Role of Inhaled Corticosteroids

Transcription

1 CHAPTER 16 Role of Inhaled Corticosteroids Paul M. O Byrne, MB, FRCPI, FRCPC, FCCP Frederick E. Hargreave, MD, FRCPC, FRCP Glucocorticosteroids have been used to treat a variety of airway diseases since an initial study in 1950 of Carryer et al 1 who reported the benefits of oral cortisone on ragweed polleninduced hay fever and asthma. This was followed by a report by Gelfand, 2 demonstrating clinical benefit from inhaled cortisone in a small group of patients with both allergic or nonallergic asthma. Subsequently, a multicenter trial run by the Medical Research Council in the United Kingdom in 1956 demonstrated improvement in acute severe asthma in a placebo-controlled trial, 3 and reports at that time described benefit in chronic asthma. 4 This demonstrated the unequivocal benefit of corticosteroids in asthma. Subsequently, both oral and inhaled corticosteroids have evolved into the most important and useful drugs currently available to treat asthma (Level IA). The initial studies evaluating the efficacy of inhaled corticosteroids in asthma were performed on patients with moderate to severe disease. At the time of their introduction to clinical practice in the early 1970s, and for many years after this, their use was mainly limited to patients who had persisting symptoms despite aggressive oral or inhaled bronchodilator use. The increased appreciation, in the mid-1980s, of the central role of airway inflammation in the pathogenesis of all asthma (Level I), 5 7 provided a rationale for the earlier introduction of inhaled corticosteroids, particularly as the ability of inhaled corticosteroids to reduce airway inflammation (Level I) 8 and improve some of the airway structural abnormalities associated with asthma was being identified (Level I). This has led to a reappraisal of how best to use inhaled corticosteroids in the management of asthma. CLINICAL USE OF CORTICOSTEROIDS Asthma is characterized by the presence of the symptoms of dyspnea, wheezing, chest tightness, and cough. These symptoms are usually caused by airflow obstruction, which is characteristically variable and by which the condition is defined. The variable airflow obstruction is associated with airway hyper-responsiveness to a variety of chemical bronchoconstrictor stimuli and physical stimuli such as exercise and hyperventilation of cold, dry air (Level I). It is now accepted that asthma symptoms, variable airflow obstruction, and airway hyperresponsiveness develop as a consequence of a characteristic form of cellular inflammation and structural changes in the airway wall (Level II). 9 The inflammation consists of the presence of activated eosinophils, lymphocytes, and an increased number of mast cells, which have been described both in bronchoalveolar lavage and airway biopsies from patients with mild stable asthma 6,7,10 as well as asthmatic subjects with more severe disease. 9 Also, there are structural changes described in asthmatic airways that appear to be characteristic of the disease and that are likely caused by persisting airway inflammation. 9 These changes include patchy desquamation of the airway epithelium, 11 thickening of the reticular collagen layer of the basement membrane, 12 and increased volume of airway smooth muscle (Level I). 9 It has been only with this increased appreciation of the pivotal role of airway inflammation in asthma that an emphasis has been placed on treating airway inflammation rather than some of the consequences of the inflammation airway constriction and asthma symp-

2 184 Evidence-Based Asthma Management Figure 16 1 Effect of treatment with either the inhaled corticosteroid budesonide or the inhaled β 2 -agonist terbutaline on the number of mast cells (MC), eosinophils (EO), or macrophages (MAC) in airway biopsies from asthmatic subjects. Open bars indicate pretreatment levels; stippled bars show levels after 6 weeks of treatment. (Reproduced with permission from Jeffrey PK, Godfrey RW, Adelroth E, et al. Effects of treatment on airway inflammation and thickening basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study. Am Rev Respir Dis 1992;195:890 9.) toms. The only antiasthma medications that have been demonstrated to improve airway inflammation (Figure 16 1) (Level I), 8,13 airway hyper-responsiveness (Figure 16 2) (Level I), 14,15 airflow obstruction, and symptoms in asthmatic patients are inhaled corticosteroids (Level IA). This evidence has been used as a rationale for using inhaled corticosteroids earlier in the treatment of asthma than was previously the case when they were suggested to be reserved for use as third- or fourth-line therapy for asthma, and only when bronchodilators were not providing asthma control. 16 Figure 16 2 Effect of 22 months of treatment with an inhaled corticosteroid plus an inhaled β 2 - agonist, or placebo plus an inhaled β 2 -agonist, on methacholine airway responsiveness in asthmatic children. The inhaled corticosteroid progressively improved methacholine airway responsiveness over time. (Reproduced with permission from van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effect of 22 months of treatment with inhaled corticosteroids and/or beta2-agonists on lung function, airway responsiveness and symptoms in patients with asthma. Am Rev Respir Dis 1992;146: )

