Inhaled glucocorticosteroids in adults and children
===================================================


## Use of glucocorticosteroids in asthma

Inhaled glucocorticosteroids are the mainstay of asthma therapy and are clearly indicated in all but the mildest cases. They relieve persistent symptoms very effectively, improve lung function, decrease bronchial hyperresponsiveness and reduce morbidity caused by asthma.[1–6]

### Initiation

The treatment of airway inflammation early in the course of asthma may prevent persistent asthma, reduce asthma severity and reduce the development of chronic airflow limitation.[7–9] Therefore, patients with variable airflow obstruction, airway hyperresponsiveness or sputum eosinophilia (with objective evidence of asthma) should be given a trial of regular treatment with an inhaled glucocorticosteroid to determine whether it is beneficial and to determine the best results obtainable from this treatment. The severity of asthma can be assessed reliably only after a trial of intensive therapy has been undertaken and the best results defined.10

The treatment of exacerbations of asthma early and effectively with inhaled glucocorticosteroids will prevent them from becoming severe, will reverse them as quickly as possible and should reduce mortality and morbidity.2

### Dose

The optimum dose for initiating treatment with glucocorticosteroid in a patient who has not previously received this drug has not been studied. It is likely to vary depending on the severity of inflammation, the severity of airflow obstruction and other characteristics of the patient. Although a dose-response relation to inhaled glucocorticosteroids can be demonstrated,[11, 12] most of the therapeutic benefit is obtained at total daily doses of 1000 μg or less of beclomethasone dipropionate, and, in most patients, only very small increases in benefit are achieved at higher doses.5

There is no advantage to starting at higher rather than lower doses. The consensus group agreed that, in general, an initial dose of inhaled glucocorticosteroids is 400-1000 μg a day of beclomethasone dipropionate, divided and inhaled via a standard metered-dose inhaler (MDI). In children, an initial dose 200 μg of beclomethasone dipropionate a day using a spacer device in divided doses may be sufficient, especially if the disease is not severe and of short duration.

The additional dose of inhaled glucocorticosteroid needed to treat uncontrolled asthma in patients already receiving regular inhaled glucocorticosteroid treatment has not been examined. A 2- or 4-fold increase in the daily dose has been suggested, but this requires formal evaluation in a randomized controlled trial.

### Duration

Benefits are usually observed within days or weeks, and most of the benefit is usually observed within 3 months of initiation of inhaled glucocorticosteroid. Once the best results have been achieved, the daily dose must be reduced at intervals of 2 weeks or longer (the exact interval needs to be studied) to identify the minimum dose needed to maintain this state. The ideal objective measurements for monitoring have not been determined.

The duration of glucocorticosteroid treatment is likely to vary with the cause of the uncontrolled asthma. For example, if the cause is exposure to allergen and this exposure has subsequently ceased, the need for treatment may be brief. However, in patients with persistent asthma, prolonged treatment is associated with progressive improvement in symptoms, PEF and methacholine PC20 (i.e., the provocative concentration of methacholine required to cause a 20% fall in FEV1).[1–6] The duration of therapy required to reach maximum clinical benefit is not known and is highly variable[4, 7, 8] Whether the therapy can be successfully stopped is not known.8 This is much more likely to be possible in children and in those with mild disease.

### Suggestions for future research

• What is the optimum dose of inhaled glucocorticosteroid at which it is preferable to add a new class of medication rather than increase the dose?

• What is the duration of therapy required to obtain maximum benefit and what are its determinants?

• What is the long-term prognosis associated with intermittent as opposed to continuous use of inhaled glucocorticosteroids once the best results have been achieved?

• Can the onset of persistent asthma be prevented by early use of inhaled glucocorticosteroid in patients with bronchial hyperresponsiveness who are at high risk for clinical asthma?

• Is doubling the dose of inhaled glucocorticosteroid effective in managing acute non-life-threatening exacerbations of asthma?

## Safety issues

Inhaled corticosteroid therapy for asthma is not devoid of adverse effects, but has a much better benefit-to-risk ratio than alternative treatments, such as prednisone, theophylline or short-acting β2-agonist inhalants[2, 12] At doses of up to 1000 μg/d, the adverse effects of inhaled glucocorticosteroids may be a nuisance, but are rarely associated with significant systemic effects.[13, 14] For children the benefits and risks of inhaled corticosteroids have recently been reviewed.15

### Pregnancy and lactation

Inhaled glucocorticosteroids are not contraindicated in pregnancy, but the use of the lowest dose consistent with achieving and maintaining optimal asthma control is recommended. There is no evidence demonstrating the deposition of inhaled corticosteroids in breast milk. Inhaled glucocorticosteroids can generally be continued during lactation.

