Dr.Palani Senthamilarasu, Paediatric registrar UK. Executive Summary The prevalence of asthma is increasing worldwide. Corticosteroids are the most effective anti

 medications for the treatment of allergic asthma, which accounts for more than 80 % of childhood asthma and 50 % of adult asthma. This paper explains in detail the mechanism of action of steroids on airways of patients with asthma. It recommends the starting dose and the maintenance dose of steroids in asthma based on current evidence. It compares the effectiveness of different steroid preparations licensed for use in asthma in different age groups. The role of oral steroids in difficult to control asthma is also explained. Study which shows that strict adherence to inhaled corticosteroids reduces asthma morbidity is also outlined. But steroids have also got their own side effects some of which are very serious and life threatening like adrenal crisis. In this paper, the dosage of steroids which can cause these side effects and the clues to pick up some of the serious side effects are explained. British Thoracic Society guidelines for the monitoring of patients on high dose steroids and their management is also outlined. Even though steroids are effective in the management of asthma, prevention and education are the cornerstones of asthma management.

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Introduction

Asthma is one of the most common chronic diseases worldwide. It is estimated that 150 million people around the world suffer from asthma. Mortality has reached over 180,000 annually. Eighty percent of childhood asthma and more than 50% of adult asthma are reported to be allergic. Most cases are initiated by IgE antibodies, and the proper nomenclature is therefore IgE-mediated allergic asthma. The goal of asthma treatment is to achieve and maintain clinical control. Over the past decade, the treatment of asthma has changed remarkably, largely because of the increased understanding of the pathophysiology of the disease, and the recognition of the importance of airway inflammation. Treatments used in asthma can be separated into specific (long term controlling) agents and symptomatic (short term relieving) agents. "Specific agents" reduce the underlying causes of asthma and thereby reduce the symptoms of the disease and the need for symptomatic agents. They include inhaled and systemic glucocorticosteroids, leukotriene modifiers, long-acting inhaled beta 2-agonists in combination with inhaled glucocorticosteroids, sustained-release theophylline,cromones, anti-IgE, and other systemic steroid-sparing therapies. Inhaled glucocorticosteroids are the most effective controller medications currently available.Inhaled corticosteroids (ICCS) reduce airway inflammation and act specifically. Studies have demonstrated their efficacy in reducing asthma symptoms, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation, reducing frequency and severity of exacerbations, and reducing asthma mortality. However, they do not cure asthma, and when they are discontinued deterioration of clinical control follows within weeks to months in a proportion of patients. Inhaled glucocorticosteroids are the preferred treatment for patients with persistent asthma at all levels of severity. The safety of inhaled steroids is of crucial importance and a balance between benefits and risks for each individual needs to be assessed.

The Effect of Corticosteroids on Inflammation and Airway Remodelling Corticosteroids have been the most extensively evaluated asthma therapy. Epithelial denudation increases the exposure of mucosal nerve endings, enhances the penetration of allergens and reduces mucocilliary clearance. Biopsy studies have demonstrated that corticosteroids partially restore the epithelial lining of the mucosa. (21) .Goblet cell metaplasia and mucus hypersecretion are also characteristic features of asthma, and corticosteroids are effective in reducing goblet cell metaplasia in animal models. Studies of basement membrane components and thickness have been difficult to interpret, and the consequences of basement membrane remodelling in asthma remain controversial. (19,20) Some investigators have shown that the thickness of the collagen is related to airway obstruction and airway responsiveness. Others have argued that these findings are of little consequence. However, fibrosis of airway smooth muscle is more likely to have functional consequences. (20)

The lamina propria may be thickened in asthma, and inhaled corticosteroids are effective in preventing and reversing the enhanced fibronectin deposition that occurs during repeated exposure to allergen. However, treatment with inhaled steroids at low doses or after allergen exposure does not affect fibronectin deposition and suggests that the dose of inhaled corticosteroids may be critical. (19)

Treatment of patients with asthma with inhaled corticosteroids for ten years markedly decreased inflammation. It is interesting however, that this reduced inflammation was not always associated with improvement of bronchial hyperresponsiveness. In a prospective study, three months of therapy with budesonide, a corticosteroid, increased the number of ciliated cells thereby increasing mucosal clearance more than bronchodilator treatment alone in patients with asthma. (19,21,22)

Inhaled Corticosteroids (ICS)

Beclomethasone, fluticasone, mometasone, budesonide, flunisolide, triamcinolone, ciclesonide

Inhaled steroids are the most effective preventer drug for adults and older children for achieving overall treatment goals.(1-5).They are also safe and effective in infants and younger children with asthma(6-9). ICS improve asthma control, reduce exacerbations and prevent asthma deaths (24).

