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September - December 2004: 
Volume 17, Issue 3

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Treatment of childhood asthma: weighing available modalities
Abstract
New treatment modalities have emerged since the introduction of inhaled drugs for the treatment of childhood asthma. Theophylline preparations are practically no longer used for asthma exacerbations, as inhaled β2-agonists and ipratropium bromide are sufficient for bronchospasm relief. Many long-term studies have established the effectiveness and safety of inhaled steroids, which henceforth replaced sodium chromoglycate, a widely used prophylactic drug. Leukotriene receptor antagonists and long acting β2-agonists are appropriate add-on treatment for those children not responding to steroid monotherapy. Patient compliance, as well as inhalation technique should always be checked before stepping up to more intensive treatment. Pneumon 2004, 17(3):251-257.
Full text

Introduction

It is widely known and accepted that the incidence of childhood asthma is globally on the rise.1,2 Therefore, treatment of children with asthma is rather troublesome. In the '80s, a transition from treatments with syrups and suppositories to inhaled drugs occurred; henceforth, inhaled agents have prevailed in the treatment of asthma. In the last decade, the treatment of asthma has been directed to combinations of noted active agents, since little progress has been made in the development of new agents. Furthermore, there is still some concern regarding the effectiveness and safety of inhaled asthma drugs.

Currently, the stepwise approach to the treatment of asthma as proposed by the International Consensus in 1995 and revised in 1998 and 2002, is still in effect.3 However, recently published evidence allows for a modification in guidelines for the treatment of children with asthma.4,5

A special feature in the treatment of childhood asthma is phenotypic variation, especially in infants and pre-school children. Children developing asthma at this age may present a remission or elimination of symptoms at the age of 6 or 7 years.6 In the past, this condition has been referred to as "asthmatic bronchitis", but presently the term "viral bronchospasm" is preferred. The decision to classify these children as suffering from asthma and prescribe long-term asthma treatment according to the GINA guidelines and the US Consensus for the Management of Asthma is based primarily on clinical grounds, i.e. the presence of one major criterion, e.g. diagnosed asthma in a parent, or a child with severe eczema; or two minor criteria, which include eosinophilia, wheezing in the absence of viral infection, and allergic rhinitis.8

Bronchodilators

Bronchodilators remain first-line drugs for the management of asthma attacks and relief of daily symptoms. Short-acting β2-agonists (salbutamol and terbutaline) in all available forms of administration (aerosol, powder, nebula, syrup) still are the most significant representatives. These agents have a strong bronchodilatory effect, but do not seem to influence the inflammatory process;9 on the contrary, their regular use has been associated with increased bronchial hyperresponsivenss.10 Nevertheless, β2-agonists provide immediate symptom relief and, hence, a sense of safety to the patients, which in turn may result in overuse and delays in seeking medical attention, with probably adverse consequences.11

Long-acting β2-agonists (formoterol, salmeterol) are constantly gaining ground in the management of symptoms of childhood asthma. They bind to β2-receptors for more than 12 hours and, hence, have the ability to protect from bronchospasm and exercise-induced asthma symptoms for longer time periods. Formoterol has a fast onset of action, comparable to that of salbutamol, whereas salmeterol has a relatively slower onset of action.12 Both drugs are safe; no adverse effects have been reported from their use in children. However, the possibility of resistance after prolonged and long-term use is still under investigation.12,13

Ipratropium bromide, alone or in combination with β2-agonists, is also an established reliever medication. In combination with β2-agonists, it has a more prominent action in children compared to adults in the management of an asthma attack; therefore, ipratropium bromide is implicitly recommended, in particular for younger children.14,15

In view of the plethora of available treatment alternatives, xanthines are no longer used for the management of bronchospasm in children. However, the intravenous administration of aminophylline is still helpful in the management of severe asthma attacks not responsive to standard treatment.16

Anti-inflammatory agents

Although reversal of bronchospasm has pivotal importance in the management of bronchial asthma, agents that intervene in the inflammatory process have an essential role as well.

According to the current Consensus Guidelines, cromones (sodium cromoglycate and nedocromil) are among anti-inflammatory agents recommended for the management of mild persistent asthma.3-5 Despite their wide use for more than thirty years, however, clinical experience recently questioned their necessity. A large clinical trial compared the effectiveness of sodium cromoglycate, taken four times daily, with very-low-dose fluticasone, 50 μg once daily, in children with mild asthma. All lung function parameters measured indicated a clear superiority of fluticasone.17 Particularly poor results were obtained with the use of sodium cromoglycate as prophylactic treatment for asthma symptoms in infants.18 Furthermore, a recent meta-analysis of all studies on the efficacy of sodium cromoglycate in childhood asthma concluded that the drug is not quite effective.19 In addition, a large multinational study conducted by the Childhood Asthma Management Program Research Group (CAMP study) showed that long-term treatment with budesonide improves bronchial hyperresponsiveness and provides better asthma control compared to sodium cromoglycate.20 Taking into account the established safety of low-dose inhaled steroids and their simple dosing regimen, the limited use of sodium cromoglycate in routine practice is easily explained. Their limited use has also led to claims that the age of cromones has passed and that these drugs should be withdrawn from practice.19,21

Inhaled steroids are currently the most important and, perhaps, the only pure anti-inflammatory drugs for childhood asthma. According to the International Consensus modified Guidelines,3 low-dose treatment with beclomethasone or budesonide (200-400 μg daily), and half-dose treatment with fluticasone (100-200 μg daily) can be safely used. As demonstrated in the START study and further relevant clinical studies, treatment with inhaled steroids leads to symptom improvement, lower rates of hospital admission, and improved lung function.22-25 Many studies have shown that inhaled steroids reduce inflammation in the bronchi, and there is evidence of a limiting effect on basal membrane thickening.26

