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Summary Background Treatment of acute asthma is based on rapid reversal of bronchospasm and airway inflammation. Magnesium sulphate (MgSO 4 ) is known to have a bronchodilator effect on smooth muscle but studies have shown conflicting results on its efficacy in acute asthma, although its use is recommended in national and international guidelines. Aims To determine if intravenous MgSO 4 , when used as an adjunct to standard therapy, improves the outcome in acute asthma. Methods A double blind, randomised placebo controlled trial comparing 1.2g MgSO 4 with standard therapy in adult patients with acute asthma. Patients had a PEF ⩽75% predicted and all were treated with oxygen, nebulised salbutamol and ipratropium, and IV hydrocortisone. They then received 1.2g IV MgSO 4 or placebo. Outcome measures were % predicted PEF at 60min and hospital admission rates. Results One hundred and twenty nine patients were studied. Placebo and active treatment groups were well matched at baseline. MgSO 4 had no benefit with regards hospital admission rates or % predicted PEF at 60min ( p =0.48) for the whole group, or for subgroups of life-threatening ( p =0.85), severe ( p =0.63) and moderate ( p =0.67) acute asthma. Conclusion This study did not show additional benefit from 1.2g IV MgSO 4 when given as an adjunct to standard therapy for acute asthma.

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids represent a management challenge. Leukotrienes play a key role in asthma pathophysiology, and since pro-inflammatory leukotrienes are poorly suppressed by corticosteroids it seems rational to add a leukotriene receptor antagonist (LTRA) when a low to moderate dose of inhaled corticosteroids does not provide sufficient disease control. Long acting beta2-agonist (LABA) treatment represents an alternative to LTRAs and both treatment modalities have been shown to provide additional disease control when added to corticosteroid treatment. To compare the relative clinical benefits of adding either a LTRA or a LABA to asthma patients inadequately controlled by inhaled corticosteroids, a randomized, double-blind, multi-centre, 48-week study will be initiated at approximately 120 centres throughout Europe, Latin America, Middle East, Africa and the Asia-Pacific region in early 2000. The study will compare the oral LTRA montelukast with the inhaled LABA salmeterol, each administered on a background of inhaled fluticasone, on asthma attacks, quality of life, lung function, eosinophil levels, healthcare utilization, and safety, in approximately 1200 adult asthmatic patients. The requirements for study enrollment include a history of asthma, FEV1 or PEFR values between 50% and 90% of the predicted value together with > or = 12% improvement in FEV1 after beta-agonist administration, a minimum pre-determined level of asthma symptoms and daily beta-agonist medication. The study will include a 4-week run-in period, during which patients previously taking inhaled corticosteroids are switched to open-label fluticasone (200 microg daily), followed by a 48-week double-blind, treatment period in which patients continuing to experience abnormal pulmonary function and daytime symptoms are randomized to receive montelukast (10 mg once daily) and salmeterol placebo, or inhaled salmeterol (100 microg daily) and montelukast placebo. All patients will continue with inhaled fluticasone (200 microg daily). During the study, asthma attacks, overnight asthma symptoms, and morning peak expiratory flow rate will be assessed using patient diary cards; quality of life will also be assessed using an asthma-specific quality-of life questionnaire. The results of this study are expected to provide physicians with important clinical evidence to help them make a rational and logical treatment choice for asthmatic patients experiencing breakthrough symptoms on inhaled corticosteroids.

Background. Dysphonia is a known local adverse eAect of inhaled corticosteroids. This symptom was investigated by laryngoscopy and assessment in a voice laboratory. The eAects of changing the treatment of patients with dysphonia, reported whilst using the pMDI, to pMDI plus Nebuhaler 1 or Tubuhaler 1 was also assessed. Methods. Seventy-two patients reporting dysphonia and taking inhaled steroids from a pMDI entered a 12-week, open, parallel group study. Fifty-one completed the study per protocol; 26 in the Nebuhaler group [21 female, mean age 57 years (22‐77)] and 25 in the Turbuhaler 1 group [18 female, mean age 58 years (21‐81)]. A dysphonia diary card was completed weekly. Voice laboratory assessments and laryngoscopy were performed on entry and at 12 weeks. Results. There were no diAerences in voice laboratory data, laryngoscopic evidence of disordered glottic closure and diary data between the two groups at 12 weeks. At study entry laryngoscopic appearances were normal in almost half the patients. Vocal cord bowing was rarely seen. Glottic closure changed in nine patients during the study period, but there was no correlation with voice symptoms. The trend of symptomatic improvement of voice status in the Turbuhaler 1 group did not correlate with voice laboratory assessments and laryngoscopic evidence of disordered glottic closure. After 4 weeks, 40% of patients using Turbuhaler 1 and 8% in the Nebuhaler 1 group scored their voice status as better (P