### Growth in children

Short-term growth as measured by knemometry (lower-leg growth) may be slowed with even low doses of inhaled glucocorticosteroids, but the effect on longer-term growth, if any, remains to be determined. Growth velocity has been found to be reduced in the intermediate term (6-12 months) with doses as low as 400 μg/d of beclomethasone dipropionate,16 although possibly not at an equivalent dose of fluticasone.17 No long-term randomized studies of adult stature in relation to inhaled glucocorticosteroid are available, but a retrospective cohort study did not find any effect on adult stature.18

### Oropharyngeal candidiasis and dysphonia

Reducing the total daily dose, dose frequency and oropharyngeal deposition (by using a spacer and mouth rinse) all reduce the occurrence of candidiasis. Such local complications are unusual in children.19 Antifungal therapy should be reserved for episodes of active thrush. In the case of dysphonia, reducing acute and chronic laryngeal stress may also be helpful.

### Adrenocortical insufficiency

The total daily dose, cumulative inhaled glucocorticosteroid dose and combined oral and inhaled glucocorticosteroid therapy interact to increase the risk of adrenocortical suppression.[2, 20] It is prudent to administer routinely a glucocorticoid supplement (100 mg hydrocortisone parenterally) if a patient receiving oral glucocorticosteroid therapy for more than 3 weeks in the previous 3 months suffers major trauma, surgery or a severe prostrating illness. The consensus group agreed that a blanket recommendation that all patients in such a situation, who are receiving more than 1000 μg/d of inhaled glucocorticosteroids, receive glucocorticosteroid supplementation is not justified in either children or adults. Acute adrenal insufficiency after discontinuation of inhaled glucocorticosteroids is seldom seen.

### Ocular complications

Inhaled glucocorticosteroid therapy increases the risk of cataract formation in a dose-dependent fashion.21 However, the benefits of inhaled glucocorticosteroid for asthma greatly outweigh this potential risk, especially in children for whom the risk of cataract appears very low.22 Routine ophthalmologic surveillance for posterior subcapsular cataract is not warranted in patients treated with an inhaled glucocorticosteroid. Incipient glaucoma may be exacerbated by inhaled glucocorticosteroid therapy for asthma, even at a low dosage.23 A case-control survey found an increased risk at doses greater than 1.5 mg/d of beclomethasone dipropionate or the equivalent.24 Risk did not increase with the duration of inhaled glucocorticosteroid treatment or cotreatment with intra nasal glucocorticoid. Whether the magnitude of this risk is a function of individual patient susceptibility, the choice of drug, the type of delivery device used, the inhalation technique or cotreatment with nebulized β2-agonist and anticholinergic bronchodilators is not known.25

### Osteoporosis

According to expert opinion, an estrogen supplement should be provided in postmenopausal women treated with oral corticosteroids for prolonged periods unless a positive contraindication exists.[26, 27] A dose-dependent osteoporotic effect of inhaled glucocorticosteroids has been demonstrated.[28, 29] The effect is not usually clinically important at doses less than 1.2 mg/d of beclomethasone dipropionate or the equivalent but might be if additional risk factors for osteoporosis and fracture are also present (Table 2).30

View this table:
[Table1](http://www.cmaj.ca/content/161/11_suppl_1/S24/T1)

Table 2: Clinical risk factors for osteoporosis20 

### Infection

Inhaled glucocorticosteroids should be avoided or used with due caution in asthmatic patients who may harbour a mycetoma or who have drug-resistant tuberculosis, atypical mycobacteria infection or immunosuppression. However, these are not absolute contraindications for the use of inhaled glucocorticosteroids. Isoniazid chemoprophylaxis is not routinely required in the presence of a positive delayed skin reaction to purified protein derivative unless there are other specific indications such as a contact history with an active case of tuberculosis. Appropriate preventive action in patients exposed to varicella or measles while receiving inhaled or oral glucocorticoid therapy is recommended.

### Minimizing risks

Environmental control measures should be promoted whenever prescribing any drug regimen for asthma. Mouth rinsing and expectoration after each dose can reduce systemic absorption up to 15%, although this is relevant only to inhaled glucocorticosteroids, such as beclomethasone dipropionate, that are only slightly inactivated by first-pass hepatic metabolism.31 The use of a spacer with a pressurized MDI rather than an MDI alone may reduce the total available systemic dose in some circumstances, but spacers may either decrease or increase the systemic absorption of inhaled glucocorticosteroids relative to MDI alone, depending on their design and how the patient uses the devices.32 Toogood and colleagues14 found that, if a spacer reduces the systemic activity of an inhaled glucocorticosteroid, the most likely explanation (and the safest assumption) is that it is concomitantly reducing intrapulmonary delivery of the inhaled glucocorticosteroid.

### Safety surveillance

There is a need for an automated surveillance system, possibly based on computer-monitored prescription, to document routinely each patient's inhaled and oral glucocorticosteroid use and to communicate this information to the responsible physician. Inhaled glucocorticosteroid should always be used in preference to an oral glucocorticoid, and the smallest effective dose should be used. The clinical benefits from the prolonged use of inhaled glucocorticosteroids should always be weighed against their potential side-effects. A continuing need for more than 1000 μg/d of beclomethasone dipropionate or the equivalent (with chlorofluorocarbon as a propellent) indicates a need for assessment by a specialist.