3 Role of Inhaled Corticosteroids 185 Objectives of Asthma Management There have been many published consensus statements, from a variety of countries, on asthma management (Level IIIA) While the consensus statements have differed in some regard, they have been remarkably consistent in identifying the objectives of asthma treatment, which are as follows: 1. To minimize or eliminate asthma symptoms 2. To achieve the best possible airway function 3. To minimize asthma exacerbations 4. To do the above with the least possible medications 5. To educate the patient about the goals and methods of management Objectives that are implied but not explicitly stated are to reverse the causal airway inflammation and to prevent the decline in lung function and the development of fixed airflow obstruction that occurs in some asthmatic patients (and which is considered to be a result of uncontrolled inflammation). In addition to these objectives, each of these documents has described what is meant by the term asthma control. This includes the above objectives of minimal or no symptoms and best airway function, but it also includes minimizing the need for rescue medications such as inhaled β 2 -agonists to less than daily use, minimizing the variability of flow rates that is characteristic of asthma, as well as enabling the patient to participate in normal activities of daily living. Achieving this level of asthma control should be the objective of the treating physician from the very first visit of the patient. Unfortunately, studies suggest that this does not happen. 20 This may be, in part, because the patient has learned to live with daily asthma symptoms and limitations in daily activities, and minimizes these problems to the physician. Alternatively, the idea of asthma control may not be widely accepted or understood by many physicians who see patients with asthma. This means that many (perhaps even most) patients with diagnosed asthma do not achieve optimal control. These concepts have resulted in a much lower threshold than previously existed for intervening with inhaled corticosteroids in asthma. This early intervention with an effective antiinflammatory medication in asthma has scientific rationale and is now being supported by clinical studies that have suggested that the delayed introduction of inhaled corticosteroids reduces the maximal benefit that is eventually achieved in children 21 and in adults. 22,23 Currently Available Inhaled Corticosteroids There are currently five topically active inhaled corticosteroids available for the treatment of asthma. These are beclomethasone dipropionate (BDP), triamcinolone, flunisolide, budesonide, and fluticasone propionate (FP) (Table 16 1). These are available in most countries in a pressurized metered-dose inhaler using chlorofluorocarbons (CFC) as propellants from the inhaler. However, BDP has, more recently, been formulated with hydrofluoroalkane (HFA) as its propellant because of the mandated phase-out of CFCs agreed to by the Montreal Protocol. This reformulation has altered the physical properties of the aerosol, which changes its lung deposition and, therefore, recommended dosage (see Table 16 1). In addition, budesonide and FP are available in dry-powder devices, the budesonide Turbuhaler and FP Diskus. Reasons for Early Intervention with Inhaled Corticosteroids Early intervention with inhaled corticosteroids in asthma means it is the first regular treatment used after a diagnosis is established. An argument for early intervention with inhaled corticosteroids could be made if one or more of the following conditions were met: Inhaled corticosteroids were more effective than other regular treatments to achieve optimal asthma control and meet the other treatment objectives

4 186 Evidence-Based Asthma Management Inhaled corticosteroids prevented the decline in airway function that occurs over time in asthmatic patients Inhaled corticosteroids were safer than an equally effective treatment modality Inhaled corticosteroids were more cost beneficial as an initial treatment of asthma than any other medication, as measured by a benefit to the patient or to society by reducing the morbidity of asthma Studies using inhaled corticosteroids have addressed all of these issues and these will be considered. Table 16 1 Dosage Equivalence for Inhaled Corticosteroids in Adults Low Dosage Intermediate Dosage High Dosage Product µg/d µg/d µg/d BDP pmdi (CFC)* < ,000 > 1,000 BDP pmdi (HFA) < > 500 BUD Turbuhaler < > 800 FP pmdi < > 500 FP Diskus" < > 500 Flunisolide pmdi # < 1,000 1,000 2,000 > 2,000 Triamcinolone pmdi # < ,600 > 1,600 *Beclomethasone dipropionate pressurized metered-dose inhaler (chlorofluorocarbon propellant). Beclomethasone dipropionate pressurized metered-dose inhaler (hydrofluoroalkane propellant). Budesonide Turbuhaler. Fluticasone propionate pressurized metered-dose inhaler. " Fluticasone propionate Diskus. # Dosage equivalences are less well studied for flunisolide and triamcinolone. Efficacy of Early Intervention with Inhaled Corticosteroids There is little debate in the literature that corticosteroids are the most effective treatment for asthma (Level IA) 24,25 and that the inhaled route is preferable to minimize unwanted effects (Level IA). There is, however, considerable debate over the early use of inhaled corticosteroids in the asthmatic patient considered to have mild asthma. 