Accuracy of asthma treatment in schoolchildren in NSW, Australia

Insufficient use of anti-inflammatory drugs, such as inhaled corticosteroids and cromoglycate, may contribute to the disease burden associated with asthma. Conversely, aggressive treatment of mild disease may result in avoidable costs and/or adverse drug effects. The aim of this study was to determine the relationship between asthma severity and inhaled corticosteroid/cromoglycate use in a large (n=4,909) random sample of children, aged 8-11 yrs, in NSW, Australia. Asthma and its treatment were assessed by questionnaire responses. Asthma, defined as diagnosis plus current wheeze, was present in 901 children (18% of the sample), of whom 225 (5%) had moderate asthma, defined as asthma plus additional symptoms (sleep disturbance), utilization (hospital, casualty), or disability (reduced activity, school absence). Use of inhaled corticosteroid/cromoglycate was reported by 636 children (13% of the sample). Determinants of use included: asthma diagnosis, current wheeze, and troublesome dry nocturnal cough. There was also a strong relationship between anti-inflammatory treatment and a multicomponent asthma severity score constructed for each child. Inhaled corticosteroids and/or cromoglycate were used by 56% of the children with asthma (24% daily) and by 76% of children with moderate asthma (42% daily). Undertreatment, defined as less than daily inhaled corticosteroids/cromoglycate in moderate asthma, was identified in 130 children (14% of those with asthma or 3% of the sample). Conversely, apparently aggressive treatment, defined as inhaled corticosteroid/cromoglycate use in children with persistent minimal symptoms (asthma severity score of less than 3) was identified in 101 children (2% of the sample). Although there were significant differences between regions in the choice of anti-inflammatory drugs and in the prevalence both of undertreatment and apparently aggressive treatment, there was no clear relationship to regional utilization of emergency and hospital services for asthma. Nevertheless, the frequency of undertreatment suggests an opportunity to reduce asthma morbidity by more consistent application of current therapeutic guidelines.     

Pharmacologic therapy of asthma during pregnancy

Asthma is a common, potentially serious medical complication during pregnancy. Optimal clinical and pharmacologic management is necessary to mitigate maternal and fetal complications. Mild asthma may be managed in most cases with inhaled beta 2-mimetics. Anti-inflammatory therapy is recommended for the treatment of moderate and severe asthma. Based on limited human experience, beclomethasone is currently the recommended inhaled corticosteroid during pregnancy. However, other inhaled corticosteroids may have advantages compared to beclomethasone because of reduced systemic absorption, which may adversely affect intrauterine growth. Based upon theoretic considerations, theophylline is now considered a secondary therapy, but data demonstrating the superiority of inhaled corticosteroids versus theophylline during pregnancy are lacking.     

Asthma treatment during pregnancy. What can be safely taken?

'Safe' pharmacological therapy for gestational asthma is defined as therapy during which the apparent risks of the drug appear to be lower than the maternal and potential fetal risks of uncontrolled asthma that could result if the drug were not used. Major malformations occur in 2 to 4% of all newborns, 1% of which can be attributed to medication in general. Information regarding the effects of drugs administered during pregnancy may come from animal studies, human case reports, and prospective cohort studies. Based on a review of the available information, it is recommended that mild asthma during pregnancy be managed with inhaled beta 2-agonists, as required; step therapy for moderate asthma would include inhaled sodium cromoglycate (cromolyn sodium), inhaled beclomethasone dipropionate and oral theophylline. Severe gestational asthma should be treated with oral corticosteroids at the lowest effective dosage. The pharmacological management of acute asthma during pregnancy should include nebulised beta 2-agonists and ipratropium bromide, and intravenous methylprednisolone. Intravenous aminophylline would not generally be recommended, unless the patient requires hospitalisation. Optimal medical practice medico-legal considerations demand that the patient's informed consent be obtained for that recommended gestational management programme.     

