Anne E. Tattersfield

Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group

BACKGROUND The role of long-acting, inhaled beta2-agonists in treating asthma is uncertain. In a double-blind study, we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. METHODS After a four-week run-in period of treatment with budesonide (800 microg twice daily), 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide plus placebo, 100 microg of budesonide plus 12 microg of formoterol, 400 microg of budesonide plus placebo, or 400 microg of budesonide plus 12 microg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma, symptoms, and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. RESULTS The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent, respectively, when formoterol was added to the lower dose of budesonide. The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent, respectively. Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent, respectively. Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide, but the improvements with formoterol were greater. CONCLUSIONS In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids, the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial. The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma.

Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study

Abstract Objective: To determine the prevalence of continuous use of oral steroids in the general population, the conditions for which they are prescribed, and the extent to which patients taking oral steroids are taking treatment to prevent osteoporosis. Design: A cross sectional study with a four year retrospective review of drug treatment. Setting: Eight large general practices in central and southern Nottinghamshire. Subjects: A population of 65 786 patients (52% women) registered with a general practitioner during 1995. Results: 303 patients (65% (197) women) aged 12-94 years were currently taking “continuous” (for at least three months) oral corticosteroid treatment. This figure represents 0.5% of the total population and 1.4% (245/17 114) of patients aged 55 years or more (1.7% (166/9601) of women). The usual steroid was prednisolone (97% (294/303)), the mean dose was 8.0 mg/day, and the median duration of oral steroid treatment determined in 149 patients was three years. The most common conditions for which continuous oral steroids were prescribed were rheumatoid arthritis (23% (70)), polymyalgia rheumatica (22% (66)), and asthma or chronic obstructive airways disease (19% (59)). Only 41 (14%) of the 303 patients taking oral steroids had received treatment for the prevention of osteoporosis over the past four years. Although 37 of the 41 patients were women, only 10% (18/181) of the women over 45 years taking continuous oral corticosteroids were currently taking hormone replacement therapy. Conclusions: If our figures are typical then they suggest that over 250 000 people in the United Kingdom are taking continuous oral steroids and that most of these are taking no prophylaxis against osteoporosis. Key messages The prevalence of use of oral corticosteroids in a community based population of 65 786 was 0.5%, rising to 1.7% in women aged >/=55 years The main indications for oral steroids were rheumatoid arthritis, polymyalgia, and asthma or chronic obstructive pulmonary disease Only 14% of patients taking oral steroids had received any treatment to prevent or treat osteoporosis These data suggest that over a quarter of a million people in the United Kingdom are currently taking oral corticosteroids and hence at risk of adverse effects

Inhaled corticosteroid use and bone-mineral density in patients with asthma

BACKGROUND Inhaled corticosteroids are absorbed into the systemic circulation, but the extent to which they have adverse effects on bone is uncertain. The question is important since 3% of the European population take an inhaled corticosteroid regularly and may do so for many years. METHODS We studied the dose-response relation between cumulative inhaled corticosteroid dose and bone-mineral density at the lumbar spine and proximal femur in 196 adults (119 women) with asthma aged 20-40 years. Patients had taken an inhaled corticosteroid regularly for at least 6 months, and had had limited exposure to systemic steroids. Cumulative dose of inhaled corticosteroid was calculated from questionnaires and computerised and written general-practice records, and its effect on bone-mineral density was estimated by multiple regression analysis. FINDINGS Median duration of inhaled corticosteroid treatment was 6 years (range 0.5-24), and median cumulative dose was 876 mg (87-4380). There was a negative association between cumulative dose of inhaled corticosteroid and bone-mineral density at the lumbar spine (L2-L4), femoral neck, Wards triangle, and trochanter, both before and after adjustment for the effects of age and sex. A doubling in dose of inhaled corticosteroid was associated with a decrease in bone-mineral density at the lumbar spine of 0.16 SD (95% CI 0.04-0.28). Similar decreases were found at the femoral neck, Wards triangle, and trochanter. Adjustment for potential confounding factors including physical activity and past oral, nasal, dermal, and parenteral corticosteroids did not weaken the associations. INTERPRETATION This study provides evidence of a negative relation between total cumulative dose of inhaled corticosteroid and bone-mineral density in patients with asthma.