26 These patients are usually treated with inhaled β 2 -agonists on demand, or with drugs considered to be clinically less effective than inhaled corticosteroids, such as cromoglycate or nedocromil sodium. In a study of newly diagnosed asthmatic patients seen in specialty clinics, early intervention with the inhaled corticosteroid budesonide was shown to be an effective first-line treatment, when compared with an inhaled β 2 -agonist, as indicated by reduced symptoms, improvements in lung function, and improvements in methacholine airway hyper-responsiveness (Level IA). 27 However, many patients considered to have mild asthma are not seen in specialty clinics but are managed in primary care practices. It is possible that these patients are, in fact, ideally controlled without the use of inhaled corticosteroids. To address this issue, one study has examined the efficacy and cost benefit of inhaled corticosteroids, supplemented with bronchodilators as needed, compared to bronchodilators alone, as first-line treatment of asthma in primary care practice (Level IA). 20 This double-blind randomized controlled trial compared budesonide 400 µg/d, budesonide 800 µg/d, and placebo in patients considered by their primary care physician to have such mild asthma that they would not derive any clinical benefit from inhaled corticosteroids. In this patient population, in whom self-reported symptoms were

5 Role of Inhaled Corticosteroids 187 Figure 16 3 Proportion of patients considered by their family physician as having mild asthma, experiencing early morning symptoms or nocturnal symptoms in the month prior to evaluation at baseline (BL) and after treatment with inhaled budesonide at treatment weeks 4 to 16 for patients on placebo (open circles), budesonide 400 µg/d (closed circles), and budesonide 800 µg/d (closed squares).* p <.05; p <.01; p <.001. (Reproduced with permission from O Byrne PM, Cuddy L, Taylor DW, et al. The clinical efficacy and cost benefit of inhaled corticosteroids as therapy in patients with mild asthma in primary care practice. Can Respir J 1996;3: ) mild at the start of the study, 40 to 70% of the patients were experiencing nocturnal or early morning symptoms in the month before entering the study (Figure 16 3). These symptoms suggest that asthma control was not optimal. The study demonstrated that inhaled budesonide 400 µg/d provided better asthma control and is cost beneficial when compared to bronchodilators alone in the management of these patients with mild asthma and that no differences could be demonstrated between the use of 400 µg/d and 800 µg/d of budesonide; however, the study had insufficient power to detect differences between dosages, had they been present. However, other studies with sufficient power have not been able to demonstrate a significant difference between these two dosages of inhaled budesonide. 28 The percentages of patients experiencing daily symptoms fell to less than 10% over the course of the study in the budesonide treatment groups (see Figure 16 3). Also, there was a mean 60 to 70 L/min increase in morning and evening peak expiratory flows (Figure 16 4) and an elimination of exacerbations of asthma requiring emergency department management, indicating that a clinically useful improvement was achieved in this patient population with a dosage of budesonide as low as 400 µg/d. This study supports the early intervention with inhaled corticosteroids for adult patients with regular daily symptoms of asthma, and suggests that low dosages (budesonide 400 µg/d or possibly less) are effective in the management of asthmatic patients with mild to moderate asthma. In addition, the study reinforced the need to strive for optimal control of asthma and, once control is achieved, to identify the minimum amounts of medication needed to maintain control. Last, this study demonstrated that inhaled corticosteroid treatments are more cost beneficial than asthma therapy with bronchodilators alone. Another reason for recommending low doses of inhaled corticosteroids as first-line therapy for asthma is the recent concern about the safety of regular daily short-acting inhaled β 2 -agonists. Sears et al 29 have demonstrated deterioration in a number of parameters of asthma control and reduced the time to an asthma exacerbation 30 when the short-acting inhaled β 2 -agonist fenoterol was used on a regular basis rather than when needed (Level IA). A subsequent study of the regular use of the short-acting inhaled β 2 -agonist salbutamol in milder asthmatic patients