Difficult asthma

Asthma is usually easy to manage, but approximately 5% of patients are not controlled even on high doses of inhaled corticosteroids. It is important to assess these patients carefully in order to identify whether there are any correctable factors that may contribute to their poor control. It is critical to make a diagnosis of asthma and to exclude other airway diseases, particularly chronic obstructive pulmonary disease (COPD), and vocal cord dysfunction ("pseudo-asthma"). Poor adherence to therapy, particularly inhaled corticosteroids, is a common reason for a poor response. There may be unidentified exacerbating factors, including unrecognized allergens, occupational sensitizers, dietary additives, drugs, gastro-oesophageal reflux, upper airway disease, or other systemic diseases, that need to be identified and avoided or treated. Psychological factors may be important in some patients, but it is difficult to know whether these are causal or secondary to troublesome disease. Some patients have instability of their asthma, with resistant nocturnal asthma, premenstrual exacerbations or chaotic and unpredictable instability (brittle asthma). A few patients are completely resistant to corticosteroids, but more patients are relatively resistant and require relatively high doses of corticosteroids to control their symptoms (steroid-dependent). Some patients develop progressive loss of lung function, as in patients with COPD. Management of patients with difficult asthma should be supervised by a respiratory specialist and should involve careful assessment to confirm a diagnosis of asthma, identification and treatment of exacerbating factors, particularly allergens, and recording of peak expiratory flow patterns. A period of hospital admission may be the best way to assess and manage these patients. Treatment involves optimizing corticosteroids therapy, assessing additional controllers such as long-acting inhaled or subcutaneous beta2-agonists or subcutaneous, theophylline and antileukotrienes. In some patients, the use of immunosuppressive treatments may reduce steroid requirements, although these treatments are rarely effective and have side-effects. In the future, the nonsteroid anti-inflammatory treatments now in development may be useful in these patients.     

Fluid-bed microencapsulation of ascorbic acid

Epidemiological studies suggest the prevalence of asthma is increasing, though some remain sceptical as to the magnitude or indeed the presence of an increase. However, despite improved diagnosis and the availability of the potent drugs now available there remains considerable respiratory morbidity associated with asthma. It is clear from a number of studies that failure to deliver drugs to the lungs when using inhaler devices is a factor contributing to this high level of morbidity. Failure of drug delivery may result from the prescribing of inappropriate devices, failure to use devices appropriately or failure to comply with a treatment regimen. For most of the currently available forms of asthma therapy there are significant advantages to be gained from administering them in aerosol form. The benefits to be derived from administering these drugs as an aerosol include a rapid onset of action for drugs such as beta-agonists and a low incidence of systemic effects from drugs such as beta-agonists and corticosteroids. Over the past 25 years our understanding of the nature of asthma has changed. Though this has been reflected in the emphasis on inhaled corticosteroid therapy in recent guidelines, it has not been reflected in the range of inhaler devices available. Manufacturers continue to place drugs such as corticosteroids in the same devices as short acting beta-agonists even though the requirements for these different drug classes are very different. It is likely that this contributes to suboptimal therapeutic responses with inhaled corticosteroids. However, the variability associated with current delivery systems is relatively small compared with the variability introduced by poor compliance. There is no work currently available to indicate how the use of cheap disposable devises which do not incorporate any form of positive feedback influence compliance with inhaled steroids. Optimising aerosolised drug delivery in childhood involves consideration of the class of drugs, the particular drug within a class but more importantly, the age and abilities of the child. Devices must be selected to suit a particular child's needs and abilities. Devices utilising tidal breathing are generally used such as spacing chambers or, less commonly these days, nebulisers. A screaming or struggling child, or failure to use a closely fitting mask, reduces drug delivery to the lungs enormously. Failure to respond to inhaled therapy in early childhood may be attributable to failure of drug delivery. Drug delivery in early childhood using current devices remains more an art than a science.     

