STEROIDS

1985 Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985; 2:686-688. [PubMed]
Children aged one to 12 years with CF received 1-2 mg/kg of prednisone or placebo on alternate days for four years. The prednisone group had better lung function, lower ESR and IgG levels and required only nine admissions compared with 35 in the control group. There were no steroid induced side effects noted in this initial report (but these appeared later). Later this and another similar study (Eigen et al, J Pediatr 1995; 126:515) both reported significant side effects including impaired glucose metabolism, cataracts and impaired growth – the latter being permanent in boys aged 18 years and older whose mean height was 4 cm less in the prednisolone treated patients (Lai HC et al. N Engl J Med 2000; 342:851). (Also Pantin CFA et al. Thorax 1986; 41:34-38 and Greally P et al. Arch Dis Child 1994; 71:35-39 for effects of a course of oral prednisolone in adults with CF).
This paper excited a great deal of interest at the time but later this use of steroids, even on an alternate day basis, was shown to have far too many side effects to be used even though alternate day prednisolone was considered to have fewer side effects than daily dosing.

1986 Pantin CF, Stead RJ, Hodson ME, Batten JC. Prednisolone in the treatment of airflow obstruction in adults with cystic fibrosis. Thorax 1986; 41:34-38. [PubMed]
Oral prednisolone 0.48 mg/kg body weight per day for 3 weeks caused no significant improvement in lung function. However, atopic subjects showed an improvement in evening recordings of peak expiratory flow rate (PEF) while taking prednisolone (p <0.05). Significant deterioration in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were seen after withdrawal of the prednisolone. Two patients developed pneumothoraces while taking prednisolone.

1988 Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone diproprionate. Lancet 1988;865. [PubMed]
This was the first report of an adverse effect on growth of some children with asthma receiving inhaled corticosteroids. It is mentioned here as many children with CF receive inhaled steroids often in very large doses in an effort to control their symptoms. Graff-Lonnevig V et al (1979 [PubMed]) had reported inhaled steroids had no effect on growth – surprisingly even though the height SDs fell slightly (but “insignificantly”) in the children receiving inhaled steroid treatment. Also Simon Godfrey had observed no adverse effect on growth (Godfrey et al. 1978. [PubMed]). However, during the Eighties there were 346 asthmatic children who attended my asthma clinic at St James’s University Hospital in Leeds at least once between April 1984 and March 1985. I noticed that after inhaled steroids were started some children had an increase in weight and reduction in asthma symptoms but, unexpectedly, had no improvement or even a fall off of height growth when one would have expected their height to be accelerating as their asthma improved with the treatment.
So we analysed the growth of all the children with asthma who were receiving inhaled steroids in the clinic. When the beclomethasone (BDP) group were compared with controls their SDS for height and weight were lower than controls. Of 16 patients studied before and after starting BDP treatment (figure 47) there was a significant negative inflection of growth pattern closely related to the start of BDP treatment – this demonstrated a definite adverse effect on height. We concluded that “Although it has been suggested that relevant clinical side effects from inhaled steroids are virtually non-existent, our data in children treated with inhaled steroids does not support this view”.

This observational study came in for heavy criticism from some respiratory paediatricians, who over some 15 years had failed to identify the adverse effect on growth (Godfrey S, et al. J Allerg Clin Immunol 1978; 62:335-339.[PubMed]) or attributed the fall off in growth rate entirely to the delay in puberty (e.g. Balfour-Lynn L. Effect of asthma on growth and puberty. Pediatrician 1987; 14:237-41.[PubMed]) Balfour-Lynn states - "The main cause of growth retardation in the past was the long-term prophylactic use of oral corticosteroids. Since the advent of inhalation steroids, this has no longer been a problem".
However, some of our children were only 7 and 8 years old when they experienced an obvious slowing of height gain at a time when their asthma was under better control!. Subsequently our observations on the adverse effect inhaled steroids on growth were confirmed in other studies although the controversy continued as for many years all were not convinced.

On reflection It seemed that many of the previous clinical trials were too short to reveal side effects such as adverse effects on growth. It was apparent that even observational studies from large clinics by experienced clinicians, who were personally involved in long term patient care, were still important to reveal long term side effects. The basic requirement to reveal these problems appeared to be many patients followed up by fewer doctors over longer periods of time. Yet another reason for patients with CF to attend CF centres for all or some of their care.