6 188 Evidence-Based Asthma Management Figure 16 4 Changes in peak expiratory flow from baseline measured in the morning upon waking in patients considered by their family physician as having mild asthma, both before and after inhaled bronchodilator treatment with inhaled budesonide for treatment weeks 4 to 16 for patients on placebo (open circles), budesonide 400 µg/d (closed circles), and budesonide 800 µg/d (closed squares). p <.01; p <.001. (Reproduced with permission from O Byrne PM, Cuddy L, Taylor DW, et al. The clinical efficacy and cost benefit of inhaled corticosteroids as therapy in patients with mild asthma in primary care practice. Can Respir J 1996;3: ) showed an overall trend toward deterioration in a number of asthma outcomes, although none were statistically significant. 31,32 Also, retrospective studies have associated increased risk of asthma mortality with the overuse of the β 2 -agonists fenoterol 32,33 and salbutamol. 33 Regular use of inhaled β 2 -agonists has been demonstrated to increase airway responsiveness in asthmatic patients (Level I) 34,35 and to result in loss of functional antagonism to the bronchoconstrictor effects of inhaled methacholine 36 and adenosine monophosphate (AMP) (Level I). 37 Effects of Inhaled Corticosteroids on Airway Function Over Time Asthmatic patients lose lung function more rapidly than nonasthmatic patients 38,39 but less rapidly than cigarette smokers. In occasional asthmatic patients, this leads to severe, permanent, fixed airflow obstruction, with all of the attendant disability and handicap associated with this condition. A number of recent studies in both adults and children have demonstrated that inhaled corticosteroids provide a protective effect against the deterioration in lung function seen with prolonged regular use of inhaled bronchodilator therapy alone. In one study, patients with asthma and patients with chronic obstructive pulmonary disease, previously treated with regular inhaled bronchodilators, were treated with inhaled beclomethasone 800 µg/d or placebo for 2 years. 40 Prior to the addition of inhaled corticosteroids, the forced expiratory volume in 1 second (FEV 1 ) had been declining at a rate of 160 ml/y. In the first 6 months of corticosteroid therapy, the FEV 1 increased by 460 ml and then continued to decline at a rate of 100 ml/y (significantly less than with bronchodilators alone). This protective effect of inhaled corticosteroids was most marked in the asthmatic patients and was associated with a significant improvement in methacholine airway hyperresponsiveness in the asthmatic patients only, and with decreased asthma symptoms and exacerbations (Level IB). A second study 22 has addressed this issue in a different way. These investigators had previously reported that the treatment of newly diagnosed asthmatic patients with inhaled budesonide 1200 µg/d for 2 years improved asthma control as indicated by reduced symptoms, improvements in lung function, and improvements in methacholine airway hyperresponsiveness when compared to inhaled β 2 -agonists. 27 The subjects receiving budesonide

7 Role of Inhaled Corticosteroids 189 were subsequently randomly allocated to continuing for a third year on a lower dosage of inhaled budesonide (400 µg/d) or placebo. The improvements in all parameters were maintained on the lower dose of budesonide but were lost on placebo. The subjects who had previously been treated with inhaled β 2 -agonists only were treated with the higher dosage of inhaled budesonide for the third year, and while they improved in all parameters when compared to the first 2 years of treatment, the improvement in lung function or methacholine airway hyperresponsiveness was significantly less than that achieved by the subjects treated for the first year of the study with inhaled budesonide. This suggests that these asthmatic patients had lost lung function that might have been preserved with the early use of inhaled corticosteroids (Level IB). A study in asthmatic children has been reported by Agertoft and Pedersen 21 who studied two cohorts for up to 7 years. One cohort was treated with inhaled corticosteroids shortly after diagnosis, while the other received a variety of other antiasthma medications, including cromones, theophylline, and regular inhaled β 2 -agonists, but not inhaled corticosteroids. Some children in the second cohort were converted to inhaled corticosteroids but not until an average of 5 years after initial diagnosis. These children in whom treatment with inhaled corticosteroids was started later did not achieve the level of lung function of the children who received early intervention with inhaled corticosteroids, even after 3 years of treatment with inhaled corticosteroids (Level II). The study also measured growth velocity in these children and concluded that dosages of inhaled budesonide up to 400 µg/d were not associated with a reduction in growth velocity. A subsequent study in adult asthmatic patients has confirmed these observations (Level II). 