Asthma is more common, more dangerous, and more treatable than is generally realized. In western countries it is the most common medical cause of physician visits and hospitalizations among
children(1). Many of these unfortunate children live restricted, miserable lives because of their disease. While it is felt that asthma is in- creasing in incidence and severity in the population, it is also true that asthma therapy is getting better, with advances in our understanding of the disease itself, and better application of technology to therapy of this formidable disease.
It is now well accepted that asthma is an inflammatory disease of the airways, and that the bronchoconstriction that gives rise to dyspnea is but a sequel to the inflammatory process. The hallmark of asthma is an abnormally high reactivity of the airways to a variety of stimuli. This heightened reactivity, known as bronchial hyper-responsiveness, is present in children with asthma
even during times when they are free of
symptoms(2), and manifests itself as bronchoconstriction in response to a variety of stimuli, leading to the symptoms of asthma. Bronchial hyper-responsiveness increases during viral respiratory infections, following exposure to pollutants, allergens and chemicals, and following administration of beta-receptor antagonists.
Along with this understanding of asthma as an inflammatory disease has come a shift in the focus of treatment from bronchodilation only to the use of drugs that reverse and prevent the airway inflammation(3). It is no longer ,considered sufficient to treat the episodes of respiratory distress as and when they occur, except in very mild cases. Children with asthma too have the right to a normal and happy child- hood, and the aims of asthma therapy today(4) (Table I) reflect our recognition of that right.
Conventionally, each acute episode of asthma is treated as and when it besets the child. This approach leads to the child having many attacks of asthma each year, loss of school days, and the child viewing himself as sick. Also, the fear of these episodes leads to many restrictions being put on the child, leading to an unhappy lifestyle. We therefore need treatment strategies that prevent the occurrence of acute episodes and restore normal lung function, in turn leading to a feeling of good health and restitution of a normal lifestyle.
"Prophylactic" Medications
Since some amount of inflammation and bronchial hyper-responsiveness is present in all children with asthma, long term therapy is reasonable(5). The most popular medications today for prophylactic use are the glucocorticosteroids
and sodium cromoglycate. Sodium cromoglycate is known to reduce the frequency of acute attacks in children with asthma, but is not effective in all children.
Glucocorticosteroids are the most effective anti-inflammatory drugs in use today. They prevent late asthmatic responses
and
allergen-induced increases in airway irritability, and cause significant improvement in airway responsiveness(6). Oral glucocorticosteroids have been used for several decades now in the treatment of asthma, but their use was restricted due to fear of the adverse effects.
TABLE I
Aims of Therapy of Childhood Asthma
|
1. To control symptoms, including nocturnal
symptoms, and allow children to lead a full and normal
life at home and at school, including full participation in sports.
2.
To restore normal lung function.
3.
To minimize the requirement for relief medication.
4. To enable normal growth and development.
5.
To avoid adverse effects of medication. |
Cromoglycate and glucocorticosteroids do not provide any bronchodilation, and
thus do not give the patient any symptomatic relief. To be
effective, they require long term administration. If taken on a
regular basis, they are able to prevent, or reduce the frequency
of, acute exacerbations. For these reasons, these drugs are
considered to be prophylactic agents in the management of asthma, though they do not prevent the development of asthma.
Theophylline has been used for several decades for the control of chronic asthma in children too young to take inhaled therapy, and has been effective. However, it has a number of side effects which make it undesirable for use when safer drugs are available.
Inhaled Glucocorticosteroids
Inhaled glucocorticosteroids have been described as the greatest advance in respiratory
therapeutics since the discovery of the anti-tubercular drugs(7).
Their introduction has made it possible to provide
relief to a large number of children with asthma who would otherwise be denied the advantages of long-term anti-inflammatory therapy because of fear of adverse effects. Inhaled glucocorticosteroids fill the need of those patients whose disease is insufficiently controlled by traditional bronchodilator therapy, but do not have a problem severe enough to warrant the risks of systemic steroid therapy(8).
