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Growth hormone and cystic fibrosis: Good for more than growth?
Growth hormone and cystic fibrosis: Good for more than growth? Malnutrition adversely affects survival in children and adults with CF,1,2 13% and 22% of whom, respectively, weigh less than the 85th percentile of their ideal body weight.3 Malnutrition and growth failure result from an unfavorable energy balance caused by the combination of low caloric intake, malabsorption of nutrients, chronic pulmonary disease, and increased energy expenditure. Nutritional supplementation promotes short-term weight gain in children with CF,4-7 but the effect on pulmonary function is controversial. Although several groups have observed that improved nutrition decreases the rate of deterioration of pulmonary function,5,7-9 the effect has not been consistently observed or sustained.10 If malnutrition adversely affects children with CF and nutritional supplementation alone is not coupled with sustained weight gain or improvement of pulmonary function, what therapeutic options remain? Recombinant human GH treatment stimulates linear growth in children with Turner syndrome and chronic renal disease. Is there reason to believe that treatment with recombinant human GH might also benefit patients with CF? Children with CF have low circulating concentrations of IGF-I, an anabolic peptide Dr Chernausek has received grants, contracts, and other support from the following manufacturers of growth hormone: Genentech, Lilly, Pharmacia, Novo-Nordisk, and Serono. Reprint requests: John C. Bucuvalas, MD, Children’s Hospital Medical Center, Divison of Gastroenterology, Hepatology, and Nutrition, 3333 Burnet Ave, Cincinnati, OH 45229.
J Pediatr 2001;139:616–8. Copyright © by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/18/119452 doi:10.1067/mpd.2001.119452
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that mediates actions of GH. IGF-I levels also correlate with height SD score, body mass index, and Shwachman score, a clinical measure of disease activity.11,12 Consequently, it makes sense to determine whether treatment with GH might increase IGF-I levels to improve lean body mass, increase the rate of growth, and retard pulmonary deterioration.
See related article, p 636. Previous reports have described the effects of GH treatment on prepubertal patients with CF. In 1997, Hardin et al13 reported results from the National Cooperative Growth Study, a postmarketing registry that tabulates growth parameters and safety information. They observed that linear growth rate and weight increased in prepubertal patients with CF who were treated with GH for 1 to 2 years.13 In a prospective study, Hardin et al14 administered human recombinant GH to 9 prepubertal children with CF for 1 year. Treatment with GH was associated with increased height velocity, weight velocity, increased muscle strength, and height z scores. Pulmonary function improved in all except 2 patients. In a subsequent report by Huseman et al,15 prepubertal children with CF received recombinant human GH subcutaneously for 12 months and had increases in growth velocity and lean body mass. However, the patient populations were small, the patients were not randomized, and no control groups were included. Moreover, the changes in the growth rate were modest, though a variation in it might have reflected changes in disease activity. In the current issue of The Journal, Hardin et al16 extend their previous ob-
servations by reporting the results of a randomized, controlled trial designed to determine whether treatment with GH for 1 year improves the clinical status of prepubertal children with CF.16 The investigators confirmed their previous uncontrolled observations that GH treatment in patients with decreased weight and height, despite apparent adequate caloric intake, increases height velocity, weight velocity, and lean tissue CF FEV1
Cystic fibrosis Forced expiratory volume in one second FVC Forced vital capacity GH Growth hormone HRQOL Health-related quality of life IGF-I Insulin-like growth factor-I