The Bronchoconstrictor Effect of Inhaled Prostaglandin D2 in Normal and Asthmatic Men

Although prostaglandin D2 is the most abundant prostanoid generated by human lung mast cells and causes bronchoconstriction in animals, its effects have not been studied in human beings. We have compared the effects of inhaled prostaglandin D2 and prostaglandin F2 alpha on specific airway conductance in seven normal subjects and seven patients with mild allergic asthma. In dose-response studies in normal subjects, prostaglandin D2 caused a significant (20 +/- 6 per cent) fall in specific airway conductance after the two highest concentrations (250 and 500 micrograms per milliliter), whereas prostaglandin F2 alpha had no effect. In the asthmatic subjects, both prostaglandin D2 and prostaglandin F2 alpha caused a dose-related fall in specific airway conductance, starting at the lowest concentration of 4 micrograms per milliliter. Prostaglandin D2 was 3.5 times more potent than prostaglandin F2 alpha. In a single-dose study of both drugs (250 micrograms per milliliter), a minor fall in specific airway conductance occurred with prostaglandin D2 in the normal subjects, and a larger fall occurred with both drugs in the asthmatic subjects. Maximum effects were seen at three minutes: there was a 75 +/- 5 per cent fall with prostaglandin D2 and a 33 +/- 8 per cent fall with prostaglandin F2 alpha. These results suggest that prostaglandin D2 may be involved in the pathogenesis of bronchoconstriction in allergic asthma.

REBOUND INCREASE IN BRONCHIAL RESPONSIVENESS AFTER TREATMENT WITH INHALED TERBUTALINE

To investigate whether cessation of regular beta-agonist treatment results in an increase in bronchial responsiveness, two double-blind, randomised crossover studies were done. Subjects with mild asthma were investigated to determine the course of change in bronchial responsiveness, measured as the provocative dose (PD20) of histamine that caused a 20% fall in forced expiratory volume in 1 s after short-term and longer term treatment with an inhaled beta-agonist. In the first study in 8 subjects, 500 and 2000 micrograms terbutaline thrice in 1 day protected against histamine-induced bronchoconstriction, and the increase in PD20 compared with placebo remained high throughout the day and overnight. In the second study 8 subjects received placebo or terbutaline 750 micrograms thrice daily for 14 days. The protection afforded by terbutaline against histamine-induced bronchoconstriction on day 14 was less than that on day 1 by 40% in the morning and 82% in the afternoon. On day 15 PD20 was lower after stopping terbutaline than placebo, with a maximum difference of 1.5 (95% CI 0.6-2.5) doubling-doses of histamine 23 h after the end of treatment. Thus treatment with terbutaline for 1 day did not result in any rebound increase in bronchial responsiveness. Treatment for 2 weeks impaired the ability of terbutaline to protect against histamine-induced bronchoconstriction, and was followed by a rebound increase in bronchial responsiveness after cessation of treatment.

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) 1, 2. Sporadic LAM affects ∼1 in 400,000 adult females; in TSC, LAM occurs in 30–40% of adult females 3, 4 and exceptionally in males and children 5, 6. Patients with LAM usually develop progressive dyspnoea and recurrent pneumothorax, chylous collections and occasional haemoptysis 1. Extra pulmonary lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas can result in abdominal and pelvic lymphatic obstruction 7. LAM is often associated with angiomyolipoma in the kidneys 8, and an increased frequency of meningioma 9. LAM varies in clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about prognosis. Diagnosis is made by tissue biopsy (generally from the lung but occasionally from lymph nodes or lymphangioleiomyomas) and/or a combination of history and high-resolution computed tomography scanning (HRCT). Pathological diagnosis relies on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies. Increasingly HRCT is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM. As LAM is rare, there have been no controlled trials of its management. Supportive treatment includes management of airflow obstruction and hypoxaemia with bronchodilators and oxygen respectively, specific treatment for surgical or pleural complications including pneumo- and chylothorax, and interventional treatment of renal lesions 10, 11. As LAM is a disease of females and is thought to be accelerated by oestrogen, oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used without evidence that they are effective. The recent finding of abnormalities in the TSC1/2 genes resulting …