Inhaled steroids should be considered for adults, children aged 5-12 and children under the age of five with any of the following features: using inhaled ?2 agonists three times a week or more; symptomatic three times a week or more; or waking one night a week. In addition, inhaled steroids should be considered in adults and children aged 5-12 who have had an exacerbation of asthma requiring oral corticosteroids in the last two years( 10-11)

Mode of Action of Inhaled Corticosteroids:

Corticosteroids bind to cytosolic glucocorticoid receptors to decrease transcription and production of inflammatory cytokines e.g. interleukin (IL)-4 (IL-4), IL-13, granulocyte macrophage colony stimulating factor (GM-CSF), eotaxin and regulated on activation, normal T cells expressed and secreted (RANTES), which function in bronchoconstriction and airway inflammation.

Corticosteroids suppress eosinophilic airway inflammation in asthma. Active eosinophilic airway inflammation (defined by sputum eosinophilia >3%) is associated with increased rates of asthma exacerbations. Management strategies that effectively suppress sputum eosinophilia have been found superior to standard monitoring of asthma (23).

Interventional endobronchial biopsy studies using ICS have repeatedly shown reduction in submucosal eosinophils and CD3+ lymphocytes. Most of these studies also report reduction in large airway reticular basement thickness, a feature of airway remodeling.

ICS administered through different devices have different therapeutic effects. For example, pressure metered dose inhalers (pMDIs) with spacer devices reduce systemic absorption, while use of turbohalers results in deeper deposition of ICS within the pulmonary tree. Ciclesonide is a newer pro-ICS drug metabolized to an active form by esterases following delivery to the lung. Delayed activation reduces local oropharyngeal effects and also the risk of suppressing the hypothalamic-pituitary-adrenal axis

Starting dose of inhaled steroids : In mild to moderate asthma, starting at very high doses of inhaled steroids and stepping down confers no benefit(12). For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.(26)

Start patients at a dose of inhaled steroids appropriate to the severity of disease. In adults, a reasonable starting dose will usually be 400 mcg per day and in children 200 mcg per day. In children under five years, higher doses may be required if there are problems in obtaining consistent drug delivery. Titrate the dose of inhaled steroid to the lowest dose at which effective control of asthma is maintained.( BTS Guideline)

Frequency of dosing of inhaled steroids :Most current inhaled steroids are slightly more effective when taken twice rather than once daily, but may be used once daily in some patients with milder disease.There is little evidence of benefit for dosage frequency more than twice daily(13)

SAFETY OF INHALED STEROIDS

The safety of inhaled steroids is of crucial importance and a balance between benefits and risks for each individual needs to be assessed. Account should be taken of other topical steroid therapy when assessing systemic risk. It has been suggested that steroid warning cards should be issued to patients on higher dose inhaled steroids, but the benefits and possible disadvantages, particularly with regard to compliance, of such a policy remain to be defined.

In adults there is little evidence that doses below 800 mcg per day cause any short term detrimental effects apart from the local side effects of dysphonia and oral candidiasis. However, the possibility of long term effects on bone has been raised. One systematic review reported no effect on bone density at doses up to 1,000 mcg per day.(14)The significance of small biochemical changes in adrenocortical function is unknown. Titrate the dose of inhaled steroid to the lowest dose at which effective control of asthma is maintained.

In Children administration of inhaled steroids at or above 400 mcg a day of BDP or equivalent may be associated with systemic side effects.(15) These may include growth failure and adrenal suppression. Isolated growth failure is not a reliable indicator of adrenal suppression and monitoring growth cannot be used as a screening test of adrenal function.(16) Clinical adrenal insufficiency has been identified in a small number of children who have become acutely unwell at the time of intercurrent illness. Most of these children had been treated with high doses of inhaled corticosteroids. The dose or duration of inhaled steroid treatment required to place a child at risk of clinical adrenal insuffi ciency is unknown but is likely to occur at ?800 mcg per day of BDP or equivalent. The low dose ACTH test is considered to provide a physiological stimulation of adrenal responsiveness but it is not known how useful such a sensitive test is at predicting clinically relevant adrenal insufficiency.(17)In addition, it is unknown how frequently tests of adrenal function would need to be repeated if a child remained on high-dose inhaled corticosteroid. At higher doses, add-on agents, for example, long-acting ?2 agonists, should be actively considered.