23 These studies suggest that inhaled corticosteroids can diminish the decline in airway function that occurs in asthmatic patients, and that early intervention with inhaled corticosteroids can optimize airway function in asthmatic patients. Each of these studies, however, has limitations mainly, that none were explicitly designed to address this issue in a prospective fashion. Therefore, while the results are consistent between the studies, they are not conclusive. This has led to the development of a large, multinational, prospective, randomized, and placebo-controlled study of the effects of early intervention with inhaled corticosteroids in both childhood and adult asthma. This study, known as the START (Steroid Therapy As Regular Treatment) trial, will evaluate the potential beneficial effects of inhaled corticosteroids treatment started within the first 2 years of the development of asthma in patients with very mild disease. Cost Benefit of Inhaled Corticosteroids in Asthma Until recently, few studies have examined the cost benefit of early intervention with inhaled corticosteroids. However, several recent studies have demonstrated that inhaled corticosteroids are cost beneficial when compared to other antiasthma treatments. For example, Adelroth and Thompson 41 have shown that when patients were treated with inhaled corticosteroids, the costs to the Swedish health care system declined because of a reduction in hospital use and physician visits when asthma control was optimized (Level II). Also, in the Canadian study discussed previously, 20 a cost-effectiveness analysis of the use of inhaled corticosteroids in patients thought to have mild asthma in primary care practice demonstrated an advantage with use of inhaled corticosteroids, also primarily by keeping patients out of hospital emergency departments, since asthma control was improved. Future Trends in Inhaled Corticosteroid Use These studies suggest that low dosages of inhaled corticosteroids should be used early in the onset of asthma and even in patients with mild disease. The impact of earlier treatment on the progression of the disease is a critical issue that needs to be evaluated in future studies. It is plausible that, by preventing the airway structural abnormalities associated with asthma, the development of fixed airflow obstruction and more severe disease can be prevented. Also,

8 190 Evidence-Based Asthma Management it is clear from the studies that the severity of asthma is often underappreciated by both patients and physicians. This leads to undertreatment, less than ideal asthma control, the attendant effects on patients quality of life, and an increased cost to society. To ensure that this does not happen, optimal treatment should be offered to all patients with established asthma; this would most often be a therapeutic trial of inhaled corticosteroids. In clinical practice, some asthma patients are overtreated with inhaled corticosteroids. Asthma can sometimes be difficult to diagnose, and diagnosis should be validated with the use of a variety of measurements that are more sensitive than symptoms and airway function, such as methacholine airway responsiveness. Clinical trials involving the reduction of inhaled corticosteroid treatment illustrate that many patients are able to discontinue treatment with inhaled steroid, or considerably reduce the dose, without a clinical exacerbation. 42 The extent of overtreatment of asthma should be investigated. Recent studies of induced sputum cell counts suggest that it maybe difficult to optimize inhaled corticosteroid treatment in some asthmatic patients without these cell counts. Sputum eosinophils can be increased when asthma is clinically controlled. 43 When inhaled steroid or prednisone is reduced, sputum eosinophils increase before symptoms or measurements of airway function worsen. 44 Therefore, there is a need to investigate the use of induced sputum cell counts to monitor optimum corticosteroid treatment although, at present, establishing reliable sputum cell counts in practice is difficult to achieve. Finally, there are several causes of airway inflammation and, consequently, different types of inflammation, which can overlap in clinical presentation. 45,46 While asthma is considered to be associated with an eosinophilic inflammation, it can occur with normal sputum cell counts 43 or with a neutrophilia without eosinophilia. 