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Figure 1 Chemical structure of hydrocortisone (cortisol) demonstrating the features common to all glucocorticoid molecules.

Table 1 Common Systemic Corticosteroids: Modifications to Basic Corticosteroid Structure and Relative Potencies

Drug

Modifications

Relative potency

Hydrocortisone Prednisolone

Methylprednisolone

Dexamethasone

Triamcinolone

Prednisone (prodrug)

Double bond between carbons 1 and 2 Double bond between carbons 1 and 2 Methyl group at carbon 6 Double bond between carbons 1 and 2 Flourination of carbon 9 Methyl group at carbon 16 Double bond between carbons 1 and 2 Flourination of carbon 9 Hydroxyl group at carbon 16 Substitution of ketone group for hydroxyl group at carbon 11a

"Requires metabolism of 11-ketone group to 11-hydroxyl group for conversion to its active form (Prenisolone).

Systemic bioavailability following administration of such enteric-coated preparations in patients with asthma has not been fully studied although there is some evidence to suggest that absorption is delayed (5), more erratic (6), and affected to a greater extent by the presence of food (7). Prednisone is absorbed at a similar rate to prednisolone undergoing rapid first-pass metabolism in the liver to convert the ketone group at carbon 11 to a hydroxyl group. In general, absorption and bioavailability of systemic corticosteroids does not appear to be significantly affected by age, smoking, or the presence of disease (7).

Corticosteroids are distributed as free molecules and also bound to the proteins transcortin, albumin, and ax-acid glycoprotein. Transcortin has a particularly high affinity for prednisolone, while other corticosteroids such as methylprednisolone and dexamethasone preferentially bind to albumin (8). Protein binding is concentration dependent such that at high concentrations there is a relatively greater free corticosteroid fraction. This leads to greater plasma clearance at high doses and an apparent increase in the volume of distribution (9), one factor leading to the non-linear pharmacokinetics observed with prednisolone (10). The free, unbound corticoste-roid molecules are thought to be responsible for the effects of these drugs, and differences in the relative concentrations of free and bound corticoste-

Table 2 Important Drug Interactions with Systemic Corticosteroids

Impaired clearance of corticosteroids with increased risk of adverse effects Oral contraceptive pill Ketoconazole Cyclosporin

Accelerated clearance of corticosteroids with reduced therapeutic effects Rifampicin

Anticonvulsants: carbemazepine, phenobarbital, and phenytoin Increased risk of hypokalaemia Amphotericin High dose ß2-agonists Theophylline Diuretics roids may account for the differences in clinical effects observed between patients treated with similar doses. While corticosteroids are metabolized in the liver, chronic liver disease does not appear to significantly alter the effects of systemic corticosteroids, since glucuronidation is maintained even in the face of advanced hepatic failure (2). A number of drugs given in addition to corticosteroids lead to inhibition of microsomal liver enzymes, resulting in impaired clearance and the potential for greater adverse effects. Conversely, drugs such as anticonvulsants may result in accelerated corticosteroid clearance due to induction of liver enzymes (2) (Table 2).

While the effect of systemic corticosteroids on circulating eosinophils and glucose is observed within minutes, improvements in airflow obstruction occur much later. Following a single dose of oral prednisolone, a significant improvement in lung function can be seen at three hours, reaching a maximal effect between 9 and 12 hours (11). Animal models have suggested that the administration of higher doses results in an increase in the duration of action rather than improvements in the maximum response (12) and support the suggestion that smaller doses given frequently may be preferable to larger single doses (13).

It has been suggested that abnormalities of steroid pharmacokinetics may account for the apparent lack of response to systemic corticosteroids in some individuals. Studies in patients with severe asthma, however, have shown relatively little variability in prednisolone absorption, distribution, and clearance between individuals (14). Nevertheless, pharmacokinetic studies may have a useful role in the clinical evaluation of individual patients with chronic corticosteroid-dependent asthma to identify abnormalities in absorption or clearance (15), and serum prednisolone concentrations interpreted alongside plasma cortisol levels may give useful evidence of non-compliance in patients failing to respond to treatment.

III. Mechanisms of Action

A. Effects at the Molecular Level

Circulating corticosteroid molecules cross the cell membrane to bind to the glucocorticoid receptor a located in the cytoplasm in a protein-bound form. The corticosteroid-receptor complex then translocates to the nucleus, where it binds to sequences of DNA in the promoter region of steroid-sensitive genes, known as the glucocorticoid response element (GRE). Such binding leads to alterations in the transcription of target genes (16). Corti-costeroids also bind to coactivator molecules, which also activate gene transcription by activating histone deacetylase. These mechanisms result in the activation of a number of genes encoding anti-inflammatory proteins, including annexin-1, interleukin-10, and secretory leukoprotease inhibitor (17). The major anti-inflammatory effects of corticosteroids are thought to result from the suppression of genes that code for inflammatory proteins, but the precise mechanism is not fully understood since GREs have not been widely demonstrated in the promoter regions of inflammatory genes that are known to be suppressed by corticosteroids in asthma (17). Recent work has suggested that suppression of the transcription of inflammatory genes may occur via the modification of core histones, e.g., by histone deacetyla-tion, resulting in disruption of chromatin structure (17,18). Whatever the precise mechanism, a wide range of inflammatory genes appear to be suppressed, including cytokines (e.g., IL-4, IL-5, IL-13, TNF-a, and GM-CSF), chemokines (e.g., IL-8, RANTES, and eotaxin), adhesion molecules (e.g., ICAM-1, VICAM-1, and E-selectin), and a number of other inflammatory enzymes and receptors. This broad effect on a number of components of the anti-inflammatory pathway appears key to the therapeutic effects of corticosteroids in asthma, since more selective agents have not had the same success (19).