BTS recommends to monitor height of children on high doses of inhaled steroids on a regular basis. The lowest dose of inhaled steroids compatible with maintaining disease control should be used.For children treated with ?800 mcg per day of BDP or equivalent specific written advice about steroid replacement in the event of a severe intercurrent illness should be part of the management plan. The child should be under the care of a specialist paediatrician for the duration of the treatment.Consider the possibility of adrenal insuffi ciency in any child maintained on inhaled steroids presenting with shock or a decreased level of consciousness; serum biochemistry and blood glucose levels should be checked urgently. Consider whether intramuscular (IM) hydrocortisone is required. Several comparative studies have demonstrated that budesonide and fluticasone propionate (FP) have less systemic effect than beclomethasone dipropionate (BDP) and triamcinolone. Patients seem to be protected from developing systemic adverse effects with high-dose fluticasone propionate therapy, as evaluated by basal and dynamic measures of hypothalamic-pituitary-adrenal axis activity. The risk of systemic effects also depends on the delivery system; use of spacers decreases the systemic bioavailability and the risk of systemic side effects for most glucocorticosteroids.

Comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma :

Children under the age of 12 years: A systematic review of clinical and cost-effectiveness studies and economic analyses were carried out by Main et al, 2008. A flexible framework was used to allow different types of economic analyses as appropriate, with either a cost comparison or cost-consequence comparison conducted. The most frequently reported relevant outcomes in the 16 RCTs were peak expiratory flow rate (13 trials), FEV1 (13 trials), symptoms (13 trials), adverse events or exacerbations (13 trials), use of rescue medication (12 trials), markers of adrenal function (e.g. blood or urine cortisol concentrations) (13 trials), height and/or growth rate (seven trials) and markers of bone metabolism (two trials). There are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. BDP CFC-propelled products are often the cheapest ICS currently available at both low and high dose, and may remain so even when CFC-propelled products are excluded. There appear to be no significant clinical differences in effects between the use of a combination inhaler versus the same drugs in separate inhalers. There are potential cost savings with the use of combination inhalers compared to separate inhalers. At present prices, the Budesonide/Formoterol fumarate combination is more expensive than those containing Fluticasone Propionate/Salmeterol, but it is not known whether there are clinically significant differences between them.(29)

Adults and children aged 12 years and over: The evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available and tend to remain so as the daily ICS dose required increases. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed for all outcome measures. The cost differences between combination therapy compared with ICS monotherapy are highly variable and dependent on the dose required and the particular preparations used. For the combination therapies of ICS/LABA there are potential cost savings with the use of combination inhalers compared with separate inhalers, with few differences between the two treatment strategies in terms of effects. The only exception to this cost saving is with BUD/FF at doses higher than 1200 microg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. Neither of the two combination inhalers (FP/SAL or BUD/FF) is consistently superior in terms of treatment effect. A comparison of the costs associated with each combination therapy indicates that at low dose FP/SAL delivered via a pMDI is currently the cheapest combination inhaler but only marginally cheaper than BUD/FF delivered as a DPI. At higher doses, both the FP/SAL combination inhalers (PMDI and DPI) are marginally cheaper than BUD/FF (DPI).( 30)

Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma :

In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled beta2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids. Greenstone et al,2005, showed that in adult asthmatics, there was no significant difference between the combination of LABA and ICS and a higher dose of ICS for the prevention of exacerbations requiring systemic corticosteroids. Overall, the combination therapy led to greater improvement in lung function, symptoms and use of rescue beta2 agonists, (although most of the results are from trials of up to 24 weeks duration). There were less withdrawals due to poor asthma control in this group than when using a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor, the two options appear safe although adverse effects associated with long-term ICS treatment were seldom monitored.( 25)

CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS : For the small number of patients not controlled at step 4 with high dose inhaled steroid and add on therapy, use daily steroid tablets in the lowest dose providing adequate control. Prednisolone is the most widely used steroid tablet for maintenance therapy in chronic asthma.There is no evidence that other formulations offer any advantage. Parenteral use of triamcinolone can abolish persisting eosinophilia and improve symptoms in patients with severe asthma; its mechanism is not understood.