Cyclosporin in severe steroid-requiring bronchial asthma

BASIC PROBLEM: Treatment of chronic severe bronchial asthma with corticosteroids is inadequate in a minority of patients and is often accompanied by considerable side effects. Additional specific immunosuppression appears to be therapeutically promising. PATIENTS AND TREATMENT: Three patients (2 women, aged 44 and 29, a man aged 57 years), all with chronic severe asthma requiring corticosteroids, were given cyclosporin (mean dose 1.8 mg/kg; serum level 72 +/- 35 ng/ml) additional to conventional bronchospasmolytic drugs for 9 to 20 months. COURSE: The frequency and intensity of asthmatic attacks markedly decreased in all three patients. The mean peak-flow measurements in the mornings before broncholysis had increased by 23% over the precyclosporin level of the calculated normal value. Peak flow variability improved by 13%. The mean one-second forced expiratory volume (FEV1) rose from 37 to 66% of the normal value (P < or = 0.05) and correlated with the serum cyclosporin level (correlation coefficient 0.58-0.97). The frequency of acute severe asthmatic attacks (FEV1 < or = 40%) requiring additional hospitalization with intravenous administration of glucocorticoids fell by 30%. The systemic corticosteroid maintenance dosage could be significantly reduced or the drug discontinued in two patients. CONCLUSION: These observations indicate that cyclosporin can be useful in the treatment of selected cases of chronic severe steroid-refractory asthma. Prospective studies are needed to judge its long-term efficacy.     

Asthma: benchmarking for quality improvement

BACKGROUND: Linked medical and pharmacy claims can be used to identify patients with asthma and benchmark current practice standards. METHOD: This was a 3-year study of five independent practice association style health maintenance organizations with an annual enrollment of 870,000. More than 28,000 members were identified with claims for asthma. OBJECTIVE: The intent of this study was to benchmark current asthma practice. Before quality improvement projects can be implemented baseline data are required. RESULTS: The prevalence of asthma varied by geographic regions. Specialty care was associated with greater use of anti-inflammatory medications and more refills of these drugs. Refill rates for inhaled corticosteroids for all patients was low. Specialty care of asthmatic members was associated with a lower rate of emergency service events and hospitalizations. CONCLUSIONS: Linked medical and pharmacy claims' databases can be used to benchmark current practice performance and serve as a reference for quality improvement programs. Appropriate use of specialty care may improve asthma outcomes.     

The effect of different corticosteroids and cyclosporin A on interleukin-4 and interleukin-5 release from murine TH2-type T cells

By secretion of interleukin-4 and interleukin-5, TH2-type T cells are thought to play an important role in the pathogenesis of asthma. Corticosteroids are currently the most effective therapy available for asthma, but recently it has been demonstrated that cyclosporin A improves lung function in patients with severe corticosteroid-dependent asthma. In order to examine the effects of corticosteroids and cyclosporin A on anti-CD3-induced production of interleukin-4 and interleukin-5 we used the murine TH2-type cell clone D10.G4.1. Interleukin-4/interleukin-5 release was inhibited by all drugs tested with the following IC50 values (nmol/l) for interleukin-4 and interleukin-5, respectively: budesonide (0.32/0.22), beclomethasone (0.65/0.33), dexamethasone (4.70/3.52), 6 alpha-methyl-prednisolone (24.04/17.02), hydrocortisone (34.27/22.55), and cyclosporin A (72.59/242.21). In conclusion, corticosteroids exert strong inhibitory effects on cytokine production by TH2-cells, which may explain, at least partly, its clinical efficacy in asthma. Cyclosporin A also showed a concentration-dependent inhibition; however, in relation to corticosteroids the inhibitory activity of cyclosporin A was found to be weaker.     

