory treatment) and after pre-treatment with 100, 200 and 400 µg of Pulmicort, respectively. 

Fig.2. Dose-response to budesonide in children with moderate and severe asthma, assessed by exercise challenge using FEV1 and FEF25-75%.

Reference:
1. Jónasson G, Carlsen K-H, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998;12:1099-1104.

2. Pedersen S, Ramsgaard Hansen O. Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 1995; 95: 29-33.

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At what age can children start to use Pulmicort Turbuhaler?

Turbuhaler is an inspiratory flow driven dry powder inhaler with an inbuilt resistance of moderate degree, which is important for the deaggregation of larger particles. The device requires a certain inspiratory effort. A peak inspiratory flow through Turbuhaler (PIF _TBH ) of 30 L/min gives an efficacy similar to that achieved when a pMDI is used correctly, but already an inspiratory flow of 13 L/min results in a clinical efficacy, although lower than that with higher flows through the inhaler (1). However, the majority of children with asthma can produce a flow of 60 L/min (Fig.1.) corresponding to that of adults with asthma (2).

In a study in 52 asthmatic children, aged 5-10 years, PIF _TBH and the inspiratory volume through Turbuhaler (IV _PIF ) were measured before, during a histamine challenge test and after inhalation of terbutaline 0.25 mg after the challenge (3,4). The children´s mean prechallenge PEF was 86.1 percent predicted, the mean lowest PEF during the challenge 61.6, and after inhalation of terbutaline 82.1 percent predicted normal. The mean prechallenge PIF _TBH was 60.4 L/min (range 41-80) and mean postchallenge PIF _TBH 57.6 L/min (range 40-81). It was found that PIF _TBH was independent of the degree of induced bronchoconstriction and that neither PIF _TBH nor IV _TBH influenced the postchallenge bronchodilator response.

From the age of 5-6 years all children can use Turbuhaler (5), which also is the lower age limit approved by regulatory authorities. Some children 3-4 years old can learn how to use Turbuhaler after having been carefully instructed.

PIF through Turbuhaler® in children
 

Fig.1. Distribution of inspiratory flows through Turbuhaler in children with asthma. (From Reference 2.)

Reference:
1. Pedersen S, Hansen O, Fuglesang G. Influence of inspiratory flow rate upon the effct of a Turbuhaler. Arch Dis Child 1990; 65: 308-310.

2. Ståhl E, Ribeiro LB, Sandahl G. Dose response to inhaled terbutaline and peak inspiratory flow through Turbuhaler in children with mild to moderate asthma. Pediatr Pulmonol 1996; 22: 106-110.

3. Nikander K, Koljonen T, Ingelin-Kuortti L, Turpeinen M. Impact of histamine bronchial challenge on asthmatic children´s peak inspiratory flow and inspiratory volume through Turbuhaler. Eur Respir J 2000; 16, suppl 31: 117s.

4. Nikander K, Koljonen T, Ingelin-Kuortti L, Turpeinen M. Peak inspiratory flow and inspiratory volume through Turbuhaler following induced bronchial obstruction in children. Am J Respir Crit Care Med 2001; 163: A851.

5. Agertoft L, Pedersen S. Importance of training for correct Turbuhaler use in preschool children. Acta Pædiatr 1998; 87: 842-847.

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How can Pulmicort be administered to children with asthma?

There are three different forms of administration of Pulmicort (budesonide for inhalation) to children with asthma:

a) children under the age of 2 years can either be treated with a nebuliser using the budesonide suspension for nebulisation (Pulmicort Respules), or use a pMDI attached to NebuChamber® or large volume spacers and face-mask.

b) children 2-5 years of age are best treated with a Pulmicort pMDI attached to a large volume spacer. Some children in this age group can use the dry powder inhaler, Turbuhaler®, or may be treated with a nebuliser.

c) from the age of 6 years children can use the inspiratory flow driven dry powder inhaler, Pulmicort Turbuhaler, which gives a significantly higher lung deposition than the two other forms of administration and thereby improving the therapeutic ratio for the medication; i.e. the ratio between wanted efficacy in the airway over the risk of systemic activity. Other treatment options are a nebuliser and a pMDI attached to Nebuchamber.

