- Email: [email protected]
Stress-related growth failure
THE LANCET
delay between specimen collection and arrival in the laboratory. The contents of each tube was then inoculated into an aerobic blood-culture bottle (Hemoline performance diphasique), which was incubated at 37°C with subculture onto heated blood (“chocolate”) agar at 24 and 72 h. Recovery of N meningitidis was recognised by colonial morphology and gram-staining. The figure shows the recovery of meningococci over a range of simulated bacteraemic loads and following different periods of delay. Generally, the higher the load, the longer the organisms remained retrievable (Spearman rank correlation coefficient, 0·93; p<0·001 by two-tailed t test). For higher loads such as would be expected in severe meningococcal disease, it was possible to recover organisms after a delay of 3 h. Results were less predictable for lower bacterial counts, perhaps reflecting inaccuracies in quantitation which are inevitable at such levels. Our results suggest that in cases of suspected meningococcal disease seen in the community, a blood sample taken into a “full blood count” tube immediately before administration of parenteral penicillin might on admission to hospital be a source of viable meningococci. This simple technique might promote the use of preadmission antibiotics by lessening concern for their sterilising effects on blood and cerebrospinal fluid. *A Berrington, S Partridge, C Bates, E Ridgway Department of Medical Microbiology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1
2
3
4
5
Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital. BMJ 1992; 305: 141–47. PHLS Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease: guidance for consultants in communicable disease control. CDR Review 1995; 5: 189–95. Irwin D, Miller JM, Cornell SJ. GPs often fail to give early parenteral benzylpenicillin in suspected meningococcal infection. BMJ 1996; 312: 1538. Sullivan TD, LaScolea LJ. Neisseria meningitidis bacteraemia in children: quantitation of bacteraemia and spontaneous clinical recovery without antibiotic therapy. Pediatrics 1987; 80: 63–67. Yagupsky P, Nolte FS. Quantitative aspects of septicaemia. Clin Microbiol Rev 1990; 3: 269–79.
Skuse and colleagues also argue that the growth hormone profiles observed are different from those described in acute malnutrition. 3 However, this is chronic malnutrition associated with pronounced stunting which, in malnourished populations, is often associated with normal body mass indices (BMI).4 Such children might well have switched off their growth hormone production as a protective mechanism to conserve muscle mass and organ function.3 Moreover, if the low growth hormone was accompanied by normal or excessive intake, this again should be associated with obesity, as in isolated growth hormone deficiency. Skuse’s underpinning argument is that the hyperphagic children differ physically as well as behaviourally from the remainder of the referred population, who they conclude are suffering from undernutrition. Yet the difference in BMI is small (0·4 SD) and the confidence intervals (not provided) widely overlap. The other children do manifest different growth hormone profiles but these are no more characteristic of malnutrition than those in the hyperphagia group. Others have argued that the abnormality is in the parents’ distorted perceptions of their children’s needs, whereas the child’s behaviour was merely a response to food restriction. I suggest that most of this referred population have experienced malnutrition, but that the hyperphagia group has encountered active withholding of food, resulting in adaptive behaviours to ensure a continued food supply. The comparisons made with the group from the Wessex growth study provide a useful estimate of prevalence of the syndrome which seems to represent only a tiny minority of children with short stature. In our experience with failure to thrive in younger children, we have not yet observed hyperphagic behaviour in any of our series of some 300 children, and proportionate short stature is comparatively rare.5 Children of this kind thus present a rare but fascinating puzzle, which is yet to be solved. However, it will be unfortunate if the main result of this study is that it perpetuates the fallacy that it is possible for children to eat and eat and yet grow neither fat nor tall. Charlotte Wright Department of Child Health, Newcastle University, Donald Court House, Gateshead NE8 3EB, UK
1
Stress-related growth failure 1
SIR—Skuse and colleagues (Aug 10, p 353) revisit the subject of psychosocial dwarfism, and investigate a population selectively referred to their tertiary centre because of growth failure associated with major family problems and abuse. They identified a subgroup of children they term hyperphagic who scavenge from dustbins, steal food, and gorge themselves. The implication of their report and Stevenson’s commentary2 is that these children are not malnourished, although no dietary data are presented. So what is the evidence that these children are not merely hungry? Reliance is placed on the observation that the disordered eating patterns have been witnessed by others and that the children are not underweight. However, being exceptionally short, these children’s replacement calorie requirements would be well below average, which suggests that the witnessed episodes of excessive eating are in fact interspersed with periods of reduced intake, otherwise the children would be fat. The main witnesses to routine eating patterns are parents who in this case are implicated in the stress and abuse experienced by these children.
