A.P. Greening

Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial

Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol. Participants Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for ≥ 1 year, a baseline forced expiratory volume in one second (FEV 1) value 50-90% predicted, and a β agonist improvement of ≥ 12% in FEV 1. Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation. Results 20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0%). With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P ≤ 0.001), whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated. Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.

Human Cytokines: Their Role in Disease and Therapy

Ed Bharat B Aggarwal, Raj K Puri Blackwell Science, £95, pp 736 ISBN 0 86542 352 0 Cytokines divide the medical profession into camps: the non-believers, the enthusiastic believers, and the “I would love to believe if only I could understand.” The first do not require a textbook, merely conversion. The second do not require a textbook but access to original papers. The third group wish to be lead gently through this enormous field with sympathy and understanding. Can one book hope to cover a …

Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids

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.

Screening for hypothalamo-pituitary-adrenal axis suppression in asthmatics taking high dose inhaled corticosteroids

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 micrograms; range 1200-2650 micrograms) 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 less than 190 nmol l-1; urine free cortisol less than 80 nmol 24 h-1; rise in cortisol in response to tetracosactrin or hypoglycaemia less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-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 (rs = 0.84; P = 0.001) and post-tetracosactrin cortisol (r = 0.75; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Highdose inhaled steroid therapy and the cortisol stress response to acute severe asthma

Systemic absorption of inhaled corticosteroids taken in high doses (⩾ 1500 μg 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 μg and 13 were taking 1500–2400 μg beclomethasone dipropionate or budesonide daily. Plasma cortisol levels in these 13 (median 594 nmol 1 −1 , interquartile range 399–620 nmol 1 −1 ) were similar to levels in those taking lower dose/no inhaled steroids (median 512 nmol 1 −1 , interquartile range 287–1050 nmol 1 −1 ): there was no relationship between inhaled steroid dose and cortisol level. Nine of the 24 patients failed to achieve plasma cortisol values >500 nmol 1 −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 ( P P

Pneumocystis carinii in bronchoalveolar lavage fluid and bronchial washings.

Antibodies to Pneumocystis carinii develop in early childhood,1 although no associated illness has been identified. The classic concept in that P carinii pneumonia in immunocompromised patients represents a reactivation of dormant childhood infection. Studies with DNA amplification, however, have failed to detect pneumocystis in sputum2 or specimens of lung tissue taken at necropsy3 from immunocompetent patients. Reinfection rather than reactivation may therefore be more relevant. To see whether P carinii exists as a commensal organism of the lower respiratory tract we examined bronchoalveolar lavage fluid and bronchial washings in apparently immunocompetent patients undergoing routine diagnostic (or research) bronchoscopy by using an immunofluorescent antibody test. We studied 220 patients with various clinical diagnoses (table). Patients were considered to have no active disease if investigations, including bronchoscopy, failed to show any lung disease. Patients with …

Immunodeficiency in non-tuberculous mycobacterial disease.

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.