1996 Doull IJ, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone diproprionate. Am J Resp Crit Care Med 1996; 151:1715-1719. [PubMed]
The effect of 7 months inhaled beclomethasone propionate 400 micrograms/day on linear growth and adrenal function in 94 chi;lren aged seven to nine years. Mean regressed daily growth was significantly decreased during the treatment period 0.79 mm versus 1.14 mm per week. At the end of the seven months study the BDP treated children had brown significantly less than the children on placebo mean 2.66 versus 3.64 mm. There was no catch up over 4 months.
So inhaled BDP at these relatively modest doses in children with mild asthma significantly decreased stat ural growth - a side effect so vigorously denied for so long by many respiratory paediatricians since the first reports (Littlewood et al, 1988 above). This is important in the context of CF as many children are treated, at times unnecessarily, with inhaled steroids (Balfour-Lynn I M et al. Am J Resp Crit Care Med 2006; 173:1356-1362), and the doses used may be large and growth impairment is not a rare finding.

Dr Iolo Doull is the Director of the Cardiff Paediatric CF Centre. He is heavily involved in both CF care and research. He has developed a shared care network for most of Wales which involves periodically travelling with his team to various general hospitals.

2000 Lai HC, FitzSimmons SC, Allen DB, Kosorok MR, Rosenstein BJ, Campbell PW Farrell PM. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Eng J Med 2000; 342:851-859. [PubMed]
The growth 6 to 7 years, after prolonged alternate-day treatment with prednisone had been discontinued, was recorded in 224 children aged 6 to 14 years with CF who had participated in a multicenter trial of this therapy from 1986 to 1991 (a treatment first reported in the paper of Auerbach et al, 1985 above). The Z scores for height of the treated patients declined during prednisone therapy; although catch-up occurred, the mean heights for boys 18 years of age or older were 4 cm less in the prednisone groups than in the placebo group, an equivalent of 13 percentile points. Among the girls, differences in height between those who were treated with prednisone and those who received placebo were no longer present two to three years after prednisone therapy was discontinued.

So amongst children with CF who received alternate-day treatment with prednisone, boys, but not girls, had persistent growth impairment after the treatment was discontinued. This was the final chapter in the long term alternate day prednisone treatment in CF first reported by Auerbach et al in 1985 (above). At the time, there had been high hopes that the prednisone treatment would favourably modify the course of the chest infection by significantly suppressing the excessive damaging inflammation in the airways. Prednisolone was used in shorter studies by Pantin et al who showed no significant effect (Thorax 1986; 41:34-38. [PubMed] above) and Greally P et al. who showed over 12 weeks improved respiratory function and some reduction in inflammatory markers (Arch Dis Child 1994; 71:35-39 [PubMed]).

2001 Wojtczak HA, Kerby GS, Wagener JS, Copenhaver SC, Gotlin RW, Riches DW, Accurso FJ. Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2001; 32:293-302. [PubMed]
There are few studies evaluating the safety of inhaled steroids in young children. The authors prospectively administered beclomethasone diproprionate (BDP) 420 microg daily for 2 months to 12 clinically stable young children with CF without affect on urine and blood cortisol levels, adrenal reserve, or increase in airway infection. Also there was a fall in bronchoalveolar lavage fluid inflammatory markers following the inhaled steroid treatment.

This was one of a number of small studies of inhaled corticosteroids in people with cystic fibrosis. Clinical experience shows that a few patients quite obviously do benefit significantly from inhaled steroids particularly young patients with troublesome wheezing and bronchial lability. However, a subsequent UK study of withdrawal of inhaled steroids from people with CF showed many patients were deriving no apparent benefit and the inhaled steroids could be withdrawn from many patients without ill effects (Balfour-Lynn et al. 2006 [PubMed] below). Undoubtedly some would have derived some benefit at the time the steroids were started and there are a minority of children with CF who do derive great benefit from inhaled steroids and these patients were not included in Balfour-Lynn's steroid withdrawal study as, understandably, their doctors (and almost certainly their parents!) were unwilling to stop their steroid treatment.
Also, although some paediatricians who published short term studies on inhaled steroids found it difficult to accept, undoubtedly in some children the rate of growth is affected by taking inhaled steroids in the doses used in this present study this will be detected provided the children are followed up for longer and measured carefully (not always the case in general paediatric clinics!).  Two months is an inadequate time to identify adverse effects on growth (see Littlewood et al, 1988 [PubMed] above for full discussion of the adverse effect on growth of inhaled steroids).

2002 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 Paediatr2002; 91:1008-11. [PubMed]
Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. This observation suggests that the metabolic clearance of budesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge.