B. Effects at the Cellular Level

As a result of the molecular interactions outlined above, corticosteroids have a range of effects on inflammatory cells in asthma, including a reduction in the number of eosinophils, T lymphocytes, mast cells, and dendritic cells. The inhibition of key cytokines, including IL-5 and GM-CSF, leads to increased eosinophil apoptosis (20) and a dramatic reduction in eosinophil survival. Mediator release from eosinophils is also directly inhibited and circulating eosinophil numbers may be reduced by a direct action on the production of eosinophils in the bone marrow. Corticosteroids are also able to inhibit the proliferation of T lymphocytes and their cytokine production, particularly of the T-cell growth factor IL-2 (21,22). In contrast, corticosteroids do not appear to inhibit neutrophilic inflammation and actually increase circulating numbers of neutrophils, possibly by preventing neutrophil apoptosis (23).

Systemic corticosteroids also have important effects on structural components of the asthmatic airway. These include inhibition of the release of cytokines and mediators from epithelial cells (24), prevention of plasma leakage through vascular endothelium (25), and reduction of mucous secretion from airway mucosal glands (26). Additionally, important effects on airway smooth muscle may occur via the suppression of inflammatory mediator release and also by the up-regulation of the number of ^-adrenoceptors in individuals with p2-agonist-induced desensitization (27,28).

IV. Clinical Effects in Asthma

A. Anti-inflammatory Effects

That systemic corticosteroids are thought to exert their therapeutic effects in asthma largely by suppressing airway inflammation has already been discussed. Perhaps surprisingly, there is rather more convincing evidence supporting the anti-inflammatory effects of inhaled rather than systemic corticosteroids in individual patients with asthma.

The few bronchoscopy studies evaluating the anti-inflammatory effects of systemic corticosteroids in vivo have not had entirely consistent results. In a double-blind, placebo-controlled study, Djukanovic et al. (29) studied the anti-inflammatory effects of prednisolone at a dose of 20 mg for two weeks followed by l0 mg for four weeks. Compared to placebo, treatment with prednisolone lead to significant reductions in submucosal eosinophils (by 81%) and mast cells (by 62%). Significant improvements in asthma symptoms and FEV1 were also seen. In similar studies, Robinson et al. (30) and Bentley AM et al. (31) randomized 18 patients with moderately severe asthma to 0.6mg/kg/day of prednisolone or placebo for two weeks and took bronchial biopsies before and after treatment. Compared to placebo, predni-solone resulted in reductions in the number of cells expressing mRNA for IL-4 and IL-5 and an increase in IFN-g expressing cells in bronchial biopsies and bronchoaleveolar lavage, although the interpretation of this data is complicated by significant baseline differences in these markers between the placebo and prednisolone treated groups. Prednisolone treatment lead to a fall in the number of CD3+ T cells, eosinophils, and mucosal-type mast cells in bronchial biopsies and in BAL eosinophils, but only the latter differed significantly from placebo.

The development of noninvasive markers of airway inflammation, particularly induced sputum eosinophil counts and exhaled nitric oxide (NO), has provided further opportunities to assess the anti-inflammatory activity of asthma treatments, but again few studies have used oral corticosteroids. Claman et al. (32) performed a randomized, placebo-controlled, doubleblind study of the effects of six days of treatment with prednisone 0.5 mg/ kg/day in 24 patients with chronic stable asthma. Compared to placebo, prednisolone lead to significant reductions in the percentage and absolute numbers of eosinophils in induced sputum and in sputum eosinophil cationic protein (ECP) levels. These changes correlated with significant increases in peak expiratory flow. Other studies have shown similar changes in sputum eosinophil and ECP levels with both inhaled and oral corticosteroids (33,34). Pizzichini et al. (35) demonstrated a significant reduction in sputum eosinophils and ECP levels in 10 patients treated with oral predni-sone for a severe asthma exacerbation, although a placebo group was not included for ethical reasons. The improvements in sputum eosinophils and ECP levels began 48 hours after treatment (and correlated with increases in FEV1) while symptoms, lung function, and blood eosinophil and ECP levels improved more quickly, within 24 hours of treatment.

Systemic corticosteroids have also been shown to reduce the elevated exhaled NO levels seen in asthma (36,37), although a number of subjects demonstrate persistently elevated NO levels despite treatment with oral prednisolone (38,39). This suggests that some aspects of the underlying airway inflammation seen in asthma are resistant to systemic corticoste-roids, at least in subgroups of patients, although the dose and route of administration may be important. A recent study by ten Brinke et al. (40) showed that the intramuscular use of triamcinolone acetate was associated with marked suppression of induced sputum eosinophilic airway inflammation in patients who had persistently elevated sputum eosinophil counts despite high doses of inhaled and/or oral corticosteroids. We have found similar results in patients with oral corticosteroid-dependent asthma attending our clinic, where sputum eosinophil counts significantly improved in all patients given intramuscular triamcinalone.