Skin thinning and bruising indicate chronic systemic glucocorticosteroid activity, but are generally not clinically important unless patients are using more than 1000 μg/d of beclomethasone dipropionate or the equivalent, especially with prednisone.32 In selected patients, morning serum cortisol level may provide additional clinically useful safety surveillance information.

If a patient beginning regular inhaled glucocorticosteroid therapy is likely to need a maintenance dose above 1000 μg/d of beclomethasone dipropionate or the equivalent, it is prudent to assess and document the presence or absence of clinical risk factors for osteoporosis and to monitor bone density according to published guidelines.[26, 27] This implies a baseline measurement by dual energy x-ray absorptiometry (DXA), follow-up measurements at appropriate intervals and, depending on the DXA results coupled with clinical considerations, the institution of appropriate drug therapy to correct or prevent bone loss. If DXA is not readily available, decisions about the need for preventative osteoporosis management must be based on the clinical risk factors summarized in Table 2.20

Routine screening for cataracts in patients taking inhaled glucocorticosteroids is not recommended as there is no evidence that early diagnosis favourably influences cataract treatment. Nevertheless, any patient who complains of impaired vision should be referred promptly to an eye specialist.32

### Suggestions for future research

• What are the benefit-to-risk ratios of the various inhaled glucocorticosteroids delivered via the inhalation devices now available?

• What is the true risk of the various reported adverse effects of inhaled glucocorticosteroids in various subgroups such as children, the elderly and postmenopausal women?

• What is the risk of clinically relevant ocular complications at moderate to high doses of inhaled glucocorticosteroids?

• What are the risks and benefits of early treatment of osteoporosis in women on high-dose inhaled glucocorticosteroids?

## Recommendations

• Inhaled glucocorticosteroids offer the best option for the initial anti-inflammatory treatment of asthma (level I).

• The initial daily dose in adults is commonly in the range of 400-1000 μg of beclomethasone dipropionate or the equivalent (Table 1); higher doses of inhaled or the addition of oral or systemic glucocorticosteroid may be required if the asthma is more severe (level III).

View this table:
[Table2](http://www.cmaj.ca/content/161/11_suppl_1/S24/T2)

Table 1: Proposed dose equivalencies for inhaled glucocorticosteroids 

• The initial daily dose of inhaled glucocorticosteroid in children should be 200-1000 μg of beclomethasone dipropionate or the equivalent; higher doses are rarely needed (level III).

• Early initiation of treatment with inhaled glucocorticosteroids in the natural history of the disease is associated with a better functional outcome (level III).

• Once best results are achieved, the dose should be reduced to determine the minimum required to maintain control (level III). This is especially true in children because they are more likely to have adverse effects but are also more likely to experience improvement or remission of their asthma (level III).

• Loss of control of asthma should be treated as early as possible to prevent exacerbation from becoming severe (level III). The dose of glucocorticosteroid required and the duration of the increase in dose depends on the severity of the exacerbation. Inhaled glucocorticosteroids must be added or increased 2- to 4-fold (level IV), or prednisone at the dose of 0.5 to 1.0 mg/kg a day (level I) must be added if the exacerbation is severe. This increased level of glucocorticosteroids must be maintained until the best results are achieved and for a minimum of 10-14 days (level III).

## Recommendations

• Inhaled glucocorticosteroids at the low and moderate doses generally required to control symptoms in asthma infrequently exhibit clinically important side-effects and provide the best risk-benefit profile (level I).

• Children who regularly require higher doses of inhaled corticosteroids (i.e., equivalent to 400 μg or more of beclomethasone dipropionate daily) should have their height measured regularly using a calibrated stadiometer (level IV). A change in growth velocity should lead to a reassessment of the therapy with emphasis on reducing glucocorticosteroid doses while maintaining adequate asthma control through environmental control and possibly the use of additional therapy.

• People who use inhaled glucocorticosteroids regularly should be encouraged to rinse and expectorate after inhalation to reduce oropharyngeal deposition and systemic absorption (level I).

• Physicians should frequently consider reducing the dose of inhaled glucocorticosteroid in patients who have achieved acceptable control of their asthma. Patients, whether children or adults, consistently requiring doses of more than 1000 μg/d of beclomethasone dipropionate or the equivalent to maintain acceptable control should be referred for specialized assessment (level IV).

• In patients with a personal or family history of glaucoma, intraocular pressures should ideally be measured within a few days of their commencing use of inhaled glucocorticosteroids, particularly if high doses are taken, and monitored at appropriate intervals (level IV).

• Patients using a pressurized inhaler should avoid depositing any of the aerosolized glucocorticosteroid in the eye. A dry powder inhaler or spacer may prevent such an occurrence (level IV).

• Bone densitometry is recommended in adult patients who require the equivalent of more than 1000 μg/d of beclomethasone dipropionate to maintain acceptable control or who have one or more risk factors for osteoporosis (level III).

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