Patients on long term steroid tablets (eg longer than three months) or requiring frequent courses of steroid tablets (eg three to four per year) will be at risk of systemic side effects.BTS recommends blood pressure should be monitored, diabetes mellitus and hyperlipidaemia may occur, bone mineral density should be monitored. When a significant reduction occurs, treatment with a long-acting bisphosphonate should be offered.(18), growth should be monitored in children, cataracts may be screened for in children through community optometric services. Fatal herpes virus infections have been reported among patients who are exposed to these viruses while taking systemic glucocorticosteroids, even short bursts Although popular in paediatric practice, there are no studies to show whether alternate day steroids produce fewer side effects than daily steroids. Although it is rare, adrenal failure may occur when a patient is withdrawn from long-term suppressive doses of oral glucocorticosteroids. Any such withdrawal should thus be observed for clinical and laboratory evidence of adrenal insufficiency.

Adherence to Inhaled corticosteroids and their impact on asthma control :Poor asthma control is associated to high morbidity. Lasmar et al ,2009, studied the association between adherence rates to beclomethasone dipropionate (BDP) and the degree of asthma control. A cohort concurrent study was carried out for 12 months with 122 asthmatic patients, aged 3-12 years, randomly selected in a pediatric pulmonology outpatient clinic, who received BDP free of charge. Adherence rates were verified by pharmacy records. Clinical control was assessed through a scoring system comprising four variables (nocturnal and morning symptoms, limitation of physical activities and exacerbations). Fewer than half (40.3% maximum) of the 122 patients maintained asthma control. Median adherence rate of groups 1 and 2 were 85.5% and 33.8%, (P < 0.001) in the 4th month, 90.0% and 48.0% (P < 0.001) in the 8th month and 84.4% and 47.0% in the 12th month (P < 0.001), respectively. Author concludes that in all periods, there were statistically significant differences in adherence rates for maintaining or not maintaining the asthma control. Optimal asthma control entailed adherence rate higher than 80%. Strategies for reducing asthma morbidity should include a regular monitoring of adherence to inhaled steroids.(27)

The above group also did a study to assess rates and factors related to low adherence to ICS over time in asthmatic children and adolescents. Factors associated to adherence rates <70% were: mother's schooling level (p = 0.03), replacement of the caregiver (p = 0.03), prescription greater than two puffs/day (p = 0.005), absence of rhinosinusitis (p = 0.002) and age under 7 years (p = 0.04). Only the number of consultations lower than two in a 4-month period was associated to a lower adherence rate in all study periods (p = 0.02). Adherence rates decreased over time, even in patients who had received the medication free of charge, and factors related to lower adherence changed during the follow-up. Results have shown that adherence had a dynamic pattern and its determinants should be re-evaluated continuously. Only the number of consultations was associated to a lower adherence rate in all periods, pointing out that health programs must recognize and facilitate the access of patients needing special care, which can contribute for better adherence and reducing asthma morbidity.(28)

Summary

Glucocorticosteroids are the preferred treatment for patients with persistent asthma at all levels of severity. However they do not cure asthma. ICS improve asthma control, reduce exacerbations and prevent asthma deaths. Steroids work by reducing airway inflammation and help in airway remodeling by various mechanisms like reduction of inflammatory cytokines, suppressing eosinophilic airway inflammation, reducing large airway basement membrane thickness. Inhaled route is the most preferred and effective method of administration for asthma. The starting dose of steroid should be appropriate to the severity of the disease. In adults, a reasonable starting dose will usually be 400 mcg per day and in children 200 mcg per day. Most current inhaled steroids are slightly more effective when taken twice rather than once daily, but may be used once daily in some patients with milder disease The dose of inhaled steroid should be titrated to the lowest dose at which effective control of asthma is maintained. Use of spacers decreases the systemic bioavailability and the risk of systemic side effects for most glucocorticosteroids. High doses of inhaled steroids may be associated with systemic side effects. In adults there is little evidence that doses below 800 mcg per day cause any short term detrimental effects. In Children administration of inhaled steroids at or above 400 mcg a day of BDP or equivalent may be associated with systemic side effects. The side effects include growth suppression and adrenal suppression. British Thoracic Society recommends to monitor height of children on high doses of inhaled steroids on a regular basis. The possibility of adrenal insufficiency in any child maintained on inhaled steroids presenting with shock or a decreased level of consciousness should be considered and written advice about steroid replacement in the event of a severe intercurrent illness should be part of the management plan The child should be under the care of a specialist paediatrician for the duration of the treatment. Studies show that there are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. In adults the evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed.

Even though steroids play a major role in the treatment of asthma, Prevention should underlie all treatment strategies. Also patient education regarding precipitants of asthma, allergic symptoms is essential. Guided self-management to prevent, assess and treat symptoms is the key to optimizing disease control.

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