45 The significance of this relates to the beneficial effect of corticosteroid treatment; eosinophilic inflammation responds, whereas there is increasing evidence that noneosinophilic inflammation does not. Systemic Side Effects Dosages of inhaled corticosteroids (beclomethasone) of >400 µg/d in children and >1000 µg/d in adults can be demonstrated to result in unwanted systemic side effects such as changes in growth velocity in children (Level I) and biochemical changes indicating effects on bone metabolism and the adrenal glands in adults (Level I). All physicians who treat asthmatic patients should be conscious of the potential for the development of adverse effects that occur in patients who use corticosteroids to treat asthma or other diseases. These potential adverse effects of corticosteroids include an influence on the hypothalamic-pituitary-adrenal (HPA) axis; osteoporosis; posterior subcapsular cataracts; growth retardation in children; steroid psychosis; risk of lung infection; and skin bruising. Effects on the Hypothalamic-Pituitary-Adrenal Axis The effects of corticosteroids on the HPA axis can be measured in a number of different ways. The commonest used and easiest to obtain, but least sensitive, method has been the measurement of early morning serum cortisol levels. Much more sensitive measurements to the effects of excess corticosteroids on the HPA axis are 24-hour urinary cortisol, 2-hourly plasma cortisol measured over 24 hours, or the short tetracosactrin (ACTH) stimulation test. 47 The different inhaled corticosteroids are not equal with regard to their effects on the HPA axis (Level I). For example, in children, a dosage-dependent effect of urinary cortisol has been demonstrated with dosages of BDP from 200 to 800 µg/d. 48 By contrast, a dosage of budesonide of 400 µg/d does not cause any effect on urinary cortisols, even when used for up to 1 year. 49 In adults, many studies have examined the effects of inhaled corticosteroids on HPA axis function, and there is no convincing evidence that dosages of BDP of <1,500 µg/d and budesonide <1,600 µg/d have any measurable effect on the HPA axis. 50 The measurable effects seen at higher doses clearly indicate systemic activity of the inhaled corticosteroid but

9 Role of Inhaled Corticosteroids 191 are of questionable clinical significance. There are only two case reports of clinically evident adrenal insufficiency in patients, who have been treated with only inhaled corticosteroids, after the inhaled corticosteroid has been withdrawn (Level IIC). These occurred in an adult who was treated with a very high dosage of inhaled budesonide (6,400 µg/d) 51 and a child who was treated with a much lower dosage (250 µg/d). 52 Osteoporosis This is an important complication of the use of ingested corticosteroids, particularly in highrisk patients such as postmenopausal women. 53 This occurs through an increase in bone resorption and a decrease in bone formation, and results in an increased risk of fractures, especially of the hip and spine. Inhaled corticosteroids have been demonstrated to have effects on bone metabolism, although there is little evidence that, at the conventionally used dosages, they cause osteoporosis, and no evidence that they cause increased risk of fractures (Level IIC). The effects of inhaled corticosteroids on bone metabolism have been demonstrated by measuring serum osteocalcin, which measures changes in bone formation, and urinary hydroxyproline (measured after a 12-hour fast), which is increased with increased bone resorption. Phenazopyridine hydrochloride cross-links in urine is another measure of bone resorption and has the advantage over urinary hydroxyproline of not being dietary-dependent; however, to date, the effects of inhaled corticosteroids on this measure of bone resorption have not been reported. The effects of BDP and budesonide on serum osteocalcin and urinary hydroxyproline have been studied in adults. Both have been shown to influence serum osteocalcin levels in a dosage-dependent manner, 54 but only BDP increases urinary hydroxyproline excretion at dosages up to 2,000 µg/d. In children, dosages of budesonide of less than 800 µg/d 55 and of fluticasone of 200 µg/d 56 have no effect on any biochemical marker of bone turnover. Bone densitometry has been measured in adult asthmatic patients taking varying doses of inhaled BDP (mean dose 630 µg/d) over 2 years. 56 This study suggested that these patients had no increase in bone loss. Also, to date, there are no studies that have demonstrated that these biochemical markers of bone turnover are associated with increased risk of bone fracture. Posterior Subcapsular Cataracts These occur more frequently in patients taking ingested versus inhaled corticosteroids, and this greatly complicates the issue of whether they occur with greater frequency in patients who are also using inhaled corticosteroids. Studies in adults 57 and children 58 suggest that once the confounding effect of ingested corticosteroids is removed, there is no evidence that inhaled corticosteroids increase the risk of developing posterior subcapsular cataracts (Level IIC). One recent study has, however, indicated that high inhaled dosages of BDP are associated with a slightly greater risk of posterior subcapsular cataracts 59 in older patients. This study did not, however, stratify for the confounding risk of allergy for cataract development in this population. Growth Retardation in Children Growth retardation in children due to the use of inhaled corticosteroids is a major reason that these drugs are used very sparingly, perhaps even underused, to treat pediatric asthma. There is little doubt that systemic corticosteroids can stunt growth in children and that this effect is usually permanent. Resolving this issue for inhaled corticosteroids in asthmatic children has been exceedingly difficult. This is partly because asthmatic children do not have the same growth patterns as nonasthmatic children. Many asthmatic children have delayed onset of puberty, and this effect appears more severe in children with severe asthma. 60 However, these