Inhaled glucocorticosteroids are lipophilic drugs. Since they are nonwater-soluble, they are not rapidly removed or absorbed from the lungs(9). The small amounts of the drug that are absorbed from the oral mucosa are largely metabolized to inactive forms during the first passage through the liver. These properties give inhaled glucocorticosteroids a high degree of safety in clinical use.
The exact mode of action of these drugs is as yet not fully known, but they act on various components of the inflammatory process in asthma. They inhibit the release of chemical mediators from macrophages and eosinophils, and thus inhibit the late asthmatic response and suppress bronchial
hyper-responsiveness. Inhaled glucocorticosteroids are more effective than oral glucocorticoids in reducing bronchial hyper-responsiveness, probably owing to action on cells close to the airway lumen(10). This reduction in bronchial hyper-responsiveness reduces broncho-constriction in response to histamine, allergens, irritants, cold air and exercise. The abnormal bronchial hyper-responsiveness continues to improve for many months on inhaled glucocorticosteroid therapy, but may never return to normalcy(11).
Glucocorticosteroids stabilize membranes of inflammatory cells, inhibit neutrophil and eosionophil chemotaxis, and reduce mediator release from inflammatory
cells. They also induce synthesis of lipomodulin, and thereby inhibit the formation of prostglandins, leukotrienes and thromboxanes. By reducing production of the mast cell-trophic lymphokine, Interleukin-3, glucocorticosteroids reduce the number of mast cells(10). They also inhibit plasma exudation and mucus secretion in inflamed airways.
Biopsy studies in asthma have shown an increased numbers of goblet cells, with a corresponding decrease of ciliated cells, leading to
increased secretions and de- creased protective function. There are also
increased numbers of dendritic cells, which are active in antigen presentation and stimulation of T-cells. These changes are seen even in patients with mild asthma. Inhaled glucocorticosteroids cause a down- regulation of the number of dendritic cells and goblet cells in the airways. They also reduce the inflammatory cell infiltrate in the bronchial walls, most importantly the numbers of eosinophils in the lamina propria and epithelium.
Inhaled glucocorticosteroids are effective in very young children too. Even infants with asthma have been shown to derive benefit from inhaled glucocorticosteroids given by nebuliser. However, nebulisers are an inefficient means of giving inhaled glucocorticosteroid therapy, as a very small proportion reaches the lungs(12-15).
Why Use Inhaled Glucocorticosteroids?
Inhaled glucocorticosteroids are of great benefit m children with asthma. They are the most effective therapeutic agents known today in returning the deranged lung functions of asthma towards normal. Children receiving inhaled glucocorticosteroids have higher peak flows, both morning and evening, and the need for bronchodilator "rescue" treatment is
reduced, signifying better control of the disease. Regular use of inhaled glucocorticosteroids has been found to reduce the number of acute asthma hospital admissions.
Since the pathophysiology of asthma appears restricted to the airways, it is logical to use topical treatment. Inhaled glucocorticosteroids provide local effect of the drug with low systemic delivery. Coupled with their property of low systemic absorption and high first-pass hepatic metabolism, this gives inhaled glucocorticosteroids
a high therapeutic ratio by minimizing side-effects(12).
Inhaled glucocorticosteroids can provide a substantially better quality of life
for children with asthma. The ability to attend school regularly,
to participate in games, sports and other childhood activities,
the ability to sleep through the night, and the child's
self-esteem are all restored by the initiation of this
prophylactic therapy. Better control of asthma usually also translates into better growth.
Beyond their beneficial effects on symptoms and pulmonary functions, the inhaled glucocorticosteroids probably improve the long term outcome of childhood asthma by reducing chronic inflammation. It is known that longstanding inflammation of the air- ways can progress to fibrosis, which makes the airway narrowing irreversible. Decline of lung function, which is typical of asthma, is slowed by the use of inhaled glucocorticosteroid therapy(11). This may be the most valuable action of inhaled glucocorticosteroid therapy.
Inhaled glucocorticosteroids can reduce the need for systemic steroids in children with severe asthma who are dependent on them. In some children, it may be possible to withdraw systemic steroids entirely, thus sparing them a multitude of side
effects.
