Editorials ASTHMA, STEROIDS, AND GROWTH

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1 EDITORIALS Editorials ASTHMA, STEROIDS, AND GROWTH L ONG-TERM administration of systemic corticosteroids is a cause of impaired growth. 1 Trials comparing inhaled corticosteroid preparations with other treatment regimens in nearly 600 children with asthma found that inhaled beclomethasone had greater therapeutic effect than did other regimens. 2-5 In the studies, each of which lasted about one year, children treated with inhaled corticosteroids had less growth in height (1 to 1.6 cm [23 to 27 percent] less) than those assigned to other treatments. The mechanisms by which this delay in growth occurs are unknown. If inhaled corticosteroids are not discontinued, does growth suppression continue, so that children with asthma who are at the 50th percentile for height at the age of six years fall to the 25th percentile by the time they are adults? Two articles in this issue of the Journal 6,7 report on growth among children with asthma who were treated for many years with inhaled budesonide in doses of about 400 µg a day. Both report a reduction of about 20 percent in growth velocity during the first year of treatment. Growth velocity subsequently recovered, however, and the children ultimately attained or are expected to attain a normal adult height. Although the results are reassuring to children receiving such treatment, their families, and pediatricians, neither study addressed the mechanism of budesonide s effect on growth in height or the growth of other organs. A strength of the study by Agertoft and Pedersen 6 is that nearly all subjects were followed until they reached their final adult height. A weakness is that there was no concurrent control group of children with asthma who had been randomly assigned not to receive inhaled budesonide. Although the mean adult height of subjects treated with inhaled corticosteroids was slightly lower than the mean value in a contemporaneous Scandinavian population, the children treated with budesonide did reach their target adult heights, as calculated from the heights of their parents. 8 The children s height was not influenced by either the duration of treatment or the cumulative lifetime dose of budesonide. Moreover, it did not differ from that of the control subjects, a heterogeneous group of children with asthma who were never treated with inhaled corticosteroids and healthy siblings of the children with asthma who received budesonide. Lung function improved markedly in budesonide-treated patients, who had substantially impaired lung function at the start of therapy. The second article is a report from the Childhood Asthma Management Program Research Group, 7 which conducted a randomized treatment trial for more than four years in more than 1000 children with mild-to-moderate asthma. The trial demonstrated substantial symptomatic improvement in children treated with budesonide as compared with nedocromil or placebo. The observation period was five years shorter and patients had milder asthma than was the case in the study by Agertoft and Pedersen. 6 Because the age of subjects was 5 to 12 years when they entered the study, their final adult height had to be estimated. Over the duration of the study, the budesonide-treated subjects grew less than those assigned to nedocromil and placebo (mean increase in height, 22.7 cm vs and 23.8 cm, respectively), and most of the difference in growth was evident during the first year of treatment. It is reassuring that the reductions in growth velocity observed in the first year of budesonide treatment were not sustained during continued treatment. However, a cautionary note is warranted: the Childhood Asthma Management Program Research Group did not report the children s pubertal status at entry or during the study. The level of sexual maturation at onset, if it differed among groups, could have influenced growth, regardless of treatment. Thus, further analysis of the data on growth, with pubertal status and sex taken into account, is warranted. Nonetheless, the differences in measured height among the groups at the conclusion of the study were small far less than the 4-to-6-cm differences projected from the growth velocity measured in studies of beclomethasone treatment lasting one year or less. The primary outcome measure, the degree of change in the forced expiratory volume in one second (FEV 1 ) after the administration of a bronchodilator, was not improved by either inhaled budesonide or nedocromil. Otherwise, virtually all measures of relevant symptoms of asthma improved in the budesonide group, and some improved to a lesser extent in the nedocromil group. No measures of lung growth and function improved significantly, except for the ratio of FEV 1 to forced vital capacity. In view of the multiple comparisons made, this effect is unlikely to be important. The normality of both the mean values and the degree of variation in measures of lung function in this population of children with asthma can be considered evidence against a progressive decline in lung function when the disease is well treated, and is a tribute to the physicians at the participating centers. This study and that by Agertoft and Pedersen clearly demonstrate that children generally older than six years of age who have asthma with a wide range of severity have improvements with budesonide treatment. One caveat is that the reassuring message about skeletal growth may not apply to the growth of other organs, such as the brain 9 and the lung. The number and branching structure of airways and conducting vessels are complete in early gestation, whereas alveoli are formed in the last months of gestation and during the Volume 343 Number