An important report as Aspergillus is increasingly common and the two drugs are used not infrequently. The occurrence was later investigated further by the Copenhagen team. Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested. [PubMed]. There was also a further case report from the UK [PubMed].

2004 Rossi L. Castro M. D'Orio F. Damonte G. Serafini S. Bigi L. Panzani I. Novelli G. Dallapiccola B. Panunzi S. Di Carlo P. Bella S. Magnani M. Low doses of dexamethasone constantly delivered by autologous erythrocytes slow the progression of lung disease in cystic fibrosis patients. Blood Cell Mol Dis 2004; 33:57-63. [PubMed]
To evaluate the safety and efficacy of the administration of low doses of glucocorticoids in patients with cystic fibrosis (CF) by using autologous erythrocytes loaded with dexamethasone 21-phosphate. Nine consecutive CF patients (patients nos. 1-9) received autologous erythrocytes loaded with increasing amounts of dexamethasone 21-phosphate to obtain a slow delivery of dexamethasone in circulation. The appearance of possible adverse effects, the reproducibility of the procedure, and the dexamethasone pharmacokinetics were evaluated. Subsequently, patient no. 9 and eight additional patients (patient nos. 10-17) received dexamethasone 21-phosphate-loaded erythrocytes at 1-month intervals to evaluate the efficacy of continuous release in circulation of low doses of dexamethasone. Erythrocytes from CF patients can be processed to be loaded with increasing dexamethasone 21-P concentrations. Once re infused in respective donors, a slow and prolonged delivery of dexamethasone in the blood stream was measured up to 28 days. Repeated administrations of drug-loaded erythrocytes at 4-week intervals for 15 months showed that very low doses of glucocorticoids provide significant improvement in FEV1 values and significant reduction of infective relapses due to Pseudomonas aeruginosa without adverse effects. The authors conclude that administration of very low doses of glucocorticoids using autologous erythrocytes is possible, with benefits for patients and without side effects. This method is likely to be extended to other chronic diseases.

It is likely that this novel technique would have some beneficial effect but experience tells us that any long term steroids treat,ment is likely to be associated with unwanted sude effects including an adverse effect on growth and glucose control. There was one further study on this treatment published in 2006 that showed some benefit in treated patients (Lucidi V et al, 2006. [PubMed]).

2006 Balfour-Lynn IM, Lees B, Hall P, Phillips G, Kahn M, Flather M, Elborn JS. On behalf of the WISE investigators. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006; 173:1356-1362. [PubMed]
On the grounds that the authors considered that inhaled steroids are widely used despite lack of evidence, this study was to test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations. Patients during the 2-month run-in period, received fluticasone; they then took either fluticasone or placebo for 6 months. There was no difference in time to first exacerbation in the two groups. So in this study population (applicable to a surprising 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids.

It would be wise to consider the individual patient's clinical history prior to their starting inhaled steroids before considering withdrawing the treatment. Note that the summary does not mention the 24 patients whose steroids the clinicians were unwilling to stop. They had more asthma, more atopic status, and more exacerbations and worse condition. Many of these patients are considerably, even dramatically, improved when they commence inhaled steroids. Trials of N=1 are obviously useful in this clinical situation.

Dr Ian Balfour-Lynn (figure 43) is consultant paediatrician at the Royal Brompton Hospital, London. He is heavily involved in both patient care and CF research

2006 Lucidi V. Tozzi AE. Bella S. Turchetta A. A pilot trial on safety and efficacy of erythrocyte-mediated steroid treatment in CF patients. BMC Pediatrics 2006;. 6:17. [PubMed]
A novel strategy for delivering low doses of steroids for long periods through the infusion of autologous erythrocytes loaded with dexamethasone has been recently set up. A recent study suggested the feasibility of therapy with low doses of corticosteroids delivered through engineered erythrocytes in CF patients. This study presents a further analysis of safety and efficacy of this therapy. Nine patients in the experimental group received the treatment once a month for a period of 24 month. Patients did not develop diabetes, cataract, or hypertension, or other typical side effects of steroid treatment during the follow up period. There was a constant improvement of FEV1 in patients undergoing the experimental treatment compared to a gradual decrease of the same parameter in the standard therapy group (P = 0.04). The average of clinic and radiological indexes did not vary. The number of infective relapses that have required antibiotic intravenous therapy was not different in the two groups, although the average of these episodes was slightly higher in the experimental therapy group. The authors concluded intraerythrocyte corticosteroid treatment may stabilize the respiratory function in CF patients but is often considered too invasive by patients. The results obtained by our study may help planning an experimental, controlled, randomised study. A sample size of 150 patients per group would be sufficient for demonstrating such a difference with a 95% confidence interval and a power of 90%.

