April, 2003. Corticosteroids [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Corticosteroids

Corticosteroids have a very complex but impressive anti-inflammatory action in a number of clinical situations. In CF they are well established as the treatment of choice for allergic bronchopulmonary aspergillosis (ABPA) (Simmonds et al, 1990). Corticosteroids should be of benefit if given long term to suppress the potentially damaging inflammatory response within the airways of the CF patient. A four year double blind placebo controlled trial of alternate day prednisone (2mg/kg alternate days to a maximum dose of 60mg) suggested a beneficial effect on lung function, a reduction of respiratory infective exacerbations, lower IgG levels and improved nutrition in the treated patients (Auerbach et al, 1985). Unfortunately, the results have not been confirmed either by longer follow-up of those original patients or by subsequent studies (Donati et al, 1990). However, these initial results prompted a multicentre, 4-year, double-blind, placebo-controlled trial of alternate day prednisone. Either 2mg/kg, 1mg/kg of prednisone or placebo were given on alternate days. The 2mg/kg treatment arm was stopped as there were unacceptable side effects (Rosenstein & Eigen, 1991). The 1mg/kg alternate day group finished in August 1991. Side effects were common including diabetes and growth problems. The prednisone treated patients had better respiratory function (FVC) than controls after 4 years but the benefit was restricted to those who had chronic P.aeruginosa infection on entry. There was no evidence that the 2mg/kg was more effective than 1mg/kg on alternate days and side effects were less with the lower dose if treatment was only for 12 months. The height standard deviation scores were lower in both the treated groups than controls and there was no catch up 12 months after treatment was stopped (Eigen et al, 1995). Growth suppression induced by long term alternate day prednisone therapy (over 3 to 4 years) may be long-lasting, especially in males with CF, and especially when prednisone was taken before adolescence (Lai et al, 1999). A recent controlled trial of oral prednisolone for 12 weeks demonstrated improved respiratory function and reduced IgG and cytokine concentrations in treated patients (Greally et al, 1994). We find that corticosteroids (oral soluble prednisolone, inhaled budesonide or fluticasone proprionate are helpful particularly in young patients who are wheezy and have associated asthma. There are surprisingly few trials of inhaled corticosteroids in CF patients as they are taken by approximately half the child and adult patients in many specialist centres. A randomised, controlled trial using budesonide (Pulmicort) 1600mcg/day for 6 weeks in CF patients with proven hyperresponsiveness showed no difference in spirometry, but there was a reduction in hyperreactivity in treated patients (Van Haren et al, 1995). Hospitalised CF patients showed greater improvement in respiratory function over 4 weeks when beclamethasone diproprionate was added to their usual antibiotic and physical therapy regimen (Nikolaizik & Schoni, 1996). A more prolonged study over 6 months showed significantly better respiratory function in the treated group (Romano et al, 1994). Even when patients with bronchial hyperreactivity were excluded, an advantage was apparent when inhaled budesonide was compared with placebo over 6 weeks (Bisgaard et al, 1994). A recent controlled trial of budesonide 800 mcg b.d. delivered as a dry powder by Turbohaler over two successive three month periods between courses of intravenous antibiotics, showed significantly slower deterioration of respiratory function in patients adhering to the steroid treatment (Bisgaard et al, 1997). However, a trial of inhaled fluticasone proprionate 500 mcg b.d. in adult patients with CF showed only minimal benefit (Neiman et al, 1996) and surprisingly, inhaled fluticasone proprionate 400mcg/day for 6 weeks in children had no effect on respiratory function or inflammatory markers in the sputum, (Balfour-Lynn et al, 1997). Nevertheless, there is increasing clinical evidence to support the theoretical prediction that inhaled steroids improve respiratory function in CF patients by suppressing the inflammatory response within the airways. A multicentre trial looking at the effect of withdrawing inhaled steroids is ongoing.

Patients on combination therapy of itraconazole and inhaled steroids should be monitored regularly for adrenal insufficiency as steroid clearance appears to be compromised by itraconazole's inhibition of cytochrome P450 enzymes (Main et al, 2002; Skov et al, 2002).

Corticosteroid treatment should be considered in adult patients with CF when other standard therapies have failed to control wheeze, when sputum production remains copious despite appropriate I.V. antibiotic treatment, or when inflammatory markers remain persistently elevated. Doses up to 20mg of prednisolone daily do not represent a contraindication to lung transplant.

Enteric-coated steroid preparations should be avoided as we have observed that they may be poorly absorbed by CF patients (Gilbert & Littlewood, 1986). It is common experience that oral steroids will frequently cause abnormalities of glucose metabolism in CF patients and precipitate diabetes mellitus. Urine and/or blood glucose levels should be monitored as appropriate.

Steroids have many important side effects including growth retardation, osteoporosis and adrenal suppression. Patients receiving long term steroids for conditions such as allergic bronchopulmonary aspergillosis should be monitored closely and considered for appropriate osteoporosis prophylaxis.

References

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Balfour-Lynn IM, Klein NJ, Dinwiddie R. Randomised controlled trial of inhaled fluticasone proprionate in cystic fibrosis. Arch Dis Child 1997; 76: 38-40

Bisgaard H, Nielson KG, Skov M, Mosfeldt E, Bjerre B, Pedersen SS et al. Inhaled steroid treatment of CF patients with chronic Pseudomonas aeruginosa (Pa) lung infection. Paediat Pulmonol 1994; Suppl 10: Poster 3959

Bisgaard H, Pederson SS, Neilson KG, Skov M, Laursen EM, Kronborg G et al. Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Pseudomonas aeruginosa infection. Am J Crit Care Med 1997; 156: 1190-1196

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Lai HC, Kosorok MR, Allen DB, FitzSimmons SC, Rosenstein BJ, Campbell PW et al. Longterm growth evaluation in children with CF with history of regular use of alternate-day prednisone therapy. Pediatr Pulmonol 1999; Suppl 19: 297

Main KM. Skov M. Sillesen IB. Dige-Petersen H. Muller J. Koch C. Lanng S.Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient.Acta Paediatrica 2002; 91(9):1008-11

Neiman R, Williams S, Maden C, Knight R, Hodson M. A double blind placebo controlled study comparing the effects of the inhaled corticosteroid fluticasone propionate 500 mg bid with placebo in adults with cystic fibrosis. Am J Respir Crit Care Med 1996; 153: A72

Nikolaizik WJ, Schoni MH. Pilot study to assess the effects of inhaled corticosteroids on lung function of cystic fibrosis patients. J Pediatr 1996; 128: 271-274

Rosenstein BE,Eigen H. Risks of alternate day prednisone in patients with cystic fibrosis. Pediatrics 1991; 87: 245-246

Skov M. Main KM. Sillesen IB. Muller J. Koch C. Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002;20(1):127-33.

Van Haren EHJ, Lammaers J-W J, Festen J, Heijerman HGM, Groot CAR, van Heerwaarden CLA. The effect of inhaled corticosteroid budesonide on lung function and bronchial hyper-responsiveness in adult patients with cystic fibrosis. Resp Med 1995; 89: 209--214

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