1104
2 3 4
5
Skuse D, Albanese A, Stanhope R, Gilmour J, Voss L. A new stressrelated syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency. Lancet 1996; 348: 353–58. Stevenson RD. Stress-related growth failure. Lancet 1996; 348: 348. Brasel JA. Endocrine adaptation to malnutrition. Pediatr Res 1890; 14: 1299–303. Waterlow J, Schuerch B. Causes and mechanisms of linear growth retardation. Proceedings of an International Dietary Energy Consultancy Group Workshop. London, UK: European Journal of Clinical Nutrition Supplement, 1993. Wright C. The Parkin Project: a study of screening and intervention in failure to thrive. University of Newcastle upon Tyne: MD thesis, 1996.
Authors’ reply SIR—Wright has fallen victim to the same state of confusion about the processes by which growth may become impaired in conditions of psychosocial adversity that has bedevilled publications for so many years. The thrust of her criticism is that we provided no evidence that the hyperphagic sample were adequately nourished. Direct measures of food consumption before hospitalisation were not practicable. However, other evidence besides that in our report militates against the starvation hypothesis.
Vol 348 • October 19, 1996
THE LANCET
*
0 BMI
4
SD scores
–1
† Weight –2
Steroid-free immunosuppression in renal transplantation
Height
–4
Time 1
Time 2
Figure: Height, weight, and body mass index (BMI) change during catch-up growth for hyperphagic cases only Values are mean SDS (and SE) for 23 of 29 children who changed domicile. Mean (SD) age at time 1 was 7·1 (3·2) years and at time 2 was 9·3 (3·7). *not significant, †p<0·001.
First, children stunted as a consequence of chronic undernutrition in the developing world do not exhibit hyperphagia but are usually difficult to re-feed. Second, malnourished children of equivalent age and stature to our study group do not show catch-up growth during later childhood and adolescence, by contrast with our hyperphagic children.1 Third, children in our study did not eat excessively in hospital for more than a few days, and their BMIs did not change significantly during the initial follow-up period, despite a substantial increase in stature (figure). Fourth, growth hormone responses to provocation tests in protein-calorie malnutrition are not “insufficient”,2 and decrease on recovery. Why then were the children with hyperphagic short stature not obese, if they ate excessively? Perhaps for the same reason that binge eaters in adulthood are not necessarily overweight.3 They did not persistently snack; they gorged and they vomited. Access to food was restricted, at home and at school; crucially, this was in response to the child’s behaviour and not vice versa. Finally, Wright marshals in defence of her argument the observation that in 300 children with failure to thrive who she studied in Newcastle, proportionate short stature is rare, and hyperphagia unknown. Yet she believes the aetiology of the failure to thrive in these 300 cases is undernutrition.4 That observation seems to prove our point. Chronic undernourishment does not lead to hyperphagia; acute malnourishment does not lead to short stature. Children with hyperphagic short stature have a constellation of symptoms (involving disorders of appetite, sleep, and urination) and physiological signs (spontaneously reversible growth hormone insufficiency) that indicates possible dysfunction of the hypothalamus from which there are close links to brain centres such as the amygdala, which regulate emotion.5 Adults with stress-related sleep disturbance and binge eating have been reported (Fairburn CG, personal communication), possibly representing the same phenotype. Hyperphagic short stature is not a normative response to starvation, but an idiosyncratic response to stress. *D H Skuse, J Gilmour, R Stanhope, A Albanese, L Voss Institute of Child Health, Behavioural Sciences Unit, London WC1N 1EH, UK
2
5
Fairburn CG, Wilson GT, eds. Binge eating: nature, assessment and treatment. New York: Guilford Press, 1993. Wright CM. The Parkin project: a study of screening and intervention in failure to thrive. University of Newcastle upon Tyne: MD thesis, 1996. Morley JE. Neuropeptide regulation of appetite and weight. Endocr Rev 1987; 8: 256–87
†
–3
1
3
Martorell R, Kettel Khan L, Schroeder DG. Reversibility of stunting: epidemiological findings in children from developing countries. Eur J Clin Nutr 1994; 48 (suppl 1): S45–S57. Ho KY, Veldhuis JD, Johnson ML, et al. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988; 81: 968–75.
