832
Editorial correspondence
immune response with long-standing and easily detectable levels of specific EBV antibodies, especially to VCA but also to the early antigen complex. 3 Variation in specific EBV antibody titers may be due to reactivation of latent virus, infection with heterologous virus with development of cross-reactive antibodies, selective stimulation of memory B cells by related antigens, or polyclonal B cell stimulation.5 These important differences from most other infectious agents and the high prevalence of past EBV infection have led to innumerable case reports in which EBV has been implicated on the basis of serologic findings alone as a cause of a variety of illnesses. 6 We must be cognizant of the nuances of serologic tests for latent viruses and circumspect in using serologic testing as the sole means of establishing a causal relationship between infection and clinical Illness.
Hal B. Jenson, MD Departments of Pediatrics and Microbiology Ciro V. Sumaya, MD Departments of Pediatrics and Pathology University of Texas Health Science Center San Antonio, TX 78284-7811 REFERENCES
I. Kinoshita S, Yoshioka K, Kasahara M, Osamu T. Acquired yon Willebrand disease after Epstein-Barr virus infection. J PEDIATR 1991;119:595-8. 2. Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children. 11. Heterophile antibody and viral-specific responses. Pediatrics 1985;75:1011-9. 3. Horwitz CA, Henle W, Henle G, Rudnick G, Latts E. Longterm serological follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect Dis 1985;151:1150-3. 4. Henle G, Henle W, Horwitz CA. Antibodies to Epstein-Barr virus-associated nuclear antigen in infectious mononucleosis. J Infect Dis 1974;130:231-9. 5. Linde A, Fridell E, Dahl H, Andersson J, Biberfeld P, Wahren B. Effect of primary Epstein-Barr virus infection on human herpesvirus 6, cytomegalovirus, and measles virus immunoglobulin G titers. J Clin Microbiol 1990;28:211-5. 6. Andiman WA. Epstein-Barr virus-associated syndromes: a critical reexamination. Pediatr Infect Dis 1984;3:198-203.
Reply To the Editor: Drs. Jenson and Sumaya comment that the febrile illness with rash that occurred 2 weeks before the onset of von Willebrand disease was not due to a primary Epstein-Barr virus (EBV) infection. We agree because of the persistent presence of antibodies to EBV nuclear antigen and the lack of IgM antibodies, so we did not call it a "primary infection." Because of the persistent presence of antibodies to EBV nuclear antigen, the increase in IgG antibodies to viral capsid antigen (VCA) was explained by reactivation of or reinfection with EBV. In this patient the Paul-Bunnell heterophil antibody titer was 256, which was not reported in the article because it was thought to be a nonspecific antibody and was assayed only once. However, the high level of Paul-Bunnell heterophil an-
The Journal of Pediatrics May 1992
tibody may suggest reinfection with EBV rather than reactivation. Viral antibodies, including those against the influenza and parainfluenza viruses, respiratory syncytial virus, adenovirus, herpes simplex virus, varicella-zoster virus, rubella and measles viruses, mumps virus, cytomegalo virus, rota virus, echovirus, coxsackievirus, and poliovirus, were examined; there was no significant increase in antibody titers in paired samples during the period. Although human herpesvirus type 6 was not examined (because the episode had occurred 5 years previously), only the EBV-VCA (IgG) antibody increased from 80 to 1280. We believe that a significant increase in EBV-VCA (IgG) antibody titer might have been caused by EBV reactivation and possibly EBV reinfection, although there is no certain proof of reinfection. We agree that the exact state of EBV infection cannot be identified by the serologic tests alone, and it is difficult to tell the precise relationship between the presence of EBV infection and the development of clinical illness. Whether EBV infection causes yon Wiflebrand disease should be further studied in additional similar cases.