While systemic corticosteroids clearly do not completely remove airway inflammation in asthma and heterogeneity to their anti-inflammatory response occurs, the overall evidence from clinical studies does support the theory that these agents exert their therapeutic effects largely by suppressing airway inflammation, particularly eosinophilic inflammation. This leads to the suggestion that exposure to the potential toxic effects of systemic corticosteroids should be confined to patients who have uncontrolled eosinophilic airway inflammation despite treatment with inhaled corticosteroids, and there is some evidence to support this. We have previously identified a group of non-eosinophilic patients with symptomatic asthma and have associated the absence of sputum eosinophils with a poor response to short-term treatment with inhaled corticosteroids (41). Little et al. (36) have similarly demonstrated that the response to a two-week course of oral prednisolone in patients with chronic stable asthma is greatest in those patients with evidence of airway inflammation demonstrated by raised sputum eosinophil counts or elevated NO concentrations. The presence of a sputum eosinophilia has also been found to predict the short-term response to oral prednisolone in patients with chronic obstructive pulmonary disease (42).

Finally, we have recently reported the results of a randomized, controlled trial of a management strategy that aimed to normalize the induced sputum eosinophil count using appropriate doses of inhaled and oral corticosteroids in patients with moderate to severe asthma (43). Compared to traditional management following British Thoracic Society guidelines, treatment directed at minimizing eosinophilic inflammation resulted in significantly fewer severe asthma exacerbations and hospital admissions. The dramatic improvement occurred despite similar overall corticosteroid doses between the two groups. In effect, in the sputum guided group, treatment was targeted to those patients with eosinophilic inflammation to prevent exacerbations, while systemic corticosteroids were required in the control group to treat exacerbations. Additionally, a subset of patients with predominantly non-eosinophilic airway inflammation was identified and in this group corticosteroids were successfully withdrawn without loss of asthma control. This study identifies sputum eosinophilia as a marker of exacerbation frequency in asthma and emphasizes the close relationship between the beneficial effect of corticosteroids and the presence of eosinophilic airway inflammation.

B. Effects on Airway Hyper-Responsiveness (AHR)

Airway hyper-responsiveness (AHR) is one of the characteristic clinical features of asthma leading to variable airflow obstruction and asthma symptoms. While AHR generally occurs along with airway inflammation, it is becoming increasingly clear that the relationship between inflammation, AHR, and clinical expression of the disease is complex. This is supported by the identification of a group of patients with eosinophilic bronchitis who have a similar corticosteroid responsive immunopathology to that seen in asthma with sputum and submucosal eosinophilia, basement membrane thickening, and increased Th2 cytokine expression, but unlike asthma is characterized by the absence of AHR (44,45). Evidence from a recent study comparing the immunopathology of eosinophilic bronchitis with asthma has suggested that microlocalization of mast cells within the airway smooth muscle is the key abnormality associated with AHR in asthma (45). It cannot therefore be assumed that systemic corticosteroids attenuate airway hyper-responsiveness in asthma via their anti-inflammatory effects. The effect of systemic corticosteroids on AHR has been assessed in a number of studies.

Bhagat and Grunstein (46) compared the effect of a one-week course of prednisolone to placebo in 10 children with atopic asthma. Prednisolone resulted in significant improvements in AHR measured as the PD20-FEV1 to methacholine, which were not seen with placebo. The improvement in PD20-FEV1 correlated with increases in the FEVl, and the greatest improvements were demonstrated in those with lower values of FEVl before treatment.

Similar improvements in AHR in adults treated with oral prednisolone have lead to somewhat conflicting results. In a study of 12 patients with well-controlled asthma, no improvements in methacholine PC20 were observed eight hours after a single dose of intravenous methylprednisolone or after eight days treatment with oral methylprednisolone (32 mg daily) (47). Jenkins and Woolcock performed a randomized, double-dummy, singleblind, cross-over study comparing the effects of three weeks treatment with inhaled beclomethasone diproprionate (BDP) 1200 mg daily with oral prednisolone 12.5 mg daily in 18 adults with asthma. No significant changes in histamine PD20 were seen with prednisolone, while inhaled BDP lead to an approximately 2.5 doubling dose improvement (48). In the bronchoscopy study of Djukanovic et al. (29) discussed earlier, subjects treated with oral prednisolone demonstrated significant improvements in methacholine PC20 but these did not differ from placebo. In contrast, the study of Robinson et al. (30) demonstrated a fourfold increase in methacholine PC20, which was significant compared to placebo. This improvement occurred despite the fact that the fall in submucosal eosinophil numbers was not significantly different from placebo, again supporting the idea that disordered airway physiology in asthma is disassociated from eosinophilic inflammation.

Meijer et al. (33) measured AHR to both methacholine and adenosine 5' monophosphate (AMP) before and after two weeks of treatment with three corticosteroid regimes: 2000 mg/day of inhaled fluticasone, 500 mg/ day of inhaled fluticasone, and 30 mg/day of oral prednisone. Changes in serum and sputum eosinophils and ECP levels were also assessed. Mean PC20 methacholine and PC20 AMP improved significantly with all three treatment regimes, but the improvements following prednisolone were significantly lower than with high-dose fluticasone. In contrast, oral predniso-lone had a significantly greater effect on suppression of peripheral blood eosinophils and ECP than either dose of inhaled steroid. Greater improvements in PC20 AMP compared to PC20 methacholine were seen for all three treatment regimes, possibly reflecting differences in the timescale of the response to corticosteroids at different parts of the inflammatory cascade. Oral prednisolone and high-dose fluticasone had similar effects on sputum eosinophils and ECP in this study, and further analysis showed that the improvement in AHR significantly correlated with reductions in sputum eosinophil counts, particularly the PC20 AMP (49).