Long-term effects of therapy on respiratory health

Only scant information is available on the long-term consequences to respiratory health of treatment with bronchodilators and oral corticosteroids. In the present study, we aimed to gain more information about these consequences. We examined 712 men working in the Paris area, by means of a subjective assessment of whether their respiratory health worsened or improved from 1960 to 1972, the decline in forced expiratory volume in one second (FEV1) over this time-period, and mortality from 1972 to 1992, in relation to respiratory therapy dispensed during a 2 year period in 1970-1971, as recorded in social security reimbursement records. As expected, subjects with respiratory symptoms or airflow limitation were more likely to have been prescribed respiratory therapy. After accounting for the effect of lung function level and smoking, subjects dispensed inhaled beta-agonists were likely to feel their condition had worsened and had a greater decline in FEV1 from 1960 to 1972. Among subjects with airflow limitation who reported asthma or persistent wheeze, having been dispensed oral corticosteroids on an intermittent basis was associated with improved survival (relative risk (RR) 0.32; 95% confidence interval (95% CI): 0.10-0.91) after adjusting for FEV1 level and smoking category. Our results add to the evidence that regular use of beta-agonist bronchodilators may be associated with adverse effects on respiratory health, whilst intermittent use of corticosteroids may be of long-term benefit.     

Beclomethasone dipropionate, budesonide and flunisolide in the treatment of bronchial asthma (a review of the literature and the authors' own research)

Inhalation corticosteroids (beclometasone dipropionate, budesonide, flunisolide) proved effective against bronchial asthma (BA) and safe as they induce no severe systemic side effects. Of these three drugs side effects arise most frequently in administration of beclometasone dipropionate, least frequently of flunisolide. These inhalation corticosteroids are indicated both in non-steroid-dependent and steroid-dependent BA to reduce the dose of oral steroids or, if possible, for their complete discontinuation. Flunisolide is the most potent and effective of all inhalation corticosteroids used in current practice.     

Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 1. General principles

The safety of long-term inhaled corticosteroid therapy at commonly prescribed doses is an issue of growing concern to physicians and international regulatory bodies. This is so because long-term use of these drugs has become the mainstay of chronic asthma management and their introduction now is widely recommended in official treatment guidelines at the 'mild persistent' stage of asthma, where regular daily therapy is first begun. In addition to more frequent use of inhaled corticosteroids, there is a further trend to use higher doses of existing inhaler therapies and to use the newer and more potent compounds that have recently become available. At the same time as these developments have been taking place, there has not been a concurrent move to a more rigorous examination of the safety profile of these inhaled corticosteroid treatments - especially to assess their effects on the hypothalamic-pituitary-adrenal (HPA) axis. Most safety data with respect to HPA axis effects have been derived from testing methods that are limited in their ability to detect HPA system impairment and, more seriously, that can give the impression of functional integrity in the HPA axis when there may be moderate (or even greater) impairment. In this first part of a two-part review of the HPA axis effects of inhaled corticosteroids and of how these effects should be assessed, we examine the currently used and the currently available testing methodologies and also review the present state of knowledge concerning the structure and function of the HPA axis and the effects of its suppression. It is clear that there are state-of-the-art tests to assess in a discriminating manner the safety profile of inhaled corticosteroids. These tests have been insufficiently employed, including during the drug development process, yet they are readily available, relatively inexpensive and can detect adrenal suppression before the appearance of clinical effects. In part 2 of this review we examine what can be learned about the effects of inhaled corticosteroid therapy on the HPA axis from the limited amount of reliable published information from clinical and pharmacological studies describing their use and safety.     

Pharmacological specificities and modalities of prescriptions for corticoids for asthmatic adults

The efficacy of corticosteroids in asthma has been recognized over 40 years ago. Since that time, the advent of inhaled forms has further improved the therapeutic of these drugs which are now recognized as the fundamental treatment for asthma, and described in detail by national and international consensus. Based on a large body of literature, it can now be recommended to prescribe inhaled corticosteroids for symptomatic asthma patients. Long-term treatment is required and dosage not exceeding 1000 micrograms/d (beclometasone dipropionate equivalent) in adults are safe. Differences in the pharmacological characteristics of the various systematic and inhaled corticosteroids can be used to adapt treatment and administration route to each patient and achieve good patient compliance with optimal therapeutic efficacy.     

Airway subsensitivity with long-acting beta 2-agonists. Is there cause for concern?

