Short stature never killed anybody

See related article, p. 608. Asthma is a serious and disabling condition from which a number of children die each year. It is a condition for which the prospects for treatment have improved greatly over recent years, largely as a result of the introduction of inhaled steroids.1British Thoracic Society Guidelines on the management of asthma.Thorax. 1993; 48: S1-S24PubMed Google Scholar The prevalence of asthma is increasing,2Anderson HR Butland BK Strachen DP. Trends in prevalence and severity of childhood asthma.BMJ. 1994; 308: 1584-1585Crossref PubMed Scopus (52) Google Scholar and so it is more likely that children will be treated with inhaled steroids. It is well established that children treated with high doses of steroids grow poorly. The mechanism by which this occurs is still unknown, although it is clearly distal to the secretion of growth hormone and its effect on the production of insulin-like growth factor-1.3Crowley S Hindmarsh PC Matthews DR Brook CGD. Growth and the growth hormone axis in pre-pubertal children with asthma.J Pediatr. 1995; 126: 297-303Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar There have been many attempts to minimize the growth-suppressing effects of steroids while maintaining their clinical effectiveness, but the overall conclusion is that there is probably a threshold (~800 μg of inhaled steroid daily) at which growth suppression becomes manifest.3Crowley S Hindmarsh PC Matthews DR Brook CGD. Growth and the growth hormone axis in pre-pubertal children with asthma.J Pediatr. 1995; 126: 297-303Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar In this issue of The Journal, Heuck et al4Heuck C Wolthers OD Kollerup G Hanson M Teisner B Adverse effects of inhaled budesonide (800 μg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration.J Pediatr. 1998; 133: 608-612Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar describe a double-blind crossover trial of the administration of budesonide (800 μg) either as a single daily dose in the morning or divided into a twice-daily dose. No data are supplied on the control of subjects’ asthma other than to show that their peak expiratory flow rates, symptom scores, and use of β2 -agonists were not different with either regimen. The asthma was sufficiently mild that inclusion in the study required that none of the patients had received treatment with inhaled glucocorticosteroids during the month before study. In other words, this was probably as close as one might reasonably get to administering inhaled steroids to normal children! The adverse effects of budesonide were analyzed in terms of suppression of growth measured over two 4-week periods by a knemometer and by analyzing changes in various substances known to be markers of collagen turnover. First of all, lower leg growth was suppressed in the boys but not in the girls. Of the many markers of collagen turnover measured, a statistical reduction during the twice-daily regimen was achieved only in the concentration of amino terminal propeptide of Type 3 procollagen in the boys. Given the number of estimations and calculations in this study, one could reasonably dismiss that isolated incident of statistical significance and concentrate on the growth alone. Knemometry5Valk IM Chabloz AMEL Smals AG Kloppenborg PW Cassorla FG Schutte EA. Accurate measurements of the lower leg length and the ulnar length and its application in short term growth measurement.Growth. 1983; 47: 53-66PubMed Google Scholar was introduced as a way of circumventing the necessity for long-term observations of growth in order to calculate growth rates. Growth in children varies with the seasons, and not all children grow at one time of the year as compared with another, but have individual variations; therefore, one needs an entire year of growth measurement to adequately compare growth velocities between groups of children treated in different ways.6Tanner JM Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and the stages of puberty.Arch Dis Child. 1976; 51: 170-179Crossref PubMed Scopus (2670) Google Scholar Investigators may try to convert growth rates over shorter periods into annualized growth velocities, but they fail to realize that the parameters by which such velocities are defined are very different from those that are properly compared with standard values.7Brook CGD Hindmarsh PC Healy MJR. A better way to detect growth failure.Br Med J. 1986; 293: 1186Crossref PubMed Scopus (25) Google Scholar There is much discussion about whether growth in children is a smooth continuum or saltatory (jumping) in nature; the proponents of knemometry are firmly in the latter camp. Therefore we need to be cautious when applying the lessons of knemometry to growth of children treated with inhaled corticosteroids over longer periods. However, it is of some interest that the once-a-day administration of a large dose of an inhaled steroid had a smaller effect on growth than the administration of the same total daily dose in a twice-daily regimen. Why might this have been? Growth hormone secretion in children is generally pulsatile, and most of the peak concentrations of growth hormone are found during the nighttime hours.8Hindmarsh PC Smith PJ Brook CGD Matthews DR. the relationship between height velocity and growth hormone secretion in short pre-pubertal children.Clin Endocrinol. 