Overall the results of these studies highlight the complexity of the relationship between airway inflammation and AHR in asthma and suggest that the dose-response to corticosteroids varies between the different outcome parameters.

C. Effects on Acute Exacerbations of Asthma

Systemic corticosteroids are widely accepted as essential in the management of patients presenting with acute severe exacerbations of asthma, and failure to prescribe them in this situation has been identified as a risk factor for asthma deaths (50). The first randomized, controlled trial of systemic corticosteroids in patients admitted to the hospital with acute severe asthma reported significant improvements in symptoms, respiratory rate, heart rate, and airflow obstruction in patients given a reducing dose of cortisone acetate compared to those treated conventionally (with subcutaneous adrenaline, inhaled isoprenaline, oxygen, antibiotics, and sedatives)

(51). These initial findings have been confirmed by a number of subsequent studies. A double-blind, placebo-controlled comparison by Loren et al.

(52) compared treatment with prednisolone 2mg/kg/day to placebo in 16 patients presenting with an acute asthma exacerbation. Patients given prednisolone required less nebulized or intravenous p2-agonist and demonstrated significant improvements in PEF compared to placebo-treated patients. Fanta et al. (53) performed a double-blind, placebo-controlled study of intravenous hydrocortisone (given as a 2 mg/Kg bolus followed by an infusion of 0.5 mg/kg/hr for 24 hours) in 20 patients who had persistent symptoms and signs of an acute severe asthma exacerbation despite eight hours of conventional treatment. Steroid-treated patients had significant improvements in lung function compared to placebo, although the improvements were not seen until 12 hours after the onset of treatment (FEV increase 118± 25% from baseline compared to 35± 22% with placebo). Littenberg and Gluck (54) performed a similar placebo-controlled study of a bolus of 125 mg intravenous methylprednisolone, given in addition to standard treatment, in 97 patients presenting to the emergency room with acute severe asthma. While a nonsignificant trend in greater improvements in FEV1 among the steroid treated patients was seen, significantly fewer patients treated with methylprednsiolone required admission to the hospital for further treatment (19% vs. 47%, p < 0.003). A contrasting study by Stein and Cole (55) was unable to demonstrate a reduction in the number of patients requiring hospital admission following treatment with an identical dose of intravenous methylprednisolone compared to placebo. The reasons for this negative finding are not obvious, but measurements of lung function were not performed, and the study included a requirement to admit patients when treatment time exceeded 12 hours.

The route of administration and dose of systemic corticosteroid in the management of acute severe asthma have been a source of debate, particularly since side effects such as myopathy are more likely to occur with high-dose regimes (56). An early study by Haskell et al. (57) suggested that 40 or 125 mg of intravenous methylprednisolone was associated with better improvements in lung function than low-dose treatment (15 mg methylprednisolone). A number of subsequent studies, however, have failed to confirm this finding (58-60). One problem is that the majority of studies of this kind have been confined to a small number of patients, and a recent meta-analysis of nine randomized, controlled trials comparing different doses of corticosteroids in adults hospitalized for acute severe asthma was undertaken (61). This pooled analysis of over 300 patients concluded that doses of systemic corticosteroids in excess of 80 mg/day of methylprednisolone (equivalent to 400 mg of hydrocortisone or l00 mg of prednisolone) offered no therapeutic benefit. Further subgroup analysis suggested that oral treatment was as efficacious as the intravenous route, although data was included from only two studies (62). Overall the evidence suggests that low-dose oral treatment will be sufficient for the majority of patients presenting with acute severe asthma, although none of the studies have included patients presenting in respiratory failure, and intravenous treatment may be warranted in a subgroup at risk of failure of absorption via the oral route, e.g., due to vomiting.

Following hospitalization due to acute severe asthma, patients are at significant risk of relapse with one study estimating that 45% of patients relapse by eight weeks following discharge (63). A number of studies have therefore addressed the use of systemic corticosteroids in the prevention of subsequent relapse. Chapman et al. (64) recruited 93 patients discharged from the emergency room following treatment for acute severe asthma and randomized them to receive either a tapering course of prednisolone (from 40 to 0 mg over eight days) or placebo. Compared to placebo, the prednisolone-treated group had significantly fewer symptoms and less use of rescue bronchodilators during the first week and had a significantly lower rate of relapse (3 of 48 compared to 11 of 45, p < 0.05). A number of other studies have shown similar results, both for short courses of oral prednisolone (65,66) and for intramuscular corticosteroid (67). A meta-analysis of the available studies concluded that as few as 13 patients needed to be treated with systemic corti-costeroids on discharge to prevent relapse requiring additional emergency care (68). There is little evidence to support the theory that the dose of corticosteroid should be slowly tapered with studies showing that the abrupt cessation of treatment after 7 to 10 days does not lead to a rebound deterioration in symptoms or airflow obstruction (69,70). It is generally recommended that the precise treatment regime be tailored to the individual patient; in some cases longer courses of systemic corticosteroids may be needed.