Though it may be possible to control symptoms with as needed or
regular use of inhaled bronchodilators, this is not the optimal management from a long term point of view. A child who requires frequent bronchodilator therapy has significant airway inflammation, and anti-inflammatory drugs are the logical choice. Bronchodilators
do not affect the underlying inflammation, and may mask the severity of the disease by relieving the symptoms. They probably allow greater exposure to allergens, irritants and other environmental triggers, causing further inflammation and exacerbating the disease(10). This may have been .the cause of the increase in asthma deaths some years ago when regular bronchodilators and home nebulisers were in vogue for the management of chronic asthma(16). If a child requires bronchodilator therapy more than two or three times a week, cromo-glycate or inhaled glucocorticosteroids
should be added. It is inappropriate to add another
bronchodilator(6), despite the popularity of such combination
products.
Indications for Inhaled Glucocorticosteroids
The very mildest asthma consists of infrequent episodes, which are treated with bronchodilators. The child is well between such episodes, never misses school because of asthma, and is able to participate in all age-appropriate physical activities. Pulmonary functions are normal between acute attacks, and the child has a more or less normal lifestyle. Such children require bronchodilator therapy on an as-needed basis.
Moderate asthma consists of symptoms on more than two days a week, with coughing and wheezing. The child has infrequent, more severe attacks, that require urgent treatment. The child coughs or
wheezes easily on exercise, and is unable to participate in games and sports because of reduced exercise tolerance. The pulmonary functions are abnormal even during periods when the child is asymptomatic, the diurnal peak flow rates showing a variability of more than 20%. There is school absence on account of asthma several times each year. Such children have reached a level of airway inflammation that requires regular anti-inflammatory
therapy(1). Long term treatment for a child should be commenced when her ability to perform nor- mal daily
activity such as going to school, playing with friends, or sleeping through the night is affected.
The drug of first choice has traditionally been sodium cromoglycate, due to its lack of side effects. Sodium cromoglycate remains
the safest drug used in the management of asthma. It should be tried for at least six weeks before concluding failure(16). Inhaled glucocorticosteroids
should be considered for any child fulfilling one or more of the criteria (Table II) inspite of receiving cromoglycate therapy.
Children with chronic, severe asthma form another group that will benefit enormously from the use of inhaled glucocorticosteroids. These children have almost continuous symptoms, pulmonary function values are often less than 60% of predicted, and peak flow rate diurnal
variations are as much as 30%. These children often have limited activity, miss school frequently, and require hospitalization off and on(17). In the past, many of these children were treated with systemic steroids, and suffered the various adverse effects of steroid therapy. Inhaled glucocorticosteroids
can bring about a reduction in the requirement of oral steroids, and in some cases the oral steroids can be stopped altogether(18).
TABLE II
Indications for Inhaled Glucocorticosteroid Therapy
|
Any of the following, in a child receiving cromoglycate regularly.
1. Symptoms, or the need for bronchodilators, several days a week.
2.
Frequent nocturnal wheezing or coughing. At least one asthma attack a month.
3. Failure of lung function to return to normal between attacks.
|
Inhaled glucocorticosteroids do not penetrate well when there is severe narrowing
of the bronchi, and have no role in the treatment of acute, severe
asthma(7,19). These emergencies require the use of systemic steroids, preferably parenterally.
Some children become refractory to the inhaled beta-2 agonists
they have been using for years. Glucocorticosteroids prevent and reverse the downregulation of pulmonary
β-agonist receptors, and are the only drugs currently used for
asthma that can reverse the airway constriction and obstruction in
these patients(20). The administration of steroids brings about a quick return to bronchodilator responsiveness.
Which One?
There are several glucocorticosteroids available for use by the inhalational route. The well known ones are beclomethasone, budesonide, flunisolide, fluticasone and triamcinolone. They are all effective topically, and at low doses, have few serious adverse effects. Only the first two are available in India. Experience with these agents over the years suggests that none is truly superior to the other(9,10). The technique of inhalation, the choice of an age-appropriate device, and attention to compliance are of more importance than the choice among the inhaled glucocorticosteroids.