mass. Furthermore, children treated with GH had improved pulmonary function and fewer hospitalizations. Evidence that GH has beneficial effects beyond short-term stimulation of growth is important and makes physiologic sense. However, there are some unresolved questions in the information presented. Was the pulmonary function at baseline consistent with previous measures? FVC percentage appeared lower in the treated group at baseline. Thus, the decreased pulmonary function at baseline in the treated group may have been a sign of occult pulmonary exacerbation or slow recovery from a previous infection. In that event, the apparent improvement of pulmonary function with GH treatment may have reflected a return to baseline function. Furthermore, FEV1 did not change. Second, what degree of overlap existed for pulmonary function and growth rate between the control and treated groups? If there is substantial overlap, then differences found to be statistically signifi-
EDITORIALS
THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 5 cant might not be clinically significant. Finally, will the beneficial effects be sustainable with a longer duration of treatment? What inferences can we make from the findings presented by Hardin et al?13,14,16,18 To address the impact of GH treatment, we should consider several measures of clinical outcome in terms of growth, pulmonary function, and safety. Perhaps most important, clincial measures should be examined in relationship to quality of life (eg, HRQOL, which measures patient or parents’ perception of the child’s state of health, their overall quality of life, and their ability to carry out age-appropriate physical and social activities). Treatment with GH consistently increases growth rate in prepubertal children with CF, though the effect of this treatment on pulmonary function remains less certain. These conflicting observations may be the result of intrasubject variability, limited sensitivity of pulmonary function tests, or the variable rate of progression of lung disease.17 Is GH safe to use in children with chronic illness? The indications for GH therapy have broadened, and as the usage has increased, health care providers have voiced concerns about adverse events associated with prolonged treatment. However, when safety has been reviewed, adverse events have occurred less frequently. Nevertheless, we need to consider the potential adverse effects of GH treatment in children and adults with CF. Diabetes is prevalent in patients with CF,18 and GH can reduce insulin sensitivity. Approximately 20% of patients older than 18 years have glucose intolerance or diabetes.3 The present study included only prepubertal children, and the effect of GH on fasting insulin was very modest. No patient developed carbohydrate intolerance, and fasting glucose did not change. However, we cannot necessarily extend these findings to older patients for whom the risk of glucose intolerance or frank diabetes is increased.
The observation that GH treatment decreased the frequency of hospitalizations may be of considerable significance. We do not know if the hospitalizations were due to pulmonary exacerbations, but if so, we should consider the recent preliminary work by Britto et al,19 which found that the number of pulmonary exacerbations was an independent negative predictor of decreases in HRQOL. The impact of the number of pulmonary exacerbations was not explained by the changes of the clinical disease severity parameters themselves. If the findings are confirmed that treatment with GH decreases the number of hospitalizations, then it could be surmised that treatment with GH would improve HRQOL. In summary, the findings of Hardin et al16 indicate that GH increases the growth rate for prepubertal children with CF and may improve pulmonary function, which is promising. However, the population studied is a small subset (n = 19) of the patient population with CF, and the impact of GH on function and long-term outcome remains uncertain. More studies are needed. We must pay careful attention in the future to outcome and potential adverse events if we consider adding GH therapy to the treatment of undernourished patients with CF. John C. Bucuvalas, MD Division of Gastroenterology, Hepatology, and Nutrition Children’s Hospital Medical Center Cincinnati, OH 45229 Steven D. Chernausek, MD Division of Endocrinology Children’s Hospital Medical Center Cincinnati, OH 45229