10 192 Evidence-Based Asthma Management Figure 16 5 Effect of treatment with placebo, prednisone 2.5 mg/d or 5.0 mg/d for 1 week, or increasing inhaled doses of budesonide, BDP, or fluticasone on lower leg growth, measured by knemometry in children. Prednisone and BDP 400 µg/d or 800 µg/d significantly reduced lower leg growth. (Reproduced with permission from Barnes PJ, Pedersen S. Efficacy and safety of inhaled corticosteroids in asthma. Am Rev Respir Dis 1993;148:S1 26.) children eventually do catch up with their nonasthmatic peers and achieve normal height. 61 Thus, studying asthmatic children and comparing them to nonasthmatic controls may not be appropriate. Also, studies examining growth in children need to be continued over several years, as individual children have different growth patterns. A surrogate method for measuring growth in children is knemometry, which measures short-term linear growth in the lower leg in children. This method is extremely sensitive to the systemic effects of corticosteroids. A daily dosage of prednisone of 2.5 mg can totally inhibit lower leg growth (Figure 16 5). 62 By contrast, a dosage of inhaled budesonide of 400 µg/d has no effect on knemometry measurements, 63 whereas a daily dosage of 800 µg/d of budesonide 63 with 400 µg/d of BDP and 200 µg/d of fluticasone does significantly inhibit them (see Figure 16 5). 64 The clinical correlation of these measurements is not known; however, only BDP at an inhaled dosage of 400 µg/d has been shown, in relatively short-term studies, to reduce linear growth in children Steroid Psychosis This may occur in as high as 2% of patients treated with systemic corticosteroids and has been reported to occur occasionally in patients taking inhaled corticosteroids. A total of eight patients have been reported, thus far, who developed symptoms within days of being treated with either inhaled BDP or budesonide. 68,69 The psychosis resolved promptly after stopping the inhaled corticosteroid. Risk of Lung Infection Risk of lung infection is not increased in patients using inhaled corticosteroids. Also, inhaled corticosteroids do not increase the risk of reactivation of pulmonary tuberculosis, and, therefore, prophylactic isoniazid treatment is not needed when inhaled corticosteroids are used in patients with inactive pulmonary tuberculosis. Skin Bruising Skin bruising occurs as a dosage-dependent side effect of inhaled corticosteroid use. It is rare at daily dosages of <1,000 µg/d, and its incidence increases with age and duration of treat-

11 Role of Inhaled Corticosteroids 193 Figure 16 6 A schematic representation of the dosage-response characteristics for efficacy and side effects for inhaled corticosteroids. ment (Level I). In one study of older patients on high doses of BDP, the prevalence of easy bruising was 47% for those on inhaled corticosteroids and 22% for those who were not. 70 Fortunately, there has been an increased appreciation over the past 5 years that the maximal clinical benefits of inhaled corticosteroids in most patients are achieved with low to moderate dosages (see Table 16 1), thereby giving a very steep efficacy dosage-response (Figure 16 6). This has been emphasized in several studies in which a dosage-response has been evaluated (Level I). 24,25 These low to moderate dosages are not associated with systemic side effects in adults (see Figure 16 6). CONCLUSION Inhaled corticosteroids are the most effective medications currently available to treat symptomatic asthma and are, fortunately, free of clinically relevant unwanted effects when used in the dosages needed to provide optimal control in most asthmatic patients. In uncontrolled asthma, not previously treated with inhaled corticosteroids, a high dose usually is not more Table 16 2 Evidence-Based Data Regarding Inhaled Corticosteroids Inhaled corticosteroids are the most effective medications currently available to treat symptomatic asthma (Level IA). Inhaled corticosteroids improve the physiologic abnormalities of variable airflow obstruction and airway hyper-responsiveness that characterize asthma (Level IA). Inhaled corticosteroids are cost beneficial as compared to other treatments (Level IA). Even low dosages of inhaled corticosteroids can cause topical unwanted effects such as oral candidiasis or dysphonia (Level IA). Inhaled corticosteroids are free of clinically relevant systemic unwanted effects when used in the dosages needed to provide optimal control in most asthmatic patients (Level IA). The addition of a long-acting inhaled β 2 -agonist to a moderate dose of an inhaled corticosteroid provides better asthma control than increasing the dose of the inhaled corticosteroid (Level IA).

