Anne E. Tattersfield

First is a paper by Tweedale et al1 which looked at short term repeatability of FEV1 and bronchodilator responsiveness in patients with airflow obstruction. The authors showed that within subject differences in FEV1 measurements made 20 minutes apart were usually within 160 ml, and that this was true whether the initial FEV1 was 1 or 5 litres. This has been enormously useful when planning studies and also when interpreting small changes in FEV1 in individual patients. The article also highlighted the difficulty of defining a bronchodilator response—whether to use a percentage change which favours patients with a low FEV1 or an absolute response exceeding 160 ml, which favours those with a high FEV1—to mention just two methods. The paper didn’t provide the answer but, by relating responses to repeatability, provided a clearer picture of how such data should be interpreted.

The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective β-agonist, isoproterenol, was isolated in 1940, followed by the development of selective β₂-agonists in the 1960s and the introduction of the long-acting β₂-agonists in the 1990s. The introduction of β₂-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The β₂-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from β₂-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

Systemic bioavailability from the gastrointestinal tract is reduced with newer inhaled corticosteroids (ICSs) such as fluticasone, but systemic absorption still occurs via the lung. Observational studies have shown an association between ICS use and several adverse outcomes such as cataracts, glaucoma, and adrenal failure, and prospective controlled studies have confirmed a causal relationship between ICS use and bruising, reduction in bone mineral density, and reduced growth velocity. The evidence suggests that the effect of ICSs on bone mineral density is small in the short term but that patients taking moderate or high doses for long periods will be at increased risk of fractures and that this could be an appreciable public health problem. There is also evidence to suggest that the risk of long-term adverse effects is likely to differ between ICSs. The clinical message that follows is that ICSs should be used widely because they reduce the need for courses of oral corticosteroids and improve quality of life, but that they need to be managed carefully to reduce the risk of adverse effects with long-term use.

The two inhaled long-acting β₂-adrenoceptor agonists, salmeterol and formoterol, have been studied extensively since their introduction in the early 1990s. In this review we consider the evidence for their efficacy and safety in adults with asthma and chronic obstructive pulmonary disease (COPD), by reviewing long-term prospective studies in which these drugs have been compared with placebo or an alternative bronchodilator. We have also assessed safety, including data from postmarketing surveillance studies and case-control studies using large databases. In patients with asthma, salmeterol and formoterol increase lung function, reduce asthmatic symptoms and improve quality of life when compared with placebo. Both drugs protect against exercise-induced asthma, although some tolerance develops with regular use. Tolerance to the bronchodilator effects of formoterol has also been seen, although this is small and most of the beneficial effects are maintained long-term. Both drugs have been shown to reduce asthma exacerbations but only in studies in which most patients were taking an inhaled corticosteroid. Adding a long-acting β₂-agonist provided better control than increasing the dose of inhaled corticosteroid in several studies. Long-acting β₂-agonists also provide better asthma control than use of regular short-acting β₂-agonists and theophylline. Their relative efficacy compared with leukotriene antagonists is uncertain as yet. Formoterol appears to be at least as safe and effective as a short-acting β₂-agonist when used on an ‘as required’ basis. In patients with COPD, both salmeterol and formoterol offer improved lung function and reduced COPD symptoms compared with placebo, and quality of life has been improved in some studies. Some tolerance to the bronchodilating effect of salmeterol was seen in one study. Most studies have not found a significant reduction in exacerbations in COPD. Both drugs have provided greater benefit than ipratropium bromide or theophylline; there are limited data on tiotropium bromide. The long-acting β₂-agonists cause predictable adverse effects including headache, tremor, palpitations, muscle cramps and a fall in serum potassium concentration. Salmeterol can also cause paradoxical bronchospasm. There is some evidence that serious adverse events including dysrhythmias and life-threatening asthma episodes can occur; however, the incidence of such events is very low but may be increased in patients not taking an inhaled corticosteroid. Salmeterol 50μg twice daily and formoterol 12μg twice daily are effective and safe in treating patients with asthma and COPD. Higher doses cause more adverse effects, although serious adverse events are rare.

Background: Lymphangioleiomyomatosis (LAM), a rare disease affecting women, is caused by somatic mutations in the tuberous sclerosis complex genes. Methods: A case–control questionnaire study was carried out examining parental and family history, prenatal events, and early life events to try to shed light on the aetiology of the condition. Forty five patients identified from a national LAM register completed a questionnaire and 31 were compared with 117 age and sex matched control subjects using conditional logistic regression. Results: No differences were found in perinatal events, childhood infections, and parental or family history, except that patients were more likely to be an only child (odds ratio (OR) 4.3 (95% confidence interval (CI), 1.5 to 11.8)) and have a relative with uterine fibroids (OR 4.2 (1.4 to 13)). Patients with LAM had had fewer pregnancies and fewer children but no differences in miscarriage rates. A non-matched analysis using all 45 cases and 117 controls gave similar results. Conclusions: No features in the family history, perinatal events, or early life events were detected that were associated with having LAM. Being more likely to be an only child and having an increased family history of uterine fibroids may, if confirmed, indicate some differences in reproductive function within the families of affected individuals.