The adverse effects of long-term treatment with high-dose inhaled steroids are a highly controversial issue. Growth inhibition is held as the most common adverse effect. Long-term treatment with moderate-dose beclomethasone or budesonide causes a growth retardation in prepubertal children of 0.5-1.5 cm.27-29 Another paediatric study, however, showed that final adult height after 9.2 years of budesonide treatment with a mean dose of 412 μg daily, was normal.30 The reduction in growth velocity observed in the initial stages of treatment may be transient. Growth inhibition was not observed in preschool children treated with fluticasone 200 μg daily.31

Recent studies have shown that bone density is not influenced by long-term use of low-dose inhaled steroids.32-34 In addition, markers of bone turnover (osteocalcin, 1-carboxyterminal propeptide, hydroxyproline) are not influenced by treatment with inhaled steroids, at least with low-dose regimens; fluticasone and budesonide are, however, also safe in higher doses.34,35

Cases of acute adrenal crisis in asthmatic children aged 7-9 years treated with high-dose fluticasone (500-2000 μg/d) for five months to five years have recently been reported.36 This clinical finding was also confirmed by laboratory testing in 17% of children and adolescents taking fluticasone >1000 μg/d for more than 6 months.37 Hence, special attention is required when treating children with high-dose inhaled steroids for long periods; monitoring and progressive tapering of inhaled steroid dosage are essential.

The above-discussed evidence supports the establishment of steroids in low-dose regimens (up to 400μg/d) as first-line anti-inflammatory drugs for the management of childhood asthma.5 What should, however, be done if symptoms persist? In this case, there are three available options: addition of a long-acting β2-agonist, or addition of a leukotriene recepror antagonist, or stepping up of the inhaled steroid.

Several reports on both adults and children indicate that the addition of a long-acting β2-agonist to the inhaled steroid treatment leads to a greater improvement in FEV1 than higher-dose inhaled steroid,38 and conduces to better symptom control.39-41

One of the main advantages of the combination of these two drugs in a single inhaler is better compliance with treatment. It has further been suggested that the addition of a long-acting β2-agonist probably enhances local anti-inflammatory effects of the inhaled steroid, resulting in better asthma control with a lower dose of the inhaled steroid.42 The drawback of such combinations is resistance to long-acting β2-agonist caused by their long-term use. This may lead to a need for a higher dose of bronchodilators for the management of exacerbations.43,44

Cysteinyl-leukotrienes are pre-inflammatory mediators that have an apparently central role in both bronchospasm and the inflammatory process implicated in asthma.45 Leukotriene receptor antagonists have recently been added to the prophylactic anti-inflammatory agents available for adults and children older than 2 years.46-48 Recent evidence has demonstrated a prophylactic effect of leukotriene receptor antagonists on both daily symptoms and exercise-induced asthma.49,50 The agent that has been used with greater effectiveness in children with asthma is montelukast. Additional advantages of montelucast include once daily oral administration and minor adverse effects. This evidence argues for the use of leukotriene receptor antagonists in combination with corticosteroids for prophylaxis in children with asthma either as an alternative to stepping up, or aiming at stepping down steroid dosage.46,51 Monotherapy with leukotriene receptor antagonists for mild persistent asthma is not supported by presently available evidence.46,52

In their long historical course, xanthines have passed through periods of acceptance and periods of rejection. The potential of long-term management with low dose theophylline, on account of its anti-inflammatory action, in combination with inhaled steroids, is being lately considered.3,16 Apparently, combination therapy with theophylline and inhaled steroids has a synergistic effect on inflammation regulating gene expression, whereas long term management with low dose regimens is relieved of the known adverse effects of xanthines.16

Monoclonal antibodies against IgE have been recently used in adults with promising results. Their use was associated with a reduction in hospital admission rates and use of oral steroids, and improved symptoms, FEV1 values, and quality of life in patients with severe asthma.53,54 Similar encouraging results were reported in trials of monoclonal antibodies against IgE on children aged 6-12 years with allergic asthma under maintenance treatment with beclomethasone.55 None of the these studies reported significant adverse effects. Nevertheless, taking into account that this treatment includes monthly subcutaneous injections, whereas adequate asthma control is achieved with currently available treatment regimens in the majority of children, the use of monoclonal anti-IgE antibodies should be reserved for children with severe asthma not responsive to other treatment alternatives.

Delivery devices

Lastly, inhalation technique for delivering asthma drugs is the cornerstone of the effectiveness of asthma management. Despite the provision of instructions for the use of an inhaler, 35% of the children fail to use an inhaler correctly.56,57 Therefore, it is essential to check inhalation technique before deciding to change a prescribed regimen.

Nebulisers should never be a first line choice for drug delivery to children with asthma.58 Less than 10% of the "nominal" dose from a nebuliser is delivered to the lungs, whereas drug delivery from spacers is about three times as much.59 In addition, drug delivery from a nebuliser is time-consuming and, hence, not popular at all.60 The use of nebulisers is therefore limited to children refusing to use a spacer.

In the last decade, inhaled drugs have been established as the bedrock of the management of childhood asthma. Steroids are prime prophylactic drugs, but there is still some reserve with respect to the safety of high-dose regimens. Recently, combination treatment with long-acting β2-agonists or leukotrienes receptor antagonists, and low-dose steroids tends to displace high-dose steroid treatment in cases with persisting asthma symptoms.

 

 

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