Descriptive epidemiology of bronchial reactivity in an adult population: results from a community study

The bronchial response to inhaled histamine has been suggested as an epidemiological tool for assessing the prevalence of asthma, though the exact relationship between reactivity and asthma is unknown. Tests of bronchial reactivity to histamine were carried out in 511 subjects aged 18-64 years, randomly selected from the population in two areas of the South of England, who had returned questionnaires on respiratory symptoms. Bronchial reactivity to less than or equal to 8 mumol histamine was present in 14% and was associated with positive skin test responses to common allergens and with smoking history. Both of these relationships were in turn dependent on age, skin sensitivity being the more important determinant of reactivity in the young and smoking the more important in older subjects. Bronchial reactivity was least prevalent in the 35-44 year age group. No independent effect on reactivity of sex, social class, or area of residence was detected, and no significant effect from recent respiratory tract infections. Interpretation of the bronchial response to histamine in selected groups of subjects must take account of age, atopic state, and smoking history.

Bronchoprotective role for endogenous prostaglandin E2.

The possibility that impaired production of bronchoprotective factors contributes to the pathogenesis of asthma cannot be excluded. Prostaglandin E2 (PGE2) could be such a factor. It is a dominant cyclo-oxygenase product of airway epithelium and smooth muscle; it has inhibitory effects on inflammatory cells and pathways involved in bronchoconstriction at concentrations known to occur in the airway; inhalation of PGE2 has considerable bronchoprotective effects in patients with asthma; and manoeuvres that increase or decrease endogenous production of PGE2 have beneficial and deleterious effects on airway function.

Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample

Magnesium is involved in a wide range of biological activities, including some that may protect against the development of asthma and chronic airflow obstruction. We tested the hypothesis that high dietary magnesium intake is associated with better lung function, and a reduced risk of airway hyper-reactivity and wheezing in a random sample of adults. In 2633 adults aged 18-70 sampled from the electoral register of an administrative area of Nottingham, UK, we measured dietary magnesium intake by semiquantitative food-frequency questionnaire, lung function as the 1-sec forced expiratory volume (FEV1), and atopy as the mean skin-prick test response to three common environmental allergens. We measured airway reactivity to methacholine in 2415 individuals, defining hyper-reactivity as a 20% fall in FEV1 after a cumulative dose of 12.25 mumol or less. Mean (SD) daily intake of magnesium was 380 (114) mg/day. After adjusting for age, sex, and height, and for the effects of atopy and smoking, a 100 mg/day higher magnesium intake was associated with a 27.7 (95% CI, 11.9-43.5) mL higher FEV1, and a reduction in the relative odds of hyper-reactivity by a ratio of 0.82 (0.72-0.93). The same incremental difference in magnesium intake was also associated with a reduction in the odds of self-reported wheeze within the past 12 months, adjusted for age, sex, smoking, atopy, and kilojoule intake, by a ratio of 0.85 (0.76-0.95). Dietary magnesium intake is independently related to lung function and the occurrence of airway hyper-reactivity and self-reported wheezing in the general population. Low magnesium intake may therefore be involved in the aetiology of asthma and chronic obstructive airways disease.

Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma

The airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind, crossover, placebo-controlled study the subjects received 2, 6, and 18 puffs of each drug with intervals of 90 min, and forced expiratory volume in 1 s, heart rate, QTc interval, plasma potassium concentration, tremor, and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol, salbutamol, and terbutaline were 29 (24) bpm, 8 (9) bpm, and 8 (14) bpm, respectively; falls in plasma potassium were 0.76 (0.62) mmol/l, 0.46 (0.32) mmol/l, and 0.52 (0.39) mmol/l, respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.