A novel method for administering anti-inflammatory treatment with dexamethasone to people with CF. However, there were no further studies up to 2011.

2007 De Boeck K. De Baets F. Malfroot A. Desager K. Mouchet F. Proesmans M. Do inhaled corticosteroids impair long-term growth in prepubertal cystic fibrosis patients?. Eur J Pediatr 2007:166:23-28. [PubMed]
Despite absence of clear proof of efficacy, the use of inhaled corticosteroids (ICS) is widespread in cystic fibrosis (CF) patients. Therefore, the effect of ICS on lung function and other clinical variables was studied in 27 prepubertal CF children with mild to moderate lung disease. In a prospective double-blind case-controlled study, fluticasone propionate 500 microg or placebo were administered twice daily during 12 months. The mean (standard error of the mean, SEM) patient age was 8.2 (0.6) years in the placebo group and 9.0 (0.5) years in the fluticasone group. The mean (SEM) forced expiratory volume in 1 s (FEV(1)) was 91% (4%) in the placebo group and 86% (4%) in the fluticasone group. There was no statistically significant difference in the evolution of lung function and the number of respiratory exacerbations between groups. However, longitudinal growth in fluticasone patients was significantly slower than in placebo patients: 3.96 (0.29) cm versus 5.49 (0.38) cm [p<0.005, analysis of variance (ANOVA)] over the 12-month study duration. This resulted in a significant change in height standard deviation score (SDS) of -0.38 (0.09) in the fluticasone group versus -0.01 (0.07) in the placebo group (p<0.003, ANOVA). No catch-up growth was noted 1-2 years after discontinuation of inhaled steroids. The use of high-dose ICS in CF patients with mild lung disease may lead to persistent growth impairment.

It is no surprise that this dose of fluticasone leads to impairement of growth - apparently in this study without any obvious clinical benefit. Although we described clearly impaired growth in some asthmatic children taking inhaled steroids in 1988 (Littlewood et al, 1988. Growth retardation in asthmatic children treated with inhaled beclomethasone diproprionate. Lancet 1988;865. [PubMed]) there has been a reluctance to accept our findings by some respiratory paediatricians. However, clinicians who carefully follow children on substantial doses of inhaled steroids for prolonged periods and chart their growth observe the slowing of growth in some is quite obvious. In fact we have observed virtual arrest of height growth in young children with CF on "heroic doses" of fluticasone to the extent that dietary intervention was suggested. Of course in such children the weight SD or centile for weight is much better than that for height.

2008 Ren CL. Pasta DJ. Rasouliyan L. Wagener JS. Konstan MW. Morgan WJ. Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis. J Pediatrics 2008; 153:746-751.[PubMed]

To assess the relationship between inhaled corticosteroids (ICS) use and lung function decline in children with cystic fibrosis (CF) using the Epidemiologic Study of Cystic Fibrosis, an observational study of patients with CF in North America. In this retrospective analysis of prospectively collected data, ICS therapy in patients with CF was associated with a significant reduction in the rate of FEV(1) decline (-1.52% vs. 0.44% pa) , decreased linear growth, and increased insulin/oral hypoglycemic use.

This study looks at the use of inhaled steroids from another angle to that of Ian Balfour- Lynn [PubMed]. These results could have been predicted and support previous knowledge of inhaled steroids. The growth effect is of course dependant on the dose used - sometimes the heroic doses used for various drugs for children with CF have serious side effects - one has seen growth totally arrested by very large doses of inhaled steroids in a small child with CF. The study leaves the paediatrician to decide in the case of individual patients if inhaled steroids are indicated. It is clear that there are some children who do benefit from inhaled corticosteroid treatment.

2009 Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, Kerem E. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros 2009; 8:253-257.
Nine patients with CF and ABPA (4 male, 5 female, ages 7-36 years) received HDIVPM (10-15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of ABPA. All patients showed clinical and laboratory improvement (FEV(1) increase, serum IgE levels and total eosinophil counts decrease) and treatment was discontinued after 6-10 pulses. Adverse effects were minor and disappeared shortly after each IV pulse therapy. The authors suggest that high-dose IV-pulse methylprednisolone is an effective treatment for ABPA in CF with minor side effects.

This is a very useful report as the side effects of oral corticosteroids (prednisolone) are often severe during treatment of ABPA.

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