Vol 348 • October 19, 1996
SIR—Ratcliffe and colleagues (Sept 7, p 643)1 conclude that late steroid withdrawal is feasible in most patients with stable graft function, although often leading to reduced function. This caution is in accord with others2 reporting a higher incidence of acute rejections, but disagrees with Opelz3 showing the best graft survival in patients on cyclosporin without steroids 1 year after transplantation. Because steroids have adverse affects on most organ systems, body appearance, psychological wellbeing, and growth in children, there has been great interest in withdrawal or avoidance of steroids, but feasibility and strategy present difficulties. Existing data are difficult to interpret because of the great variation in immunosuppressive strategies and the selection of patients included in the few controlled and uncontrolled studies that have been done. Since the immune system adapts to the agents given, steroids should be withdrawn with caution, once they have been given. Adverse effects can be expected, which is underlined by the reported occurrence of acute rejections and reduced graft function. In our centre we have used another approach,4,5 which is to avoid steroids from the very beginning. Since 1983 we have based our protocol on cyclosporin monotherapy (Sandimmun, Sandoz). We give 12 mg/kg daily on day 0–2, 10 mg/kg daily on day 3–7, then 8 mg/kg daily as long-term maintenance; in living-related donor transplantation 10 mg/kg, 12 mg/kg, 10·5 mg/kg, on days ⫺2 and ⫺1, and +1, respectively, followed by 10 mg/kg for 6 days and then 8 mg/kg daily as maintenance. From 1986 we used the monoclonal agent muromonab-CD3 (OKT3, Cilag) (5 mg daily, 10 days) as first-line therapy in case of acute cellular rejection. From 1990 we supplemented the protocol with an initial 10-day course of polyclonal antilymphocyte globulin (Minnesota-ALG, University of Minnesota; 20 mg/kg daily), later antithymocyte globulin (Thymoglobulin, PasteurMérieux; 1·25 mg/kg daily). From 1994, we used Sandimmun/Neoral (Sandoz) (same doses as above, adjusted regularly according to blood trough concentrations), and from 1995 we added mycophenolate mofetil (CellCept, Year 1991
1992
1993
1994
1995
3479 616 2863
3678 647 3031
3880 687 3193
4069 729 3340
4222 765 3457
Cumulative no of functional grafts Denmark Odense Other centres in DK
925 174 751
1012 177 835
1084 193 891
1139 203 936
1172 198 974
Functional grafts as % of all transplanted Odense Other centres in Denmark
28 26
27 28
28 28
28 28
26 28
Cumulative no of all transplantations Denmark Odense Other centres in DK
DK=Denmark.
Table: Transplanted patients in Denmark, in four centres, functioning grafts at the end of each year, and functioning grafts as percentage of all transplanted
1105
delay between specimen collection and arrival in the laboratory. The contents of each tube was then inoculated into an aerobic blood-culture bottle (Hemoline performance diphasique), which was incubated at 37°C with subculture onto heated blood (“chocolate”) agar at 24 and 72 h. Recovery of N meningitidis was recognised by colonial morphology and gram-staining. The figure shows the recovery of meningococci over a range of simulated bacteraemic loads and following different periods of delay. Generally, the higher the load, the longer the organisms remained retrievable (Spearman rank correlation coefficient, 0·93; p<0·001 by two-tailed t test). For higher loads such as would be expected in severe meningococcal disease, it was possible to recover organisms after a delay of 3 h. Results were less predictable for lower bacterial counts, perhaps reflecting inaccuracies in quantitation which are inevitable at such levels. Our results suggest that in cases of suspected meningococcal disease seen in the community, a blood sample taken into a “full blood count” tube immediately before administration of parenteral penicillin might on admission to hospital be a source of viable meningococci. This simple technique might promote the use of preadmission antibiotics by lessening concern for their sterilising effects on blood and cerebrospinal fluid. *A Berrington, S Partridge, C Bates, E Ridgway Department of Medical Microbiology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1
2
3
4
5
Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital. BMJ 1992; 305: 141–47. PHLS Meningococcal Infections Working Group and Public Health Medicine Environmental Group. Control of meningococcal disease: guidance for consultants in communicable disease control. CDR Review 1995; 5: 189–95. Irwin D, Miller JM, Cornell SJ. GPs often fail to give early parenteral benzylpenicillin in suspected meningococcal infection. BMJ 1996; 312: 1538. Sullivan TD, LaScolea LJ. Neisseria meningitidis bacteraemia in children: quantitation of bacteraemia and spontaneous clinical recovery without antibiotic therapy. Pediatrics 1987; 80: 63–67. Yagupsky P, Nolte FS. Quantitative aspects of septicaemia. Clin Microbiol Rev 1990; 3: 269–79.