REFERENCES 1. Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:58391. 2. Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and manage-
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
ment in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr 1992;55:108-16. Cystic Fibrosis Foundation, Patient Registry 1998 Annual Data Report. 1998. Baur LA, Waters DL, Allen BJ, Blagojevic N, Gaskin KJ. Nitrogen deposition in malnourished children with cystic fibrosis. Am J Clin Nutr 1991;53:503-11. Dalzell AM, Shepherd RW, Dean B, Cleghorn GJ, Holt TL, Francis PJ. Nutritional rehabilitation in cystic fibrosis: a 5 year follow-up study. J Pediatr Gastroenterol Nutr 1992;15:141-5. Shepherd R, Cooksley WG, Cooke WD. Improved growth and clinical, nutritional, and respiratory changes in response to nutritional therapy in cystic fibrosis. J Pediatr 1980;97:351-7. Shepherd RW, Holt TL, Thomas BJ, Kay L, Isles A, Francis PJ, et al. Nutritional rehabilitation in cystic fibrosis: controlled studies of effects on nutritional growth retardation, body protein turnover, and course of pulmonary disease. J Pediatr 1986;109:788-94. Heijerman HG, Bakker W, Sterk PJ, Dijkman JH. Oxygen-assisted exercise training in adult cystic fibrosis patients with pulmonary limitation to exercise. Int J Rehabil Res 1991;14:101-15. Heijerman HG, Bakker W, Sterk PJ, Dijkman JH. Long-term effects of exercise training and hyperalimentation in adult cystic fibrosis patients with severe pulmonary dysfunction. Int J Rehabil Res 1992;15:252-7. Hanning RM, Blimkie CJ, Bar-Or O, Lands LC, Moss LA, Wilson WM. Relationships among nutritional status and skeletal and respiratory muscle function in cystic fibrosis: does early dietary supplementation make a difference? Am J Clin Nutr 1993;57:580-7. Laursen EM, Juul A, Lanng S, Hoiby N, Koch C, Muller J, et al. Diminished concentrations of insulin-like growth factor I in cystic fibrosis. Arch Dis Child 1995;72:494-7. Taylor AM, Bush A, Thomson A, Oades PJ, Marchant JL, Bruce-Morgan C, et al. Relation between insulinlike growth factor-I, body mass index, and clinical status in cystic fibrosis. Arch Dis Child 1997;76:304-9. Hardin DS, Sy JP. Effects of growth hormone treatment in children with cystic fibrosis: the National Cooperative Growth Study experience. J Pediatr 1997;131:S65-9. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in 617
EDITORIALS
prepubertal children with cystic fibrosis. Horm Metab Res 1998;30:636-41. 15. Huseman CA, Columbo JA, Brooks MA, Smay JR, Greger NG, Sammut PH, et al. Anabolic effect of biosynthetic growth hormone in cystic fibrosis patients. Pediatr Pulmonol 1996;22:90-5. 16. Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone improves clinical status in pre-
618
THE JOURNAL OF PEDIATRICS NOVEMBER 2001 pubertal children with cystic fibrosisresults of a randomized controlled trial. J Pediatr 2001;139:636-42. 17. Ramsey BW, Boat TF. Outcome measures for clinical trials in cystic fibrosis. Summary of a Cystic Fibrosis Foundation consensus conference. J Pediatr 1994;124:177-92. 18. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K,
Wilson DP. Glucose tolerance in patients with cystic fibrosis: five year prospective study. BMJ 1995; 311:655-9. 19. Britto MT, Wilmott RW, Kotagal UR, Hornung RW, Kociela VL, Tsevat J. The association between clinical disease severity and quality of life in patients with cystic fibrosis. Pediatr Pulmonol 1999;(Suppl 19):325.
J Pediatr 2001;139:616–8. Copyright © by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/18/119452 doi:10.1067/mpd.2001.119452
616
that mediates actions of GH. IGF-I levels also correlate with height SD score, body mass index, and Shwachman score, a clinical measure of disease activity.11,12 Consequently, it makes sense to determine whether treatment with GH might increase IGF-I levels to improve lean body mass, increase the rate of growth, and retard pulmonary deterioration.