Regular treatment with both long- and short-acting beta 2-agonists results in tolerance to their bronchoprotective effects, although the relevance of this phenomenon in terms of long term asthma control remains unclear. However, there appears to be no appreciable difference between the 2 long-active beta 2-agonists, salmeterol and formoterol, in their propensity to induce beta 2-adrenoceptor down-regulation and subsensitivity. The degree of subsensitivity appears to be somewhat greater with indirect stimuli such as exercise and allergen challenge, compared with direct stimuli such as histamine and methacholine. This loss of functional antagonism with long-acting beta 2-agonist therapy is partial and is not prevented by concomitant inhaled corticosteroid therapy. However, the protective effects of inhaled corticosteroids on their own appear to be additive to those of long-acting beta 2-agonists when both drugs are concomitantly administered in the long term. The subsensitivity to bronchoprotection may be of clinical relevance in terms of patients who are inadvertently exposed to indirect bronchoconstrictor stimuli such as allergens or exercise, suggesting that long-acting beta 2-agonists should not be taken on a regular basis for this particular indication. There is a greater tendency for bronchodilator subsensitivity to develop with longer-acting, than with shorter-acting beta 2-agonists, and this may reflect the longer duration of beta 2-adrenoceptor occupancy and consequent downregulation. As with the bronchoprotective effects of long-acting beta 2-agonists, the development of bronchodilator subsensitivity is only partial and occurs regardless of whether patients are taking concomitant inhaled corticosteroid therapy. The long-term bronchodilator action of the long-acting beta 2-agonist itself is maintained within the twice daily administration interval. However, subsensitivity occurs in relation to a blunted response to repeated doses of short-acting beta 2-agonists, as in the setting of an acute asthma attack. There is considerable inter-individual variability in the propensity for downregulation and subsensitivity, which is determined by genetic polymorphism of the beta 2-adrenoceptor. Current international asthma management guidelines suggest that long-acting beta 2-agonists should be used on a regular basis in patients who ware inadequately controlled on inhaled corticosteroid therapy, so the addition of long-acting beta 2-agonist therapy is an alternative to using higher doses of inhaled corticosteroids. There are, however, concerns that regular long-acting beta 2-agonists might result in masking of inadequately treated inflammation in patients receiving suboptimal inhaled corticosteroid therapy. Physicians should be aware of the airway subsensitivity that develops with long-acting beta 2-agonist therapy, and patients should be warned that they may have to use higher than conventional dosages of short-acting beta 2-agonists to relieve acute bronchoconstriction in order to overcome this effect. In patients receiving an optimised maintenance dose of inhaled corticosteroid, if long-acting beta 2-agonists are to be used on an as required basis, it would seem rational to use formoterol for this purpose, due to its faster onset of action than salmeterol.     

New strategies in the medical management of asthma

Asthma, a common chronic inflammatory disease of the airways, may be classified as mild intermittent or mild, moderate, or severe persistent. Patients with persistent asthma require medications that provide long-term control of their disease and medications that provide quick relief of symptoms. Medications for long-term control of asthma include inhaled corticosteroids, cromolyn, nedocromil, leukotriene modifiers and long-acting bronchodilators. Inhaled corticosteroids remain the most effective anti-inflammatory medications in the treatment of asthma. Quick-relief medications include short-acting beta2 agonists, anticholinergics and systemic corticosteroids. The frequent use of quick-relief medications indicates poor asthma control and the need for larger doses of medications that provide long-term control of asthma. New guidelines from the National Asthma Education and Prevention Program Expert Panel II recommend an aggressive "step-care" approach. In this approach, therapy is instituted at a step higher than the patient's current level of asthma severity, with a gradual "step down" in therapy once control is achieved.     