Skuse and colleagues also argue that the growth hormone profiles observed are different from those described in acute malnutrition. 3 However, this is chronic malnutrition associated with pronounced stunting which, in malnourished populations, is often associated with normal body mass indices (BMI).4 Such children might well have switched off their growth hormone production as a protective mechanism to conserve muscle mass and organ function.3 Moreover, if the low growth hormone was accompanied by normal or excessive intake, this again should be associated with obesity, as in isolated growth hormone deficiency. Skuse’s underpinning argument is that the hyperphagic children differ physically as well as behaviourally from the remainder of the referred population, who they conclude are suffering from undernutrition. Yet the difference in BMI is small (0·4 SD) and the confidence intervals (not provided) widely overlap. The other children do manifest different growth hormone profiles but these are no more characteristic of malnutrition than those in the hyperphagia group. Others have argued that the abnormality is in the parents’ distorted perceptions of their children’s needs, whereas the child’s behaviour was merely a response to food restriction. I suggest that most of this referred population have experienced malnutrition, but that the hyperphagia group has encountered active withholding of food, resulting in adaptive behaviours to ensure a continued food supply. The comparisons made with the group from the Wessex growth study provide a useful estimate of prevalence of the syndrome which seems to represent only a tiny minority of children with short stature. In our experience with failure to thrive in younger children, we have not yet observed hyperphagic behaviour in any of our series of some 300 children, and proportionate short stature is comparatively rare.5 Children of this kind thus present a rare but fascinating puzzle, which is yet to be solved. However, it will be unfortunate if the main result of this study is that it perpetuates the fallacy that it is possible for children to eat and eat and yet grow neither fat nor tall. Charlotte Wright Department of Child Health, Newcastle University, Donald Court House, Gateshead NE8 3EB, UK
1
Stress-related growth failure 1
SIR—Skuse and colleagues (Aug 10, p 353) revisit the subject of psychosocial dwarfism, and investigate a population selectively referred to their tertiary centre because of growth failure associated with major family problems and abuse. They identified a subgroup of children they term hyperphagic who scavenge from dustbins, steal food, and gorge themselves. The implication of their report and Stevenson’s commentary2 is that these children are not malnourished, although no dietary data are presented. So what is the evidence that these children are not merely hungry? Reliance is placed on the observation that the disordered eating patterns have been witnessed by others and that the children are not underweight. However, being exceptionally short, these children’s replacement calorie requirements would be well below average, which suggests that the witnessed episodes of excessive eating are in fact interspersed with periods of reduced intake, otherwise the children would be fat. The main witnesses to routine eating patterns are parents who in this case are implicated in the stress and abuse experienced by these children.
1104
2 3 4
5
Skuse D, Albanese A, Stanhope R, Gilmour J, Voss L. A new stressrelated syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency. Lancet 1996; 348: 353–58. Stevenson RD. Stress-related growth failure. Lancet 1996; 348: 348. Brasel JA. Endocrine adaptation to malnutrition. Pediatr Res 1890; 14: 1299–303. Waterlow J, Schuerch B. Causes and mechanisms of linear growth retardation. Proceedings of an International Dietary Energy Consultancy Group Workshop. London, UK: European Journal of Clinical Nutrition Supplement, 1993. Wright C. The Parkin Project: a study of screening and intervention in failure to thrive. University of Newcastle upon Tyne: MD thesis, 1996.
Authors’ reply SIR—Wright has fallen victim to the same state of confusion about the processes by which growth may become impaired in conditions of psychosocial adversity that has bedevilled publications for so many years. The thrust of her criticism is that we provided no evidence that the hyperphagic sample were adequately nourished. Direct measures of food consumption before hospitalisation were not practicable. However, other evidence besides that in our report militates against the starvation hypothesis.
Vol 348 • October 19, 1996
THE LANCET
*
0 BMI
4
SD scores
–1
† Weight –2
Steroid-free immunosuppression in renal transplantation
Height
–4
Time 1
Time 2
Figure: Height, weight, and body mass index (BMI) change during catch-up growth for hyperphagic cases only Values are mean SDS (and SE) for 23 of 29 children who changed domicile. Mean (SD) age at time 1 was 7·1 (3·2) years and at time 2 was 9·3 (3·7). *not significant, †p<0·001.