1987; 27: 581-591Crossref PubMed Scopus (163) Google Scholar Nobody knows the time relationship between the generation of a growth hormone peak, the paracrine release of insulin-like growth factor-1, and its translation into a downstream message of growth. If steroids are known to decrease growth rates and if most growth (as your grandmother said) takes place at night, it would not be surprising that a nighttime dose of steroid would be more growth-suppressive than a morning dose of twice its size, the effect of which would have worn off by the evening. More interesting to me is the difference between boys and girls in the study by Heuck et al.4Heuck C Wolthers OD Kollerup G Hanson M Teisner B Adverse effects of inhaled budesonide (800 μg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration.J Pediatr. 1998; 133: 608-612Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar We know few clinical details of the studied patients, except that they had a mean age of 9.2 years, with a range in age from 5.6 to 12.5 years. Because the mean is higher than halfway between the extent of the range, there were clearly more boys and girls older than 9.2 years of age. This is important because one would have predicted that pubertal growth would have started in some of the girls but not yet in the boys. I suspect that this is the reason that the girls were comparatively immune to the effects of the nighttime dose of budesonide. One would expect the growth of 9-year-old boys to be affected by the secretion of the adrenal androgens, which stimulate the mid-childhood growth spurt. These we believe to be driven by corticotropin, because adrenal androgens can be stimulated by corticotropin and suppressed by dexamethasone. Because corticotropin levels rise in the middle of the night and generate the morning peak of cortisol, one would expect boys who are receiving nighttime corticosteroids to have blunted adrenal androgen levels and slower growth rates. The observation by Heuck et al4Heuck C Wolthers OD Kollerup G Hanson M Teisner B Adverse effects of inhaled budesonide (800 μg) on growth and collagen turnover in children with asthma: a double-blind comparison of once-daily versus twice-daily administration.J Pediatr. 1998; 133: 608-612Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar therefore makes intuitive good sense. As with all interesting studies, more questions arise than are solved. The main issue is whether clinicians can establish, once and for all, that a single early morning dose of an inhaled corticosteroid is as effective in the treatment of asthma as a more frequent daily regimen. From the point of view of the suppressive side effects on growth, this would be an important finding. Conventional replacement steroid regimens in children with adrenal insufficiency have traditionally administered two thirds of the dose in the morning. It is only when symptoms of unwanted corticotropin drive (as in congenital adrenal hyperplasia) supervene that the doses are increased in the evening. In normal children the concentrations of glucocorticoids present in the serum in the late afternoon are often below the limits of detection of an assay. Finally, I wish to return to the title of this editorial. Asthma is a killing disease, but nobody died of being short. I urge clinicians first and foremost to aim at optimal disease control; children with uncontrolled asthma grow poorly anyway. If a child’s asthma requires doses of steroid medication that are growth-suppressive, I would regard it as a price worth paying, particularly because the long-term effects of such treatment seem largely to be on the timing of the onset of puberty rather than on actual final height.9Balfour Lynn L. Growth and childhood asthma.Arch Dis Child. 1986; 61: 1049-1055Crossref PubMed Scopus (228) Google Scholar The same consideration applies to the linear growth of children with atopic dermatitis.10Patel L Clayton PE Addison GM Price DA David TJ. Linear growth in prepubertal children with atopic dermatitis.Arch Dis Child. 1998; 79: 169-172Crossref PubMed Scopus (38) Google Scholar The upshot of this valuable contribution will be to suggest to physicians that they might attempt to titrate treatment regimens, trying to give a larger dose of steroid in the morning. As long as they achieve symptom control, they may well have a better growth outcome in the short term. Because most children with asthma do well in the long term anyway, they should remember the dictum that nobody died of being short.