D. Effects in Chronic Asthma

The highly effective anti-inflammatory properties of inhaled corticosteroids mean that the vast majority of patients with asthma achieve adequate control without the need for systemic corticosteroid treatment, except perhaps for the occasional severe exacerbation. The introduction of inhaled corti-costeroids enabled many patients with chronic asthma to stop or dramatically reduce their dose of oral treatment (71,72). A small number of patients, however, have persistent symptoms, airflow obstruction, and/or recurrent severe exacerbations of asthma despite the use of high-dose inhaled corticosteroids and additional therapy such as long-acting |b2-agonists, methylxanthines, and leukotriene modifiers. In this group of patients the regular use of maintenance doses of oral corticosteroids requires careful consideration in view of the unfavorable therapeutic ratio. There are surprisingly few studies supporting the use of maintenance oral corticosteroids in these circumstances, with placebo-controlled evidence dating back to the original Medical Research Council trial (51). This was a randomized, placebo-controlled study in 96 patients with chronic symptomatic asthma comparing the effects of oral cortisone acetate at a dose of 300 mg/day, reducing to l00 mg/day after one week then tapered according to clinical need. Attempts were made to withdraw treatment after 24 weeks. Compared to placebo, patients receiving cortisone had fewer symptoms and physical signs, better exercise tolerance, and were less likely to be withdrawn from the study due to poor asthma control (73). Despite this, few patients in either group were able to withdraw their study medication, and by three months the differences in the two groups were no longer significant. The majority of cortisone-treated patients experienced side effects, most commonly weight gain, hypertension, and edema.

Subsequent clinical studies have largely compared the use of maintenance oral corticosteroids with alternative anti-inflammatory treatments, particularly inhaled corticosteroids. The British Thoracic and Tuberculosis Association published the results of a double-blind, placebo-controlled, cross-over study comparing the effects of oral prednisolone with the inhaled steroids BDP and betamethasone valerate in 75 patients with mild to moderate asthma, with a 24-week treatment period. Prednisolone was started at a dose of 20 mg daily, reducing by 5 mg weekly until asthma control was lost, while inhaled corticosteroids were given initially at 800 mg daily, reducing in a similar fashion by 200 mg weekly. Upon loss of asthma symptom control, treatment was increased again until a dose that lead to satisfactory control was achieved. Prednisolone 7.5 mg daily achieved equivalent asthma control to 400 mg of inhaled corticosteroid in the form of number of ''failure days'' (defined as a day on which regular treatment needed to be increased or < 4 puffs of rescue bronchodilator was needed), mean monthly PEF, and percentage of patients requiring an increase in treatment or rescue oral prednisolone. Around 30% of patients receiving systemic treatment reported steroid-related side effects (e.g., weight gain, edema, and dyspepsia) compared to none receiving inhaled treatment. A number of other, smaller studies of shorter (two to four weeks) duration have reported similar findings suggesting that oral prednisolone 7.5-12 mg/day appear to be as effective as 300-2000 mg/day of inhaled beclomethasone or equivalent (74-77). These studies have been the subject of a Cochrane review (78), although differences in study design have precluded a formal meta-analysis.

It has been suggested that where maintenance systemic corticosteroids are required an alternate-day regime may provide sufficient therapeutic benefit while minimizing adverse effects (79). This recommendation appears to be based on an early study by Harter et al., which assessed various oral corticosteroid dosing schedules and concluded that single doses given at 48hour intervals resulted in adequate asthma control with minimal side effects (80). This study predated the widespread introduction of inhaled corticosteroids, however, and it has subsequently been reported that inhaled corticosteroids appear to be more effective than alternate-day doses of prednisolone up to 60 mg (78,81), in contrast to the findings with daily regimes. Furthermore, there is no evidence to support the suggestion that a significant reduction in side effects is seen with intermittent dosing (82).

A further option for the systemic administration of corticosteroids in chronic asthma is the use of intramuscular triamcinolone acetate. A small number of randomized, controlled trials support its use in this setting. McLeod et al. (83) performed a double-blind, cross-over study in 17 patients with chronic severe asthma comparing triamcinolone 80 mg IM with prednisolone l0 mg daily, each drug given for 24 weeks. Asthma symptom scores, lung function, need for rescue prednisolone, and weight gain were all significantly better in the triamcinolone-treated group, although side effects, particularly adrenal suppression, bruising, and hirsuitism, were reported more commonly. Similar findings were reported by Willey et al. (84). Higher doses of triamcinolone were used in the study of Ogirala et al. (85) Here 12 patients with chronic oral corticosteroid-dependent asthma undertook a randomized, double-blind, cross-over study comparing triamcinolone 120 mg daily for three days with oral prednisolone at a median dose of 12.5 mg daily. Treatment with triamcinolone resulted in significant improvements in peak expiratory flow, emergency room visits, and hos-pitalizations than oral prednisolone, although side effects again tended to be more common. The results of this study have been criticized, however, since the use of inhaled corticosteroids was not reported, and since patients were encouraged to taper their treatment, including the trial tablets, when they felt that their symptoms were well controlled. This has raised the question that patients may have been under-treated during the oral corticoste-roid treatment period, although one could argue that the tapering of treatment during a period of apparent stability reflects the behavior of many patients in routine clinical practice. The available data, along with the clear anti-inflammatory effects of intramuscular triamcinolone (40), do support a role for its use in a small number of patients who are for some reason unable to tolerate or absorb oral corticosteroids or who fail to comply with prescribed regimes, although the risk of side effects must be carefully considered. Further prospective studies in this area are required.

V. Safety

A. Adverse Effects

As in other chronic inflammatory diseases the major limitation for the use of systemic corticosteroids in asthma is their propensity for potentially serious adverse effects. Since all nucleated cells have glucocorticoid receptors, a wide range of complications affecting most organ systems can occur. The frequency of such complications in asthma is difficult to determine due to a lack of reliable studies, and there is little evidence to suggest that the profile of adverse effects in asthma differs from that seen in other cortico-steroid-dependent diseases. Those that are a frequent cause of morbidity in patients with asthma requiring systemic corticosteroids are discussed below, and a more comprehensive list of potential adverse effects is given in Table 3.