See related article, p 636. Previous reports have described the effects of GH treatment on prepubertal patients with CF. In 1997, Hardin et al13 reported results from the National Cooperative Growth Study, a postmarketing registry that tabulates growth parameters and safety information. They observed that linear growth rate and weight increased in prepubertal patients with CF who were treated with GH for 1 to 2 years.13 In a prospective study, Hardin et al14 administered human recombinant GH to 9 prepubertal children with CF for 1 year. Treatment with GH was associated with increased height velocity, weight velocity, increased muscle strength, and height z scores. Pulmonary function improved in all except 2 patients. In a subsequent report by Huseman et al,15 prepubertal children with CF received recombinant human GH subcutaneously for 12 months and had increases in growth velocity and lean body mass. However, the patient populations were small, the patients were not randomized, and no control groups were included. Moreover, the changes in the growth rate were modest, though a variation in it might have reflected changes in disease activity. In the current issue of The Journal, Hardin et al16 extend their previous ob-
servations by reporting the results of a randomized, controlled trial designed to determine whether treatment with GH for 1 year improves the clinical status of prepubertal children with CF.16 The investigators confirmed their previous uncontrolled observations that GH treatment in patients with decreased weight and height, despite apparent adequate caloric intake, increases height velocity, weight velocity, and lean tissue CF FEV1
Cystic fibrosis Forced expiratory volume in one second FVC Forced vital capacity GH Growth hormone HRQOL Health-related quality of life IGF-I Insulin-like growth factor-I
mass. Furthermore, children treated with GH had improved pulmonary function and fewer hospitalizations. Evidence that GH has beneficial effects beyond short-term stimulation of growth is important and makes physiologic sense. However, there are some unresolved questions in the information presented. Was the pulmonary function at baseline consistent with previous measures? FVC percentage appeared lower in the treated group at baseline. Thus, the decreased pulmonary function at baseline in the treated group may have been a sign of occult pulmonary exacerbation or slow recovery from a previous infection. In that event, the apparent improvement of pulmonary function with GH treatment may have reflected a return to baseline function. Furthermore, FEV1 did not change. Second, what degree of overlap existed for pulmonary function and growth rate between the control and treated groups? If there is substantial overlap, then differences found to be statistically signifi-
EDITORIALS
THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 5 cant might not be clinically significant. Finally, will the beneficial effects be sustainable with a longer duration of treatment? What inferences can we make from the findings presented by Hardin et al?13,14,16,18 To address the impact of GH treatment, we should consider several measures of clinical outcome in terms of growth, pulmonary function, and safety. Perhaps most important, clincial measures should be examined in relationship to quality of life (eg, HRQOL, which measures patient or parents’ perception of the child’s state of health, their overall quality of life, and their ability to carry out age-appropriate physical and social activities). Treatment with GH consistently increases growth rate in prepubertal children with CF, though the effect of this treatment on pulmonary function remains less certain. These conflicting observations may be the result of intrasubject variability, limited sensitivity of pulmonary function tests, or the variable rate of progression of lung disease.17 Is GH safe to use in children with chronic illness? The indications for GH therapy have broadened, and as the usage has increased, health care providers have voiced concerns about adverse events associated with prolonged treatment. However, when safety has been reviewed, adverse events have occurred less frequently. Nevertheless, we need to consider the potential adverse effects of GH treatment in children and adults with CF. Diabetes is prevalent in patients with CF,18 and GH can reduce insulin sensitivity. Approximately 20% of patients older than 18 years have glucose intolerance or diabetes.3 The present study included only prepubertal children, and the effect of GH on fasting insulin was very modest. No patient developed carbohydrate intolerance, and fasting glucose did not change. However, we cannot necessarily extend these findings to older patients for whom the risk of glucose intolerance or frank diabetes is increased.