Of 65 patients presenting with pulmonary eosinophilia to one Respiratory Unit during a 20-year period, 12 (18%) had systemic features associated with their pulmonary disease. Eleven had fever, three night sweats, three arthralgia, three vasculitic rashes and two weight loss. Anaemia, myalgia, peripheral neuropathy, mononeuritis, pericardial effusion and photosensitivity rash were each recorded in single patients. None had evidence of hypersensitivity to drugs, helminthes or other allergens. Ten of the 12 patients could be classified as cryptogenic pulmonary eosinophilia and two as Churg Strauss syndrome. Ten were female. The maximum recorded eosinophil counts were higher in the 12 patients with systemic features compared with the remaining 53 patients [mean (SD) 5613 (3883) vs. 2359 (3046) x 10(6) 1(-1), P < 0.02], whereas both asthma and recurrent episodes of eosinophilia were significantly less common. Steroid therapy achieved a good clinical response and radiological clearing in the majority of patients. All 12 patients were treated with prolonged duration oral prednisolone [mean (SEM) dose 8.5 (3.8) mg day-1 duration 5.5 (1.3) years]. The two patients with Churg Strauss syndrome required azathioprine in addition to long-term prednisolone. There were no deaths and currently four patients are off all steroids and six receive less than 5 mg day-1. During a median follow-up period of 11 years, there was no significant decline in FEV1 or VC, measured as percent predicted values. Persistent radiographic abnormalities consistent with fibrosis or bronchiectasis were not seen.(ABSTRACT TRUNCATED AT 250 WORDS)

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 μg; range 1200–2650 μg) beclomethasone dipropionate ( n = 69) or budesonide ( n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol −1 ; urine free cortisol −1 ; rise in cortisol in response to tetracosactrin or hypoglycaemia −1 and/or achieved cortisol −1 . HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol ( r s =0·84; P =0·001) and post-tetracosactrin cortisol ( r =0·75; P 95%); 9 am cortisol was much less sensitive. Measuring 24-h urine free cortisol excretion is a simple, sensitive way of screening for clinically important hypothalamo-pituitary-adrenal suppression from high dose inhaled corticosteroids and avoids the risk of hypersensitivity reactions to tetracosactrin.

Systemic absorption of inhaled corticosteroids taken in high doses (or = 1500 micrograms beclomethasone dipropionate or budesonide daily), may cause suppression of the hypothalamo-pituitary-adrenal axis. Patients taking long-term high dose inhaled steroid therapy might therefore be at risk of adrenal crisis at times of stress. Plasma cortisol levels were measured in 24 adults with severe acute asthma who had not received treatment with systemic corticosteroids prior to hospital attendance. Seven were not taking inhaled steroids, four were taking 600-1200 micrograms and 13 were taking 1500-2400 micrograms beclomethasone dipropionate or budesonide daily. Plasma cortisol levels in these 13 (median 594 nmol l-1, interquartile range 399-620 nmol l-1) were similar to levels in those taking lower dose/no inhaled steroids (median 512 nmol l-1, interquartile range 287-1050 nmol l-1): there was no relationship between inhaled steroid dose and cortisol level. Nine of the 24 patients failed to achieve plasma cortisol values500 nmol l-1 (the normal response to an insulin stress test). When compared with the remaining 15, they had less severe asthma as indicated by higher arterial oxygen tension (P0.01) and peak expiratory flow (P0.03). Patients taking long-term high dose inhaled corticosteroids appear to be able to mount an appropriate adrenocortical response to the stress of severe acute asthma.