Osteoporosis

The frequency of osteoporosis in chronic systemic corticosteroid use is thought to be similar to that seen in Cushing's disease at around 30% to 50% (86). The effects appear to depend on both the cumulative dose and duration ofuse, with highest rates of bone loss within the first six months of treatment (87). Fracture risk declines rapidly on stopping treatment but may not return to baseline. Alternate-dose regimens have been advocated but do not prevent accelerated bone loss (88). It has been suggested that doses of < 7.5 mg prednisone or equivalent may be safe (86), but this is controversial since accelerated rates of bone loss have been described in patients with additional risk factors (such as postmenopausal status) taking lower oral doses (89) and with inhaled corticosteroids (90). It has been suggested that corticoste roids contribute to an increased fracture risk over and above their effects on bone mineral density with higher risks of fracture than are seen in postmenopausal osteoporosis (91). A retrospective cohort study comparing almost a quarter of a million oral corticosteroid users in the United Kingdom with age- and sex-matched controls calculated relative risks for vertebral fractures in patients taking oral corticosteroids at a daily dose of < 2.5 mg prednisolone of 1.55 (95% CI 1.20-2.01) rising to 5.18 (CI 4.25-6.31) at doses of 7.5 mg or greater (92).

Corticosteroids predispose to osteoporosis via a range of mechanisms on calcium and bone metabolism. Gastrointestinal absorption of calcium is impaired and renal calcium excretion increased leading to secondary hyper-parathyroidism and subsequent bone resorption. Further effects occur via the suppression of pituitary and anabolic sex hormones. Additionally, cor-ticosteroids directly reduce bone formation by inhibition of osteoblast proliferation and synthesis of Type I collagen and other proteins (93). In adults these mechanisms preferentially result in loss of trabecular bone, predisposing them to spinal and rib fractures.

All patients requiring long-term systemic corticosteroids should be given general advice to reduce bone loss, including good nutrition, adequate dietary calcium, appropriate physical activity, and minimization of tobacco use and alcohol abuse (87). Supplementation with calcium and vitamin D should be considered for all patients receiving long-term corticosteroids since several randomized, controlled trials have shown that this strategy

Table 3 Potential Adverse Effects Associated with Systemic Corticosteroid Treatment

Metabolic Hyperglycaemia Weight gain Hyperlipidaemia Hypokalaemia

Endocrine

Suppression of growth in children Adrenal suppression Cushingoid habitus Amenorrhoea

Musculoskeletal

Osteoporosis

Myopathy

Aseptic necrosis of bone

Ophthalmological

Cataracts

Glaucoma

Psychological and central nervous system

Altered mood

Insomnia

Psychosis

Pseudotumor cerebri Immunological

Reduction of circulating immunoglobulins

Reactivation of previous infection including latent tuberculosis

Cardiovascular

Hypertension

Edema

Gastrointestinal

Gastric ulceration and hemorrhage Pancreatitis

Dermatological Acne

Increased skin fragility Subcutaneous tissue atrophy Impaired wound healing can significantly reduce and even reverse bone loss (94-96). Calcium alone does not have a similar protective effect (96). Measurements of bone mass using dual X-ray absorpiometry (DEXA) should be considered to assess fracture risk and is recommended by some groups (97). Bone-protective therapy should then be offered to all patients shown to have low-bone mineral density and bone mineral density measurements repeated on an approximately annual basis. The use of bone-protective therapy for all patients at high-fracture risk (e.g., aged over 65 years or with past history of fragility fracture) regardless of baseline bone densitometry is an alternative approach (87). Studies have suggested that in postmenopausal women, hormone replacement therapy (HRT) prevents bone loss in those receiving low to moderate doses of systemic corticosteroids (98). No studies, however, have demonstrated similar efficacy in those requiring higher dose treatment or have evaluated the role of HRT in preventing bone loss at the initiation of corticosteroid treatment. Furthermore, there have been recent concerns over the association between HRT and increased rates of breast cancer and other diseases (99,100). Several large randomized, controlled trials have shown that the bisphosphonates etidronate, alendronate, and risedronate are effective in both the prevention and treatment of corticosteoid-induced osteoporosis (101-103). While fracture prevention was not a primary end point of any of these trials, post hoc and safety analyses have suggested that each of these agents leads to a reduction in vertebral fracture (95,102,104). The data for pamidronate and clodronate are less consistent (105,106). Cal-citonin has been suggested as an alternative bone-sparing agent but needs to be given via the intranasal and subcutaneous route and studies of its effect have been inconsistent (107,108). Bisphosphonates used in conjunction with calcium and vitamin D supplements are therefore probably the treatment of choice for the prevention and treatment of osteoporosis in the majority of patients requiring long-term systemic corticosteroids.