Recommended age ranges for different types of inhaler
 

Fig. 1. Recommended age ranges for different types of inhaler

Reference:
1. Ilangovan P, Pedersen S, Godfrey S, et al. Treatment of severe steroid dependent preschool asthma with nebulised budesonide suspension. Arch Dis Child 1993; 68: 356-359.

2. Wennergren G, Nordvall SL, Hedin G et al. Nebulized budesonide for the treatment of moderate to severe asthma in infants and toddlers. Acta Paediatr 1996; 85: 183-189.

3. deBlic J, Delacourt C, Le Bourgeois M et al. Efficacy of nebulised budesonide in treatment of severe infantile asthma: a double-blind study. J Allergy Clin Immunol 1996; 98: 14-20.

4. Agertoft L, Pedersen S. Importance of training for correct Turbuhaler use in preschool children. Acta Pædiatr 1998; 87: 842-847.

5. Jackson W. Nebulised Pulmicort Therapy. A scientific and practical review. Oxford, UK 1998.

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Is treatment with Pulmicort safe in children?

There are several long-term studies in children evaluating the safety of Pulmicort. In placebo-controlled trials no statistically significant differences in adverse events have been found between Pulmicort- and placebo-treated patients.

The most widely discussed possible adverse events during treatment with inhaled corticosteroids in children have been the effects on growth and on bone mineral density (BMD). A decrease in BMD could result in an increased risk for osteoporosis and bone fractures.

Agertoft & Pedersen treated 157 children with Pulmicort in doses adjusted according to disease severity (mean daily dose 504 µg) for 3 to 6 years. BMD was measured by X-ray absorptiometry. There was no significant difference in BMD between Pulmicort-treated children and those receiving non-steroid reference therapy (Fig.1).

Bone mineral density (BMD)
 

Fig. 1. Bone mineral density in 157 children treated with Pulmicort and in a reference group of children receiving non-steroid therapy for 3 to 6 years. (From Reference 1.)

In the CAMP study (Childhood Asthma Management Program) (2) there was no significant difference in bone age between children treated with Pulmicort (mean 13.7 years) and those receiving nedocromil (mean bone age 13.6 years) or placebo (mean 13.7 years). The difference between bone age and chronological age in the three groups was 0.2, 0.4 and 0.4 years, respectively. Similarly, the change in BMD did not differ significantly between the three groups (Fig. 2.).

CAMP: Bone Mineral Density in children
 

Fig. 2. Change in bone mineral density (BMD) in children treated with inhaled Pulmicort, nedocromil or placebo in the CAMP study (From Reference 2.)

Reference:
1. Agertoft L, Pedersen S. Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide. Am J Respir Crit Care Med 1998; 157: 178-183.

2. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063.

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Does Pulmicort treatment affect growth of children with asthma?

The potential effects of inhaled corticosteroid therapy on growth in children have received widespread attention. Several short-term studies using stadiometry (accurate measurements of height) have reported reductions in growth in asthmatic children treated with inhaled corticosteroids. Similarly, short-term studies using knemometry (a sensitive measure of lower leg growth) have shown reductions in growth rate at medium doses of Pulmicort. It is now recognized, however, that these short-term studies are of limited value predicting the effects of long-term treatment with inhaled corticosteroids, for several reasons.

a) growth rate in normal children is variable over short periods of time
b) asthma itself affects growth (see Paediatric asthma: What is the influence of asthma on growth?)
 c) growth rate vary in different phases of childhood, which makes extrapolation of results from one age group to another impossible
d) clinically relevant safety data should be obtained from studies in which the dose of inhaled corticosteroid is tailored to the severity of asthma.

In longer-term studies with inhaled corticosteroids the effect on growth has been most marked at the beginning of treatment (1). There is clear evidence from studies with budesonide that catch-up growth occurs following this initial decrease in growth rate (2,3).

Because of the conflicting results between short-term and intermediate-term clinical studies it is obvious that long-term study results are required showing the final height of children treated with inhaled corticosteroids. Such results have been obtained in an continuing long-term study involving 332 children with asthma (4), of whom 300 were treated with Pulmicort at doses titrated according to disease severity. To date 142 budesonide-treated children have reached their adult height. The mean daily dose of Pulmicort in these children has been 412 µg and the duration of treatment has ranged from 3 to 13 years (average 9.2 years). There was no significant difference between the final height attained by these children and their predicted final height (see Fig. 1.)