Beclomethasone has been in clinical use
for over two decades now, and the experience with budesonide is almost as much. They have both been found to be equally effective at conventional doses, with a similar side effects profile.
Fluticasone is an inhaled glucocorticosteroid that has been shown to be effective at half the dose required with beclomethasone and budesonide. In a trial on children comparing it with beclomethasone, it was. found to produce less adrenal suppression when used at half the dose of beclomethasone(21). It has been found to provide swifter and greater improvement in. lung function than budesonide when given at the same dose(22). Like other steroids this drug also causes adrenal suppression and slowing of growth when given at higher doses(23). This drug may become available in India in the near future.
Availability
Beclomethasone is available as metered dose inhalers releasing 50,100, and 200
micrograms per actuation. It is also available as dry powder inhaler capsules containing 100 and 200 micrograms. The other inhaled glucocorticosteroid available in India at present is budesonide, which is available as a metered dose inhaler which delivers 100 micrograms per actuation. These drugs are also available in combination with beta-2 agonists. Such combinations are not recommended by any authority.
The use of a metered dose inhaler requires co-ordination between inspiration and actuation. This
is usually not possible for children under the age of ten years.
Studies in adults have shown that as many as fifty per cent were
unable to use a metered dose inhaler efficiently, and two-thirds preferred to use dry powder inhalers. Self-actuated metered dose inhalers are also available, which discharge the dose
of
the drug when the patient inspires. How- ever, young children tend to close the glottis at the moment of actuation(4), and children under the age of seven are often un- able to derive adequate benefit from these devices.
Dry powder inhalers contain the drug in powder form which is sucked up by the patient's own inspiratory effort. Thus, these devices do not require any co-ordination and can be used by children over the age of five years. Dry powder inhalers contain lactose or glucose as a vehicle, which can irritate the respiratory mucosa and give rise to cough. The dry powder needs to be suspended in the inspiratory airflow to properly reach the airways. Devices such as the Rotahaler require an inspiratory flow of 90 liters per minute to achieve this(4), a flow rate that young children may not be able to generate.
Dose and Duration
It is not always possible to fine tune the dose of inhaled glucocorticosteroids, be- cause they are available as metered dose inhalers or dry powder inhaler capsules dispensing a fixed amount of the drug, which cannot be varied. Initially the drug should be given as one or two puffs four times a day, and switched to twice daily administration when the symptoms are controlled. During episodes of exacerbation of asthma with poor control, it is helpful to return to three or four times a day administration.
The inhaled glucocorticosteroids are effective in very small doses because of very high topical potency. A dose of 400 micrograms per day of beclomethasone has the same therapeutic effect as 10 to 12.5 mg of oral prednisolone(8), with only a fraction of the adverse effects potential. Current evidence suggests that doses up to 400 micrograms per day are safe in childhood from
the point of view of systemic adverse effects(10,11,24,25).
Moderate asthma can be adequately controlled in most children at doses of 100 to 600 micrograms per day. At this dose, the child may also have improvement in morning and evening PEFRs and reduction in use of beta-2 agonists. Increasing the dose does not provide an improvement in these parameters(26).
When initiating treatment, it is better to start with a higher ,dose, and then reduce the dose after control is achieved(4). For safety reasons, the dose should gradually be reduced to the lowest level compatible with acceptable control of asthma. Doses below 400 micrograms per day are rarely associated with side-effects. Increasing the dose is necessary if the response is inadequate, but side effects become significant at doses above 600 micrograms per day of either beclomethasome or budesonide(27), probably with very little added benefit. The highest benefit-risk ratios are achieved at lower doses of inhaled glucocorticosteroids(25).
Once started, inhaled glucocorticosteroids should be continued for a pro-longed period. Over a period of several months, reductions in dose can be carried out. Most children will eventually be able to maintain good asthma control on about a third of the dose they originally started with, and a few may be able to stop the drug entirely. Withdrawal of the drug should only be tried when there has been little or no need for bronchodilators for several months.