The frequency of hypothalamo-pituitary-adrenal (HPA) axis suppression in asthmatics taking high dose (greater than 1000 micrograms daily) inhaled corticosteroids is unknown. HPA function was studied in 78 adult asthmatics taking long-term inhaled corticosteroids (median dose 1600 micrograms, range 1200-2650 micrograms daily). All patients except one were using metered dose aerosols; 15 were using large volume spacer devices. Median duration of high dose therapy was 13 months (range 1-54). Sixty-nine patients were taking beclomethasone dipropionate (1500 micrograms, n = 36; 2000 micrograms, n = 26, greater than 2000 micrograms, n = 7) and nine budesonide (1200 micrograms, n = 2; 1600 micrograms, n = 6; 1800 micrograms, n = 1). Four patients, all of whom were taking greater than 2000 micrograms beclomethasone dipropionate, were taking 200-400 micrograms of their total dose intranasally. Twenty-six patients had discontinued long term systemic corticosteroid treatment (at least 5 mg prednisolone daily, or equivalent, for a minimum of 6 months) between 7 months and 22 years prior to assessment. All patients had measurements of 9 am serum cortisol and 24-h urine free cortisol excretion and a short tetracosactrin test. Subnormal results were: 9 am cortisol less than 190 nmol l-1; rise in serum cortisol in response to tetracosactrin less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1; urine free cortisol less than 80 nmol 24 h-1. Hypothalamo-pituitary-adrenal suppression was defined as subnormal results in at least two of the three tests. Tests were performed at least 2 weeks after completion of any short course prednisolone treatments. Suppression was found in 16 (20.5%) patients (1500 micrograms, n = 6; 1600 micrograms, n = 1; 2000 micrograms, n = 7; 2400 micrograms, n = 2). Risk factors identified for this suppression were: (a) previous requirement for long-term systemic corticosteroids (10/26, chi 2 = 6.1, P less than 0.02); and (b) increasing duration of high dose inhaled therapy (median 28.5 months in suppressed vs. 12 months in normal, P less than 0.05). No clear relationship was identified between HPA function and dose, even when corrected for body surface area and there was no relationship between suppression and number of short courses of prednisolone in the preceding 12 months. Screening tests of HPA function should be performed in all asthmatics taking greater than or equal to 1500 micrograms inhaled corticosteroid daily. Unless function has been shown to be normal, all patients taking these doses should carry steroid cards.

Tremor and headaches are reported as common adverse events to &agonists. However, rapid, tachyphylaxis usually occurs. There is some concern with the short-acting /3,-agonist, fenoterol, which has the least selectivity for &compared with /3,-adrenoceptors (1). Bremner et al. (2) compared formoterol(24 pug), fenoterol(400 pug) and salbutamol (4OOpg) in an acute event study. Fenoterol had the greatest, and salbutamol the least, cardiac and metabolic effects. One question still to be answered is whether there is tachyphylaxis to the beneficial effects of &agonists. There are a number of studies that indicate that regular use of long-acting &agonists results in tolerance to bronchoprotective effects. However, in the clinic, sahneterol and formoterol work very well as bronchodilators following longterm administration, and therefore tachyphylaxis may be largely irrelevant both in terms of efficacy and safety.

T-cell immunity was investigated in eight patients with non-tuberculous mycobacterial disease, to see whether impaired immune function might be the explanation for their infection. Cellular immune function was evaluated in vitro by measuring the proliferation of peripheral blood mononuclear cells in response to both non-specific mitogens (phytohaemagglutinin and pokeweed mitogen) and specific recall antigens (streptokinase-streptodornase and purified protein derivative from Mycobacterium tuberculosis), and in vivo, by measuring the skin test response to a panel of recall antigens. Functionally relevant T-lymphocyte sub-populations (CD4, CD8, activated CD3 and gamma/delta T-cells) were enumerated by two-colour flow cytometry. The results were compared with those for a group of patients with pulmonary tuberculosis, with groups of controls matched for age and smoking habit, and with a patient group receiving steroid treatment. The patients with non-tuberculous mycobacterial disease had poor or absent skin test responses; in vitro, their response to recall antigens was depressed, although their response to mitogens was normal. The patients had significantly raised levels of CD8 lymphocytes and activated T-cells, but lacked any circulating gamma/delta T-cells. There were also differences between the various control groups. In conclusion, this study demonstrates a deficiency in the cellular immune system of these patients, which is most readily detectable by skin testing, or by measuring lymphocyte proliferative responses to recall antigens. However, the study also shows changes in cellular immune responses in controls matched for age and smoking and in patients on steroid treatment, and underscores the need for matched controls. Further work needs to be done to ascertain whether the cellular immune deficiency is a cause of, or is caused by, the mycobacterial infections, and also to investigate the pathological significance of the alterations in T-cell sub-populations.