Final height
 

Fig.1. Relationship between final adult height and predicted adult height in 142 asthmatic children treated with Pulmicort for an average of 9.2 years at a mean daily dose of 412 µg (range 110-877 µg).

In a cross sectional study in Sweden it was also found that adolescents with asthma treated with Pulmicort attained normal final height (5).

Reference:
1. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled corticosteroids. Arch Dis Child 1998; 78: 172-173.

2. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343: 1054-1063.

3. Turpeinen M, Nikander K, Pelkonen A, Syvänen P, Sorva R, Raitio H, Malmberg P, Juntunen-Backman K, Haahtela T. Daily versus as-needed inhaled corticosteroid for mild persistent asthma. The Helsinki Early Intervention Childhood Asthma Study. Archives of Disease in Childhood 2007(online first 18 July; 20 pp).

4. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343: 1064-1069.

5. Larsson L, de Verdier MG, Lindmark B, Norjavaara E. Budesonide-treated asthmatic adolescents attain target height: a population-based follow-up study from Sweden. Pharmacoepidemiol Drug Saf 2002;11(8):715-20.

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What is the influence of asthma on growth?

Asthma as a disease itself - not as a disease treated with inhaled corticosteroids - has a delaying effect on growth, although asthmatic children appear to grow for a longer time than non-asthmatic children and eventually attain their predicted final height (1). This effect may be due to a delaying effect of asthma on the onset of puberty. Children with poorly controlled asthma also tend to grow less than children with a well-controlled disease.

Recent epidemiological studies have shown that the difference in attained adult height between asthmatic and non-asthmatic populations, although usually small, can be approximately 1-2 cm in patients with severe asthma (2,3).

Reference:
1. Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986; 61: 1049-1055.

2. Norjavaara E, Gerhardsson de Verdier M, Lindmark B. Reduced height in Swedish men with asthma at the age of conscription for military service. J Pediatr 2000; 137: 25-29.

3. Norjavaara E, Gerhardsson de Verdier M, Lindmark B. Adult height in women with childhood asthma - a population-based study. Pharmacoepidemiol Drug Safety 2001; 10: 121-125.

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Can Pulmicort affect the symptoms of croup?

The most frequent cause of acute inspiratory stridor in early childhood is acute viral laryngotracheobronchitis, also called croup. Systemic steroids have been widely used in the treatment of croup and a meta-analysis of nine randomized studies with 1,126 children supported the use of corticosteroids in hospitalized but unintubated children (1).

Husby et al (2) used nebulized budesonide. They treated 32 children with
1 mg Pulmicort Respules with a 30-min interval, or with placebo in a randomized, double-blind study. Two hours after the start of treatment there were clinically significant improvements in stridor, cough, and total croup scores in the steroid-treated group compared with placebo (see Fig.1).

Godden et al (3) performed a double-blind, placebo-controlled study across the entire spectrum of children admitted to hospital with croup, regardless of initial croup severity. There were 87 patients (89 admissions) aged 7 months to 9 years. The children received 2 mg Pulmicort Respules (4 ml) or nebulised placebo (4 ml) every 12 hours throughout admission. The main outcome variables were the duration of in-patient stay and croup scores at 30 minutes, 1, 2, 4, 12 and 24 hours. Treatment with Pulmicort was associated with a 33% reduction in hospital stay. Statistically significant reductions in croup scores were observed at 12 and 24 hours. Treatment with Pulmicort Respules thus appears to be effective for the whole range of children admitted to hospital with croup.

Budesonide in croup
 

Fig.1. Total symptom scores at baseline and 2 hours in the study by Husby et al. (From Ref. 2.)

Reference:
1. Kairys SW, Olmstead EM, O´Connor GT. Steroid treatment in laryngotracheitis: a meta-analysis of the evidence from randomised trials. Pediatrics 1989; 83: 683-693.

2. Husby S, Agertoft L, Mortensen S, Pedersen S. Treatment of croup with nebulised steroid (budesonide): a double-blind, placebo controlled study. Arch Dis Child 1993; 68: 352-355.

3. Godden CW, Campbell MJ, Hussey M, Cogswell JJ. Double blind placebo controlled trial of nebulised budesonide for croup. Arch Dis Child 1997; 76: 155-158.

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