Adverse Effects
Inhaled glucocorticosteroids are relatively new additions to clinical therapeutics, and long term safety is an important concern, especially since they usually need
to be taken for several months, if not years. Though they have a high therapeutic ratio,
they are not 'totally free of side effects. Like all steroid therapy, inhaled glucocorticosteroids too have the potential. for serious complications.
Adrenal suppression and growth retardation are well known adverse effects of prolonged systemic glucocorticosteroid therapy, but are rare with inhaled glucocorticosteroid therapy due to the low doses used, and the poor systemic absorption. The toxicity of these drugs can be attenuated by the use of an appropriate device, adherence to precautions, and using the minimum effective dose.
Inhaled glucocorticosteroids produce some topical adverse effects that are
unique to this form of therapy. The two most common local side effects are oral candidiasis and dysphonia. Oral thrush occurs in about one per cent of children on regular therapy(9,28), and can be easily cured by stopping therapy, or applying oral nystain suspensions. Dysphonia
is much less common and is thought to be due to a weak- ness of the laryngeal adductor muscles. These local side effects can be reduced by using a spacer with the metered dose in- haler. Dry powder inhaler users can derive the same protection by rinsing the mouth after inhalation.
There is no evidence that inhaled glucocorticosteroid therapy causes bronchial epithelial atrophy or thinning, bronchial infections, or increased pulmonary infections, even after many years(2,8,10).
Various inhalational devices deposit different proportions of the drug in the oropharynx, to be later swallowed. Most of this is inactivated by first-pass metabolism in the liver. The drug that is deposited in the lungs is absorbed gradually, and reaches the systemic circulation directly,
bypassing the liver, This is believed to contribute to the systemic side-effects seen with high-dose inhaled glucocorticosteroid therapy.
The most feared side effects of inhaled glucocorticosteroid therapy are adrenal and growth suppression. Besides these, cataracts(29,30) have also been reported infrequently, usually in patients who also have received intermittent systemic steroids. Osteoporosis is a known and worri-some
complication of steroid therapy in adults. A study that followed
children receiving 400 to 800 micrograms of inhaled glucocorticosteroids per day for periods of more that two years found no effect on bone metabolisin(31). It is speculated that the difference from adults is due. to the different metabolism of growing bone.
Growth Suppression with Inhaled
Glucocorticosteroids
It is not very clear what effect inhaled glucocorticosteroids have on growth in children with asthma, partly because the disease itself delays puberty and curtails growth. One study found no effect on growth in adolescents given 600 micrograms per day of budesonide(32). Another study in children with severe and poorly controlled asthma found no reduction in growth velocity on addition of inhaled glucocorticosteroid therapy at a median dose of 800 micrograms per day(33). This study also found that the major determinant of growth velocity was the degree of control of the disease.
Doses in excess of 600 micrograms per square meter per day can
cause a temporary slowing of lower leg growth. Studies following children receiving 400 micrograms beclomethasone dipropionate per day for three to five years have found no effect on growth(28). Doses of 800 micrograms per day of inhaled budesonide were
found to reduce lower leg growth velocity, when given to older children. This effect was not seen at lower doses of 400 and 200 micrograms per day(24). However, the growth suppression with 800 micrograms per day of inhaled budesonide is less than that with 2.5 mg of oral prednisolone per day(17), so there should be no reservation in prescribing inhaled glucocorticosteroids as a replacement for systemic steroids.
It is not clear what effect inhaled glucocorticosteroid therapy has on final adult height. Some studies have found that final adult height was not affected by steroid therapy(34), suggesting catch-up growth after stoppage of therapy. It is also important to remember that the high doses that can affect growth are only used in severe asthma, which itself has a growth suppressing effect.
Adrenal Suppression with Inhaled Glucocorticosteroids
Inhaled glucocorticosteroids do pro- duce adrenal suppression at high doses. Studies have found them to reduce serum and urinary levels of cortisol, and to blunt the adrenal response to stress. Any child receiving the equivalent of 8 micrograms per Kg per day of beclomethasone or more, or an equivalent dose of any other inhaled glucocorticosteroid, should be considered to be potentially adrenal suppressed(17). These children may require steroid support during stressful situations such as surgery, trauma, or major illnesses. The adrenal suppression persists for several months
after stoppage of the drug.