One year follow-up study of endocrine and lung function of asthmatic children on inhaled budesonide

Inhaled corticosteroids have become a mainstay in the management of chronic asthma. Their use had been considered safe, although some degree of adrenal suppression has been demonstrated after 2 and 4 weeks of treatment with either 400 microg x day(-1) of beclomethasone dipropionate or budesonide. To weigh the benefits and risks of long-term treatment, 12 children with moderately severe asthma were assessed in a follow-up study on budesonide 200 microg b.i.d. After 1 yr, the nocturnal cortisol production was significantly reduced by 19%, but no greater compared to 2 and 4 weeks of treatment. Growth and growth hormone levels were normal. Lung function tests were significantly better, not only versus baseline values but also versus 2 and 4 weeks of treatment. We conclude that systemic effects of inhaled corticosteroids in conventionally low doses do not accumulate with length of treatment, whilst lung function parameters will continue to improve. Therefore, inhaled corticosteroids once started in asthmatic children not controlled on other medications should be continued, but their use should be carefully considered and the minimal dose required to control the asthma employed.     

Influence of cataract surgery on the diabetic eye: a prospective study

The aims of treating patients with asthma are to relieve symptoms, to prevent symptoms and exacerbations, and to prevent long-term deterioration in lung function. It is the role of medical practitioners to inform the patient what asthma is, and to develop a plan to achieve the aims for the individual, recognizing that asthma is frequently a chronic, lifelong disease. Most patients can be diagnosed, assessed for severity and causes, and treated in primary care practices, however, sometimes help from an asthma clinic of a specialist is required. The most important management decision is to determine whether the patient needs inhaled corticosteroids; subsequently, decisions about dose, duration and method of delivery of treatment can be tailored to the individual depending on the preferences and social conditions of the patient. The aim of this article is to present the latest strategies for the management of asthma and the simplest methods for their implementation. Important new strategies include careful assessment of the severity; immediate introduction of a plan that is tailored of the individual and aimed at the possible reversing of the disease; detailed instructions for management of exacerbations and the combined use of inhaled corticosteroids with a long-acting bronchodilator. It is becoming clear that these strategies obviate dependence on oral corticosteroids in newly diagnosed asthmatic patients. Furthermore, relatively low doses of inhaled corticosteroids can be used to maintain good control if used in conjunction with other therapies. The role of newly developed antagonists to leukotrienes is not yet known but it may well be useful in mild asthma and in special forms of the disease, such as those sensitive to aspirin. In the future, the most important strategy will be to prevent the disease.     

Churg-Strauss syndrome associated with zafirlukast

The leukotriene receptor antagonist zafirlukast (Accolate; Zeneca Pharmaceuticals; Wilmington, Del) recently was approved for use as maintenance therapy for persistent asthma. This new product has been well received due to convenient dosing and relatively few side effects. Based on initial success with this product, it is likely that similar compounds will be available for use in the near future. In this report, a case is described of a 47-year-old white man with moderate persistent asthma in whom Churg-Strauss syndrome developed while he was receiving zafirlukast therapy. Acute respiratory insufficiency, arthralgia, and prominent rash developed which required hospitalization. The patient's symptoms rapidly reversed following discontinuation of zafirlukast therapy and administration of systemic corticosteroids. Although the incidence of Churg-Strauss syndrome associated with zafirlukast therapy is rare, this case report illustrates steps that may be taken to diagnose quickly and treat this life-threatening condition should it occur.     

Nedocromil sodium (Tilade)

Nedocromil sodium is a well-tolerated antiasthmatic agent for initial therapy in patients with mild or moderate asthma not well controlled with inhaled beta-2 agonists and/or where methylxanthines are indicated. Like cromolyn sodium, nedocromil sodium offers a potential alternative to inhaled corticosteroids as maintenance therapy in patients with mild or moderate asthma not adequately controlled by bronchodilators. Furthermore, cromolyn sodium and nedocromil sodium may also reduce the usage of corticosteroids and provide some additional symptom control in patients whose asthma is not suitably controlled by optimal doses of inhaled corticosteroids. Both nedocromil sodium and cromolyn sodium are more efficacious than placebo for controlling of asthma, however, few studies have compared the effectiveness of cromolyn versus nedocromil at this time. Further experience and comparison studies of nedocromil sodium with cromolyn sodium in children are required before the role of nedocromil sodium as maintenance treatment in young asthmatic patients can be defined.