Inhaled corticosteroids have revolutionised the treatment of asthma. As they provide the most potent and consistent long-term control of asthma they have been recommended by GINA (Global initiative for asthma) guidelines as first line therapy for asthma management.

Budesonide is an inhaled glucocorticosteroid with prolonged anti-inflammatory activity and negligible systemic availability ensuring safety even in one-year old children. However, many physicians are concerned about the potential adverse effects of long-term corticosteroid treatment, particularly on growth.

A number of trials assessing growth during therapy with inhaled corticosteroids have been conducted, but for a year or less. Therefore their practical relevance is uncertain.
A 13-year long Danish study evaluating the effect of long-term treatment with inhaled budesonide is the longest trial of its kind worldwide. The study, conducted by Dr. Lone Agertoft and Dr. Soren Pederson assessed the treatment's impact on adult height in children with asthma. The data analysed was collected from January 1986 through August 1999.

This prospective-controlled study followed 211 children with asthma.
 

• 142 budesonide-treated children with asthma
• 18 control patients with asthma who had
• never received inhaled corticosteroids.
• 51 healthy siblings of patients in the budesonide
• group who also served as controls.

Children whose asthma was considered to be acceptably controlled without the continuous use of inhaled corticosteroids were changed to treatment with inhaled corticosteroid (budesonide) and at each six month visit, their height, weight, lung function, number of hospital admissions for acute asthma, dose and frequency of administration of all prescribed drugs, including inhaled budesonide were recorded.

The study demonstrated that children reached their final expected adult height even after an average of 9.2 years (range: 3 to 13 years) of long-term treatment with inhaled budesonide with a mean cumulative dose of 1.35 gm (range: 0.41 to 3.99 gm), yielding a mean average daily budesonide dose of 412 g (range: 110 to 877 g). There was no significant correlation between the duration of treatment (or the cumulative dose of budesonide) and the difference between the measured and target adult heights. It was observed that long-term treatment with inhaled budesonide did not have any clinically important adverse effects on adult height. This corroborated the results of retrospective studies of smaller groups of children treated for shorter periods with inhaled corticosteroids. The growth rate during the first year of treatment was found to be on average 1 cm less than that during the run-in-period. Thus, the results were consistent with those of shorter studies (1 year or less) on inhaled corticosteroids, which reported growth retardation of approximately
1.5 cm/year in children. This had led to the inclusion of warnings about growth retardation in the package inserts for inhaled corticosteroids in US. However, this 13-year study indicated that the initial reduction in the annual growth rate did not persist in children treated with budesonide. They reached their target adult height to the same extent as their healthy siblings and the children in the control group.

 

Corticosteroids tend to suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. Budesonide has low systemic availability, which is attributed to its rapid and extensive hepatic metabolism into metabolites with low intrinsic corticosteroid activity. A double-blind, double-dummy, randomised, placebo-controlled, parallel-group; multi-centre clinical trial was conducted to assess the effect of budesonide on the HPA axis in adult patients with mild, non-steroid-dependent asthma. The selected budesonide doses were in the upper range of clinically recommended doses (800 and 1600 mcg/day), along with a dose twice the maximum recommended dose (3200 mcg/day). A total of 64 patients were randomised to the double-blind phase of this study. Of these, 13 patients received 80 mcg/day budesonide, 12 patients received 1600 mcg/day, 13 patients received placebo and 13 patients received 10 mg once daily prednisone.

Adrenal stimulation was induced by continuous infusion of synthetic ACTH - cosyntropin as approved by FDA. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during the 6-hour infusion of cosyntropin. After 6 weeks of treatment with budesonide, plasma cortisol concentrations were found to reduce by 4% in the placebo group; by 13%, 11% and 27% in budesonide groups (800, 1600 and 3200 mcg/day respectively); and by 35% in the prednisone group. The
decrease was significant only in the 3200 mcg/day budesonide and prednisone group. Over the same time period, decrease in basal plasma cortisol concentrations were 1% in placebo group; 19%, 19% and 34% in three respective budesonide groups and 37% in prednisone group. Thus, the study showed that inhaled budesonide at doses recommended for clinical use (800 or 1600 mcg/day) did not produce any statistically significant suppression of the HPA axis compared with placebo.

Mucus plugs expectorated from an asthmatic. Sometimes asthmatics cough up firm rubbery plugs of mucus which can be teased out into casts of the airways as in these dramatic examples. The expectoration of these plugs may be associated with considerable relief of symptoms. In fatal cases of asthma many airways are found to be occluded by such plugs .

1.British Medical Journal 1999; 319: 595-600.
2.Drugs 2000; 60 (5): 1141-78.