The observation that GH treatment decreased the frequency of hospitalizations may be of considerable significance. We do not know if the hospitalizations were due to pulmonary exacerbations, but if so, we should consider the recent preliminary work by Britto et al,19 which found that the number of pulmonary exacerbations was an independent negative predictor of decreases in HRQOL. The impact of the number of pulmonary exacerbations was not explained by the changes of the clinical disease severity parameters themselves. If the findings are confirmed that treatment with GH decreases the number of hospitalizations, then it could be surmised that treatment with GH would improve HRQOL. In summary, the findings of Hardin et al16 indicate that GH increases the growth rate for prepubertal children with CF and may improve pulmonary function, which is promising. However, the population studied is a small subset (n = 19) of the patient population with CF, and the impact of GH on function and long-term outcome remains uncertain. More studies are needed. We must pay careful attention in the future to outcome and potential adverse events if we consider adding GH therapy to the treatment of undernourished patients with CF. John C. Bucuvalas, MD Division of Gastroenterology, Hepatology, and Nutrition Children’s Hospital Medical Center Cincinnati, OH 45229 Steven D. Chernausek, MD Division of Endocrinology Children’s Hospital Medical Center Cincinnati, OH 45229
REFERENCES 1. Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:58391. 2. Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and manage-
3. 4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
ment in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr 1992;55:108-16. Cystic Fibrosis Foundation, Patient Registry 1998 Annual Data Report. 1998. Baur LA, Waters DL, Allen BJ, Blagojevic N, Gaskin KJ. Nitrogen deposition in malnourished children with cystic fibrosis. Am J Clin Nutr 1991;53:503-11. Dalzell AM, Shepherd RW, Dean B, Cleghorn GJ, Holt TL, Francis PJ. Nutritional rehabilitation in cystic fibrosis: a 5 year follow-up study. J Pediatr Gastroenterol Nutr 1992;15:141-5. Shepherd R, Cooksley WG, Cooke WD. Improved growth and clinical, nutritional, and respiratory changes in response to nutritional therapy in cystic fibrosis. J Pediatr 1980;97:351-7. Shepherd RW, Holt TL, Thomas BJ, Kay L, Isles A, Francis PJ, et al. Nutritional rehabilitation in cystic fibrosis: controlled studies of effects on nutritional growth retardation, body protein turnover, and course of pulmonary disease. J Pediatr 1986;109:788-94. Heijerman HG, Bakker W, Sterk PJ, Dijkman JH. Oxygen-assisted exercise training in adult cystic fibrosis patients with pulmonary limitation to exercise. Int J Rehabil Res 1991;14:101-15. Heijerman HG, Bakker W, Sterk PJ, Dijkman JH. Long-term effects of exercise training and hyperalimentation in adult cystic fibrosis patients with severe pulmonary dysfunction. Int J Rehabil Res 1992;15:252-7. Hanning RM, Blimkie CJ, Bar-Or O, Lands LC, Moss LA, Wilson WM. Relationships among nutritional status and skeletal and respiratory muscle function in cystic fibrosis: does early dietary supplementation make a difference? Am J Clin Nutr 1993;57:580-7. Laursen EM, Juul A, Lanng S, Hoiby N, Koch C, Muller J, et al. Diminished concentrations of insulin-like growth factor I in cystic fibrosis. Arch Dis Child 1995;72:494-7. Taylor AM, Bush A, Thomson A, Oades PJ, Marchant JL, Bruce-Morgan C, et al. Relation between insulinlike growth factor-I, body mass index, and clinical status in cystic fibrosis. Arch Dis Child 1997;76:304-9. Hardin DS, Sy JP. Effects of growth hormone treatment in children with cystic fibrosis: the National Cooperative Growth Study experience. J Pediatr 1997;131:S65-9. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in 617
EDITORIALS
prepubertal children with cystic fibrosis. Horm Metab Res 1998;30:636-41. 15. Huseman CA, Columbo JA, Brooks MA, Smay JR, Greger NG, Sammut PH, et al. Anabolic effect of biosynthetic growth hormone in cystic fibrosis patients. Pediatr Pulmonol 1996;22:90-5. 16. Hardin DS, Ellis KJ, Dyson M, Rice J, McConnell R, Seilheimer DK. Growth hormone improves clinical status in pre-
618
THE JOURNAL OF PEDIATRICS NOVEMBER 2001 pubertal children with cystic fibrosisresults of a randomized controlled trial. J Pediatr 2001;139:636-42. 17. Ramsey BW, Boat TF. Outcome measures for clinical trials in cystic fibrosis. Summary of a Cystic Fibrosis Foundation consensus conference. J Pediatr 1994;124:177-92. 18. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K,
Wilson DP. Glucose tolerance in patients with cystic fibrosis: five year prospective study. BMJ 1995; 311:655-9. 19. Britto MT, Wilmott RW, Kotagal UR, Hornung RW, Kociela VL, Tsevat J. The association between clinical disease severity and quality of life in patients with cystic fibrosis. Pediatr Pulmonol 1999;(Suppl 19):325.