2 first years of postnatal life. The number of alveoli increases by a factor of about six after birth, mostly in the first two years. Formation of alveoli is complete by the age of five to eight years. 10,11 Thereafter, the lung grows by increasing the size of airways and alveoli already present. Glucocorticoids accelerate the development of many features of the lung, particularly the formation of normal lung architecture. These features of lung development have been clarified in a glucocorticoid-deficient mouse model, in which the hormone decreases cell proliferation and increases architectural maturation. 12 The administration of corticosteroids during a period of alveolar development results in decreased lung-cell mass 13 and in the presence of too few abnormally large alveoli. 14 With the exception of assays of amniotic fluid before birth, we lack surrogate markers of accelerated or delayed lung development. We cannot readily detect decreased numbers and surface area of alveoli. For example, total lung capacity, a measure of lung size rather than surface area, is normal in older children who have a marked reduction in the number of alveoli as a result of congenital diaphragmatic hernia, bronchopulmonary dysplasia, or lobar resection. The lungs of young children have relatively thick airway walls, diminished elastic recoil, and increased airway compliance all features that contribute to the amplification of airway responsiveness. Smooth muscle may not respond to stretching, an important factor in diminishing airway-wall tone, in the same way as when the airway is mature. These features of the lungs in children less than two or three years of age conspire to make the diagnosis of asthma difficult, as epidemiologic studies have demonstrated. 15 Until more is known about the influence of corticosteroids on the development of the lung and other organs, and until better tools are developed to assess organ growth, it may be prudent to avoid the use of inhaled corticosteroids in young children with very mild asthma. The sparseness of the data on the influence of corticosteroids on organ development cautions against extending the beneficial findings of the studies of Agertoft and Pedersen and the Childhood Asthma Management Program Research Group to young children, particularly those with relatively mild disease. REFERENCES MARY ELLEN B. WOHL, M.D. JOSEPH A. MAJZOUB, M.D. Children s Hospital Boston, MA Davis PB, Kercsmar CM. Growth in children with chronic lung disease. N Engl J Med 2000;342: Tinkelman DG, Reed CE, Nelson HS, Offord KP. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993;92: Doull IJM, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995;151: Simons FER, Canadian Beclomethasone Dipropionate Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337: Verberne AAPH, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997;156: Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343: The Childhood Asthma Management Program Research Group. Longterm effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343: Luo ZC, Low LCK, Karlberg J. A comparison of target height estimated and final height attained between Swedish and Hong Kong Chinese children. Acta Paediatr 1999;88: Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 2000;47: Reid LM. Lung growth in health and disease. Br J Dis Chest 1984; 78: Brody JS, Thurlbeck WM. Development, growth, and aging of the lung. In: Handbook of physiology. Section 3. The respiratory system. Vol. 3. Mechanics of breathing, part 1. Bethesda, Md.: American Physiological Society, 1986: Muglia LJ, Bae DS, Brown TT, et al. Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice. Am J Respir Cell Mol Biol 1999;20: Carson SH, Taeusch HW Jr, Avery ME. Inhibition of lung cell division after hydrocortisone injection into fetal rabbits. J Appl Physiol 1973;34: Massaro GD, Massaro D. Formation of alveoli in rats: postnatal effect of prenatal dexamethasone. Am J Physiol 1992;263:L37-L41. [Errata, Am J Physiol 1992;263:section L following table of contents, 1993;264:section L following table of contents.] 15. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332: , Massachusetts Medical Society. MELATONIN, CIRCADIAN RHYTHMS, AND SLEEP D ISTURBANCES in circadian rhythms often result in disturbances in sleep. Examples include syndromes in which sleep time is delayed or advanced, the sleeping problems associated with jet lag and shift work, and the sleep disorders that occur in totally blind persons with free-running circadian rhythms (i.e., rhythms that are not synchronized to the 24-hour day). 1 The hormone melatonin can be used both to characterize and to treat such disorders. The circadian rhythm of melatonin secretion is generated by the central pacemaker, or clock, in the suprachiasmatic nuclei of the hypothalamus, and like many other circadian rhythms, it is synchronized to a 24-hour period largely by cues from the light dark cycle that are received by the suprachiasmatic nuclei. Melatonin secretion is therefore a hand of this clock in the sense that it responds to signals from the suprachiasmatic nuclei and in that the timing of the melatonin rhythm indicates the status of the clock, at least in terms of phase (i.e., internal clock time relative to external clock time). It is notable that melatonin can provide feedback to this clock, thus modifying the 1114 October 12, 2000