First, children stunted as a consequence of chronic undernutrition in the developing world do not exhibit hyperphagia but are usually difficult to re-feed. Second, malnourished children of equivalent age and stature to our study group do not show catch-up growth during later childhood and adolescence, by contrast with our hyperphagic children.1 Third, children in our study did not eat excessively in hospital for more than a few days, and their BMIs did not change significantly during the initial follow-up period, despite a substantial increase in stature (figure). Fourth, growth hormone responses to provocation tests in protein-calorie malnutrition are not “insufficient”,2 and decrease on recovery. Why then were the children with hyperphagic short stature not obese, if they ate excessively? Perhaps for the same reason that binge eaters in adulthood are not necessarily overweight.3 They did not persistently snack; they gorged and they vomited. Access to food was restricted, at home and at school; crucially, this was in response to the child’s behaviour and not vice versa. Finally, Wright marshals in defence of her argument the observation that in 300 children with failure to thrive who she studied in Newcastle, proportionate short stature is rare, and hyperphagia unknown. Yet she believes the aetiology of the failure to thrive in these 300 cases is undernutrition.4 That observation seems to prove our point. Chronic undernourishment does not lead to hyperphagia; acute malnourishment does not lead to short stature. Children with hyperphagic short stature have a constellation of symptoms (involving disorders of appetite, sleep, and urination) and physiological signs (spontaneously reversible growth hormone insufficiency) that indicates possible dysfunction of the hypothalamus from which there are close links to brain centres such as the amygdala, which regulate emotion.5 Adults with stress-related sleep disturbance and binge eating have been reported (Fairburn CG, personal communication), possibly representing the same phenotype. Hyperphagic short stature is not a normative response to starvation, but an idiosyncratic response to stress. *D H Skuse, J Gilmour, R Stanhope, A Albanese, L Voss Institute of Child Health, Behavioural Sciences Unit, London WC1N 1EH, UK
2
5
Fairburn CG, Wilson GT, eds. Binge eating: nature, assessment and treatment. New York: Guilford Press, 1993. Wright CM. The Parkin project: a study of screening and intervention in failure to thrive. University of Newcastle upon Tyne: MD thesis, 1996. Morley JE. Neuropeptide regulation of appetite and weight. Endocr Rev 1987; 8: 256–87
†
–3
1
3
Martorell R, Kettel Khan L, Schroeder DG. Reversibility of stunting: epidemiological findings in children from developing countries. Eur J Clin Nutr 1994; 48 (suppl 1): S45–S57. Ho KY, Veldhuis JD, Johnson ML, et al. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988; 81: 968–75.
Vol 348 • October 19, 1996
SIR—Ratcliffe and colleagues (Sept 7, p 643)1 conclude that late steroid withdrawal is feasible in most patients with stable graft function, although often leading to reduced function. This caution is in accord with others2 reporting a higher incidence of acute rejections, but disagrees with Opelz3 showing the best graft survival in patients on cyclosporin without steroids 1 year after transplantation. Because steroids have adverse affects on most organ systems, body appearance, psychological wellbeing, and growth in children, there has been great interest in withdrawal or avoidance of steroids, but feasibility and strategy present difficulties. Existing data are difficult to interpret because of the great variation in immunosuppressive strategies and the selection of patients included in the few controlled and uncontrolled studies that have been done. Since the immune system adapts to the agents given, steroids should be withdrawn with caution, once they have been given. Adverse effects can be expected, which is underlined by the reported occurrence of acute rejections and reduced graft function. In our centre we have used another approach,4,5 which is to avoid steroids from the very beginning. Since 1983 we have based our protocol on cyclosporin monotherapy (Sandimmun, Sandoz). We give 12 mg/kg daily on day 0–2, 10 mg/kg daily on day 3–7, then 8 mg/kg daily as long-term maintenance; in living-related donor transplantation 10 mg/kg, 12 mg/kg, 10·5 mg/kg, on days ⫺2 and ⫺1, and +1, respectively, followed by 10 mg/kg for 6 days and then 8 mg/kg daily as maintenance. From 1986 we used the monoclonal agent muromonab-CD3 (OKT3, Cilag) (5 mg daily, 10 days) as first-line therapy in case of acute cellular rejection. From 1990 we supplemented the protocol with an initial 10-day course of polyclonal antilymphocyte globulin (Minnesota-ALG, University of Minnesota; 20 mg/kg daily), later antithymocyte globulin (Thymoglobulin, PasteurMérieux; 1·25 mg/kg daily). From 1994, we used Sandimmun/Neoral (Sandoz) (same doses as above, adjusted regularly according to blood trough concentrations), and from 1995 we added mycophenolate mofetil (CellCept, Year 1991
1992
1993
1994
1995
3479 616 2863
3678 647 3031
3880 687 3193
4069 729 3340
4222 765 3457
Cumulative no of functional grafts Denmark Odense Other centres in DK
925 174 751
1012 177 835
1084 193 891
1139 203 936
1172 198 974
Functional grafts as % of all transplanted Odense Other centres in Denmark
28 26
27 28
28 28
28 28
26 28
Cumulative no of all transplantations Denmark Odense Other centres in DK
DK=Denmark.
Table: Transplanted patients in Denmark, in four centres, functioning grafts at the end of each year, and functioning grafts as percentage of all transplanted
1105