Myopathy

Prolonged treatment with moderately high doses of systemic corticosteroids is associated with the development of a chronic myopathy, predominantly affecting the proximal limb muscles. The weakness tends to develop gradually and may be accompanied by reduced respiratory muscle force. The incidence of this complication has not been clearly evaluated but in one study a degree of muscle weakness was observed in over 60% of patients with asthma taking at least 40 mg of prednisone per day, but was almost never seen in patients taking less than 30 mg a day (56). No correlation between the degree of muscle weakness and biochemical markers, including muscle enzymes and urinary creatinine excretion, was seen in these patients, and there is currently no reliable biochemical test to confirm the diagnosis. A number of case reports have described the development of an acute-onset severe generalized myopathy in patients admitted to the hospital with acute severe exacerbations of asthma (109,110). The majority of patients developing this complication had been intubated for a near fatal attack and had received both parenteral corticosteroids and muscle relaxants. Recent cohort studies have estimated that of patients undergoing mechanical ventilation for severe asthma, around 30% of those treated with both corticosteroids and a neuromuscular blocking agent develop acute myopathy compared to between 0% and 10% in those who receive corticosteroids alone (111,112). Very high levels of skeletal muscle enzymes associated with diffuse skeletal muscle necrosis may be seen, although the exact mechanism is unclear (109). Patients may require extensive rehabilitation over several months before fully regaining muscle function.

Adrenal Suppression

It is well recognized that systemic oral corticosteroids lead to suppression of the adrenal cortex, with a significant dose-related reduction in morning cortisol (77,113). This may lead to isolated central adrenal insufficiency with prolonged suppression of the hypothalamic-pituitary axis but normal adrenal function or, in more severe cases, complete suppression of the hypothalamic-pituitary-adrenal axis (114). Patients tend to present in a nonspecific manner and adrenal insufficiency should therefore be considered in all patients receiving at least 5mg of prednisone or equivalent per day. Confirmation of the diagnosis requires the demonstration of subnormal cortisol levels that remain low despite adrenal stimulation and should be treated with adequate glucocorticoid replacement therapy. The risk of adrenal suppression increases with increased steroid potency, and there is some evidence to suggest that taking corticosteroids only on alternate days may reduce the risk of adrenal suppression (115).

All patients requiring long-term systemic corticosteroid therapy should be considered at risk of adrenal insufficiency and advised to increase their usual maintenance dose to cover intercurrent illnesses or surgery (116). Recent evidence suggests that relatively low doses of additional corticosteroid will prevent adrenal crises (117), and even that simply continuing the maintenance dose on the day of surgery is sufficient (118). The risk of adrenal insufficiency persists up to 12 months after cessation of systemic corticosteroids (119). It is thought that a protocol of slow tapering of the corticosteroid dose minimizes the risk of adrenal crisis, but controlled trials comparing this approach to abrupt steroid cessation following prolonged steroid use have not been done.

Cataracts

Prolonged use of systemic corticosteroids is an important risk factor for the development of posterior subcapsular cataracts (120). Cataracts were reported in 18% of respiratory patients requiring long-term corticosteroids compared to 8% of matched controls in one recent study (121). It is not clear whether the risk of cataracts is dose dependent (122), and it has been suggested that a subset of patients may be particularly susceptible (123).

The mechanism by which corticosteroids predispose to cataract formation is unknown and treatment requires surgical removal of the lens.

B. Interaction with Other Drugs

A number of other drugs may affect the pharmacokinetics of corticosteroids, increasing the potential for adverse effects and in some circumstances reducing the therapeutic response. Common drug interactions are given in Table 3.

C. Special Situations

Children

The main concern when using systemic corticosteroids in children is the risk of suppression of linear growth. Even small daily doses of 2.5-5 mg of prednisolone per day given to children with mild asthma over periods as short as two weeks have been associated with growth suppression in children with asthma (124). Systemic corticosteroid naive children with asthma are also at risk of growth retardation. Chang et al. (125) studied over 230 asthmatic children and found that those who had never received oral corticosteroids or who had been given only occasional rescue courses had an average height of around one standard deviation lower than their age- and sex-specific predicted means. Children treated with oral corticosteroids for two years or more had a mean height of two standard deviations lower than predicted (125). No difference was seen between children treated with an alternate day or daily corticosteroid regime, although other studies have suggested that inhibition of growth may be less with an alternate-day regime (126,127). The mechanisms of linear growth suppression are poorly understood but may be analogous to those leading to osteoporosis in corticosteroid-treated adults. Aside from growth delay, children may be particularly susceptible to the other corticosteroid-related side effects outlined earlier. Adrenal suppression, for example, has been observed in 20% of children receiving four or more short-rescue courses of oral corticoste-roids per year for asthma exacerbations (128). Children are particularly vulnerable to the development of posterior subcapsular cataracts, which occur at lower corticosteroid doses than in adults (129) and have been seen after only six months of systemic treatment (122). As in adults, prolonged treatment with systemic corticosteroids should be recommended only where absolutely necessary and where a clear clinical benefit can be demonstrated (see recommendations).

Pregnancy and Breastfeeding

Approximately 10% to 15% of pregnant women with asthma experience at least one acute exacerbation requiring emergency treatment (130). Concern over the safety of oral corticosteroids in pregnancy has at times resulted in a reluctance to prescribe oral steroids in this setting (131). Numerous studies, however, including a large case-control study of over 20,000 subjects, have shown no association between the use of systemic corticosteroids in pregnancy and adverse fetal events, including congenital malformation (132,133). Findings of an early animal study that raised questions over the development of cleft palate (134) have not been confirmed in humans (132). The results of one case-control study, which did report a possible link between oral corticosteroid use and cleft lip, are seriously limited by flaws in study design (135) and an alternative analysis of the data does not support a positive association (136). Both severe asthma and systemic corticosteroids have been associated with an increased risk of maternal pre-eclampsia (137,138). Finally, a recent multicenter, prospective study of over 2000 patients with asthma found that the use of oral steroids during pregnancy was associated with both preterm delivery [odds ratio (OR) 1.54, 95% CI 1.02-2.33] and low birth weight < 2500g (OR 1.8, 95% CI 1.13-2.88), even controlling for asthma severity (139). Despite this, the major risk to both mother and fetus during pregnancy comes from inadequate treatment of severe asthma, and pregnancy should never be a contraindication to the use of systemic corticosteroids in asthma (82).