Importance of Spacers
When a metered dose inhaler is used for drug delivery, only about ten per cent of the drug reaches the lungs. The other ninety per cent is deposited in the mouth and eventually swallowed. When a spacer
is used with the metered dose inhaler, the large particles are deposited on the walls of the device. Spacers reduce the velocity of particles before they reach the mouth. Also, more of the propellant evaporates, so that the particles become smaller and penetrate deeper into the airways(4). As a result of all these actions the inspired fraction of the drug may increase to twenty per cent(35). Perhaps more importantly, sixty per cent of the drug is deposited inside the spacer, and only about twenty per cent is deposited in the oropharynx, reducing the side effects considerably. In a recently reported study, 47 per cent of children using beclomethasone directly from a metered dose inhaler had adrenal suppression compared to 8 per cent using a spacer device(36). A metered dose inhaler with spacer is today considered the best choice for children, keeping both effectiveness and safety in mind. This is especially so when high doses of inhaled glucocorticosteroids are to be used.
After actuation of the metered dose inhaler into the spacer, the child should immediately take a few breaths, sufficient to open and close the valve each time. Children over the age of two can be taught this technique. Children less than two years of age can also use a metered dose inhaler with a spacer fitted with a mask. The spacer should be washed frequently, to prevent build up of a static electricity charge on the walls, which can reduce the amount of drug reaching the lungs.
Compliance Issues
Non-compliance is common because patients do not get any symptomatic benefit from these drugs. They are often given up as being ineffective, unless some time is given to explaining the concept behind the use of these drugs. The parents should know that beneficial effects may not become evident for a week or more.
As with all inhalational therapy, attention to technique and proper selection of the device to prescribe are very important. While it is established that a metered dose inhaler with a spacer device gives the best drug delivery with minimum systemic-absorption, the scientifically most correct choice may sometimes have to be passed
over in favour of patient or parent preference. In general, dry powder inhalers are easier to use than metered dose inhalers. Spacers are difficult to carry around, in contrast to the dry powder inhalers, which come in convenient pocket-sized boxes, with space for the capsules. Whatever the device chosen, the technique must be demonstrated repeatedly, and checked at
each consultation.
Inhaled glucocorticosteroids have been found to be effective when given twice a day(8), in patients whose asthma is well- controlled. As with all other medication, compliance improves with less frequent dosing. More frequent dosing should only be prescribed during times of exacerbation, or in those few patients who do not do well on twice daily dosing.
Many patients do not take these drugs because of fear of side effects. These issues need to be discussed in detail, and the risk-benefit profile of uncontrolled asthma, as well as that of frequent courses of "rescue" systemic steroids, should be communicated to the parents.
Conclusion
Children die of asthma. We are used to thinking of asthma as a troublesome disease that doesn't go away, but it is essential
to remember that it is a serious disease with life-threatening consequences, if inadequately treated. Patients on inhaled glucocorticosteroids therapy have been shown to have considerable protection from mortality(37).
We must keep in mind that asthma is a serious disease with grave morbidity, potential for mortality, and significant effect on growth and quality of life. Inhaled glucocorticosteroids
offer satisfactory control of the disease and a good risk-benefit ratio. These drugs also offer a better quality of life to children with asthma, and, under proper supervision, can be used with safety and greatdinical benefit.
Now that it is fairly well established that inhaled glucocorticosteroid therapy
is safe in low doses, there should be no second thoughts in cases
of moderate asthma not achieving good control with other therapy.
Severe asthma is a dangerous entity, with a much higher mortality than asthma as a whole(10). Children with severe asthma sometimes require inhaled glucocorticosteroids in doses that are in the range of possible toxicity, but the risk of adverse effects must always be weighed against the dangers of uncontrolled asthma. The balance of evidence available today indicates that there is no reason to avoid this extremely effective therapy when appropriately indicated.