3 EDITORIALS rhythm of its own production and of other circadian variables. 2 In this issue of the Journal, Sack et al. 3 take advantage of this action of melatonin to restore a more normal pattern of sleep in totally blind persons with free-running circadian rhythms and associated sleep disorders. Normally, melatonin is produced during the night. In most species, including humans, its secretion is related to the length of the night: the longer the night, the longer the duration of secretion. In many species, this pattern of production serves as a time cue for seasonal rhythms. 2 Whether melatonin has an essential role in mammalian circadian rhythms has been much debated. Certainly, the evening increase in melatonin secretion is associated with an increase in the propensity for sleep. 4 Secretion of melatonin during the day, as occurs in diverse pathologic or occupational health situations, is strongly associated with daytime sleepiness or napping, 5 and the administration of melatonin during the day induces sleepiness. 2 In the early 1980s, the results of two independent studies (one in rats and one in humans) showed that daily timed administration of melatonin could shift the phase of the internal clock and (in rats) entrain it to a normal cycle. 2 These observations led directly to the current interest in melatonin and its analogues for the treatment of circadian-rhythm disorders. A sleep wake cycle that is not synchronized to the 24-hour day is a disorder associated with blindness and may well represent the most important application of melatonin treatment, since in most other circumstances, timed treatment with sufficiently bright light can (at least in theory) reestablish a normal rhythm. 6 In studies of many blind people, my colleagues and I have found that the presence of a free-running rhythm is directly related to a greater degree of visual loss. 7 In addition, the incidence of this disorder increases with decreases in the perception of light; it occurred in all of our subjects who had no eyes. Treatment with light for synchronization to the 24-hour day is, of course, impossible for persons with no light perception (unless extraocular light proves to be effective). The properties of melatonin thus make it the optimal treatment, if indeed it can entrain free-running circadian rhythms in humans. Melatonin (in a dose of 5 mg daily, timed to advance the phase of the internal clock) can maintain synchronization of the circadian rhythm to a 24-hour cycle in sighted persons who are living in conditions likely to induce a free-running rhythm, and it appears to synchronize the rhythm in some persons after a short period of free-running. 8 In blind persons with freerunning rhythms, it has been possible to stabilize, or entrain, the sleep wake cycle to a 24-hour period, with resulting improvements in sleep and mood. 2 However, it has proved difficult to show that the clock itself could be entrained. Two groups have recently reported that complete synchronization can be achieved in some, but not all, blind persons. Sack et al. 3 attribute their success to the use of a higher dose of melatonin (10 mg daily, as compared with the 5 mg daily used in most previous studies) and to careful timing of the treatment to start an hour before the preferred bedtime, as the subjects free-running rhythms approached a normal phase. Previous, unsuccessful studies in which the 5-mg dose was used took this approach to timing, and thus perhaps the use of the higher daily dose was the key to success. However, earlier this year, Lockley et al. 9 reported complete synchronization in three totally blind men with only 5 mg of melatonin, timed to advance the phase of the internal clock (as in the current study, but with a more precise definition of phase). Sensitivity to melatonin varies among individual people, as do the pharmacokinetics of the drug. 2 This variation may explain the discrepancies among the results of these studies, especially because the number of subjects in whom synchronization has been achieved to date is very small. The timing of the start of melatonin treatment may be critical. In theory, if melatonin is given daily at the same clock time to a person with a free-running circadian rhythm for a treatment period lasting longer than a complete cycle (i.e., the time taken for the circadian rhythm to become delayed, or very rarely advanced by 24 hours), at some point in the cycle the timing will be optimal for synchronization to occur. This happens in rats, 2 but some people treated for years with melatonin continue to have a free-running rhythm, 10 albeit with subjective improvement in sleep. These observations underline the importance of assessing the circadian phase before treatment of a circadian-rhythm disorder begins (whether the treatment consists of light, melatonin, or another method). The rhythm of melatonin secretion can be determined by measurements of plasma or salivary melatonin or urinary 6-hydroxymelatonin sulfate (a particularly practical method in field studies). 2 The most noteworthy observation in the study by Sack et al. 3 is the maintenance of synchronization with a reduction in the dose of melatonin to 0.5 mg daily. Maintenance of synchronization with melatonin at physiologic concentrations supports the view that melatonin is an important component of the human circadian system. Sleep wake disorders involving a circadian cycle longer than 24 hours are a lifetime problem for blind persons, and it is of the utmost importance that the lowest possible dose of melatonin be used and that long-term safety be evaluated. 10 The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour Volume 343 Number

4 society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits. JOSEPHINE ARENDT, PH.D. University of Surrey Guildford, Surrey GU2 7XH, United Kingdom REFERENCES 1. Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 3rd ed. Section 8. Disorders of chronobiology. Philadelphia: W.B. Saunders, 2000: Arendt J. Melatonin and the mammalian pineal gland. London: Chapman & Hall, Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000; 343: Shochat T, Haimov I, Lavie P. Melatonin the key to the gate of sleep. Ann Med 1998;30: Lockley SW, Skene DJ, Tabandeh J, Bird AC, Defrance R, Arendt J. Relationship between napping and melatonin in the blind. J Biol Rhythms 1997;12: Czeisler CA, Johnson MP, Duffy JF, Brown EN, Ronda JM, Kronauer RE. Exposure to bright light and darkness to treat physiologic maladaptation to night work. N Engl J Med 1990;322: Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R. Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 1997;82: Middleton B, Arendt J, Stone BM. Complex effects of melatonin on human circadian rhythms in constant dim light. J Biol Rhythms 1997;12: Lockley SW, Skene DJ, James K, Thapan K, Wright J, Arendt J. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164:R1-R Arendt J. Safety of melatonin in long-term use. J Biol Rhythms 1997; 12: , Massachusetts Medical Society. The Journal will be adding a full-time Deputy Editor to its in-house staff. Applicants must have an M.D. degree; experience in clinical investigation, practice in a teaching hospital, or both; and appropriate academic credentials. Editorial experience is desirable. Those interested should write to the Editor-in-Chief (marking the envelope personal attention ), 10 Shattuck St., Boston, MA 02115, enclosing a curriculum vitae. The Massachusetts Medical Society is an equal-opportunity employer October 12, 2000

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