There is no evidence to support the theory that maternal systemic cor-ticosteroid use leads to adrenal suppression in the fetus (140). Similarly, the incidence of maternal adrenal suppression is unknown, although guidelines suggest that intravenous hydrocortisone should be administered during labor to women receiving prednisolone of more than 7.5 mg daily for more than two weeks in view of the theoretical risk (82). Concentrations of corticosteroids in the breast milk of mothers treated with systemic steroids are very low, and there are no clinically important risks to breastfed infants (141).

VI. Recommendations

A. Systemic Corticosteroids in the Management of Acute Severe Asthma

Systemic corticosteroids are essential in the management of asthma exacerbations. Current guidelines recommend that they be given in all but the mildest of exacerbations (defined as a prompt response to inhaled |b2-agonists resulting in a PEF of > 80% of predicted or best after one hour) (142). Unless there are problems of absorption or recurrent vomiting, oral administration is as effective as the intravenous route, although intramuscular injections may be considered where compliance is in doubt yet hospital admission is not required (141,143). Daily doses of 40-50 mg of prednisolone, 60-80 mg of methylprednisolone, or 400 mg of hydrocortisone (l00 mg every six hours) are recommended for adults and l mg/kg/day for children (82,141). Systemic corticosteroids should be continued until recovery and, therefore, the optimum duration of treatment should be tailored to the individual, although at least five days is usually needed (82). Providing inhaled corticosteroids are given, abrupt cessation of treatment is appropriate except in the few patients receiving prolonged courses of oral corticosteroids (82).

B. The Management of Chronic Oral Corticosteroid-Dependent Asthma

Where adequate control of symptoms, airflow obstruction, and/or recurrent exacerbations cannot be achieved with inhaled corticosteroids and bronchodilators, maintenance doses of oral corticosteroids may be considered. Given the narrow therapeutic window and potential severity of adverse effects we suggest that a number of steps be made before systemic corticosteroids are recommended in this way. First, failure to respond to conventional treatment, including inhaled corticosteroids, should always prompt a review of the accuracy of the asthma diagnosis. Objective confirmation of a diagnosis of asthma may be particularly difficult in this group since it is often difficult to withdraw treatment such as high-dose broncho-dilators, the presence of which may limit the interpretation of physiological tests. Nevertheless, stringent attempts at demonstrating variable airflow obstruction should be made using peak expiratory flow monitoring, spiro-metry before and after bronchodilators and/or oral corticosteroids, and measurements of AHR to methacholine, histamine, or exercise (141). The demonstration of airway inflammation using induced sputum and/or exhaled nitric oxide (NO) may also be helpful, although no test is specific to asthma. Alternative diagnoses should be rigorously excluded in patients with a lack of objective evidence of asthma coupled with a poor response to inhaled treatment.

Second, even where objective confirmation of asthma is obtained, consideration of additional comorbidities should be given since current symptoms may not be due to asthma. Thus, the presence of dysfunctional breathlessness, gastroesophageal reflux, rhinosinusitis, nasal polyposis, bronchiectasis, and other additional pathologies should be identified and appropriately treated. Inhaled corticosteroids are less effective in cigarette smokers (144) and smoking cessation advice should be given. Third, non-concordance to inhaled treatment should be considered, although this may be difficult to identify. This may arise for a number of reasons, including poor technique with the prescribed device, a lack of understanding of the rationale of treatment, concern over potential side effects, or because the patient's perception of the goals of treatment differs from that of their health professional. Successful strategies for managing non-concordance remain unclear, although patient education, including the provision of written material, may help (145).

Having addressed these areas consideration should be given to the nature and extent of the underlying pathophysiology, since this may provide important information about the likelihood of systemic corticosteroid response. The identification of persistent eosinophilic airway inflammation, for example, appears to be a marker not only of recurrent severe exacerbations but also of a potential for improvement with additional antiinflammatory treatment (36,43). Conversely, neutrophilic airway inflammation has been associated with a poor response to corticosteroids (146,147). Additionally, patients who achieve significant improvements in symptoms and airflow obstruction following short treatment trials may be more likely to benefit from systemic corticosteroids in the longer term.

Once a decision to treat with systemic corticosteroids has been made priority should be given to the prevention of adverse effects. The lowest possible dose to control symptoms, airflow obstruction, and exacerbations should be given and the addition of steroid-sparing agents should be considered. High doses of inhaled corticosteroids have been shown to be the most effective of these (148) and should always be continued. Additional options include methotrexate, gold, and cyclopsorin, although the response to these agents is unpredictable (82). The use of alternate-day dosing regimes is controversial, being recommended by some guidelines (141) but not others (82). Oral corticosteroids have a preferable side-effect profile, although intramuscular triamcinolone is a useful alternative, particularly where non-concordance is an issue. Patients and clinicians should be aware of the range of potential side effects and, in particular, strategies for the prevention of osteoporosis should be applied as already discussed. Finally, patients receiving chronic systemic corticosteroid treatment should remain under specialist care and the continuing need for this treatment should be reassessed at every opportunity.

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