12 194 Evidence-Based Asthma Management effective than a lower dose in controlling symptoms or airway function. Inhaled corticosteroids also improve the physiologic abnormalities of variable airflow obstruction and airway hyper-responsiveness that characterize asthma, as well as reduce the decline in lung function over time that occurs in asthmatic patients. Inhaled corticosteroids are cost beneficial as compared to other treatments, even in patients with milder asthma treated in primary care. For these reasons, inhaled corticosteroids are now being considered the first-line therapy for patients with daily asthma symptoms. They should be started early after a diagnosis is made, rather than delaying until all other treatment options have been found not to provide optimal control of asthma. Evidence-based data regarding inhaled corticosteroids is presented in Table There are, however, several issues regarding the early intervention with inhaled corticosteroids that have not yet been resolved. One such issue is whether inhaled corticosteroids should be used in asthmatic patients who have very mild and infrequent symptoms, or who develop symptoms only after being exposed to a stimulus of airway constriction, such as exercise or cold air, and who have normal airway caliber most of the time. The current consensus statements do not recommend regular treatment in such patients. These asthmatic patients do have evidence of airway inflammation and structural changes in airway biopsies; however, we do not yet know whether they lose lung function more rapidly than nonasthmatic patients, or whether the morbidity of having very mild asthma warrants the use of regular treatment. This information may be available when the results of the START trial are available. Also, not enough data is yet known about the long-term effects of even low doses of inhaled corticosteroids. Although the study by Agertoft and Pedersen 21 has provided details of some of the potential unwanted effects in children after as many as 7 years of treatment, such studies will need to be of a longer duration before the concerns and fears about using inhaled corticosteroids very early in asthma will be allayed. REFERENCES 1. Carryer HM, Koelshe GA, Prickman LE, et al. The effect of cortisone on bronchial asthma and hay fever occurring in subjects sensitive to ragweed pollen. J Allergy 1950;21: Gelfand ML. Administration of cortisone by the aerosol method in the treatment of bronchial asthma. N Engl J Med 1951;245: Medical Research Council. Controlled trial of effects of cortisone acetate in status asthmaticus. Lancet 1956;2: Foulds GS, Greaves DP, Herxheimer H, Kingdom LG. Hydrocortisone in treatment of allergic conjunctivitis, allergic rhinitis, and bronchial asthma. Lancet 1955;1: O Byrne PM. Airway inflammation and airway hyperresponsiveness. Chest 1986;90: Kirby JG, Hargreave FE, Gleich GJ, O Byrne PM. Bronchoalveolar cell profiles of asthmatic and nonasthmatic subjects. Am Rev Respir Dis 1987;136: Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989;139: Jeffery PK, Godfrey RW, Adelroth E, et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study. Am Rev Respir Dis 1992;145: Dunnill MS, Massarell GR, Anderson JA. A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969;24: Jeffery PK, Wardlaw AJ, Nelson FC, et al. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989;140: Laitinen LA, Heino M, Laitinen A, et al. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985;131: Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatic patients. Lancet 1989;1:520 4.

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