Seiji Kinoshita, MD Keiichiro Yoshioka, MD Motoko Kasahara Osamu Takamiya Department of Pediatrics and Clinical Laboratory Osaka National Hospital 2-1-14, Hoenzaka, Chuo-ku Osaka 540, Japan
Growth hormone therapy in children with Down syndrome To the Editor: The article by Torrado et al. 1 showed that children with Down syndrome can respond to treatment with recombinant human growth hormone by increasing their annual rate of growth. In a small group they showed that there were no significant short-term side effects. They concluded, by analogy to Turner syndrome, that these children should be treated with growth hormone. Missing from the discussion of the ethical aspects of treating children who have Down syndrome with growth hormone was a clear statement of the benefits of the treatment for these patients. In what way do the authors, the patients, and their parents believe that these children will benefit by being taller? Do these benefits outweigh any inconvenience and discomfort from the treatment? Do the authors believe that it is obligatory to treat all children who have Down syndrome with growth hormone? Is treatment required if it is against the wishes of the parents? Who should be required to pay for the treatment? Before patients are treated with this or any other therapy, a clearly defined benefit should be seen to outweigh the risks of therapy, including those risks that cannot be foreseen at present.
Nancy D. Binder, MD, PhD Oregon Health Sciences University Portland, OR 97201
Volume 120 Number 5
REFERENCE
1. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J PEDIATR 1991;119:478-83.
To the Editor." Torrado et al. I concluded that it is appropriate to treat children who have Down syndrome with growth hormone (GH) because the authors believe that these children are GH deficient. The evidence for this belief is weak. Of the 13 treated patients, 7 had endogenous serum GH responses > 10 ng/ml in response to at least one provocative test. Such responses do not exclude GH deficiency, nor can they be used to make the diagnosis. The authors based their belief that GH deficiency is present on speculation by Youlton et al. 2 that disparate GH responses might indicate GH deficiency, and on the suggestion by Shulman et al. 3that elonidine might differ from other provocative stimuli by giving false-positive results in some GH-deficient children. Neither of these points is widely accepted as valid. Likewise, "GH neurosecretory dysfunction" is not widely accepted as a definable entity. The guidelines for therapeutic use of GH, suggested in 1983 by the American Academy of Pediatrics and the Lawson Wilkins Pediatric Endocrine Society,4 encourage physicians to doeument GH deficiency before recommending GH therapy. This recommendation was not followed in the study by Torrado et al. The investigators leave the reader with the implication that increased head circumference during GH therapy provides some special benefit to the patient, but they did not show that increased head size related to improved intellectual performance. It is probable that some parents of children with Down syndrome might assume that increased head circumference can be equated with improved intellectual capacity and might pursue GH therapy for their child for inappropriate reasons. It seems likely from the limited information presented that some patients did not meet reasonable criteria (or the criteria proposed by the investigators) for treatment with GH. The mean height standard deviation score was -2.2 _+ 0.8 (SD). The 3rd percentile is approximately -1.8 SD below the mean; the reader must infer that several of the patients were not short. It is inappropriate to use a pretreatment growth velocity that is "less than normal" as a criterion for therapy; the authors should have defined "less than normal" as less than the 50th percentile or less than the 3rd percentile for age. The mean growth velocity of their patients before treatment was 5.4 _+ 1.6 cm/yr, suggesting that some of these children were growing at a normal rate. It is not my purpose to propose that patients with Down syndrome should never be treated with GH. It is important, however, not to Undertake treatments that are difficult and expensive if the patient does not benefit or is harmed. The investigators focus on lack of development of carbohydrate intolerance in their treated patients but fail to express concern about reports of leukemia in GH-deficient children treated with GH. 5 This is particularly pertinent in Down syndrome because these patients have a predisposition to leukemia.
Editorial correspondence
833
Physicians and parents of children with Down syndrome should be wary about treating these children with GH before controlled studies are completed. These studies should include assessment of the child's biologic and psychologic need for GH, the potential benefits to the child, and the potential physical and psychologic risks of treatment, some of which may be unique to patients with Down syndrome. The matter of informed consent is especially pertinent because many of these children are limited in their ability to understand the complex issues involved in GH treatment. We might serve the needs of children with Down syndrome better by questioning the assumption that "taller is more desirable" and by committing the resources that would have been applied toward GH therapy to meeting their other needs.
Louis E. Underwood, MD Professor of Pediatrics University of North Carolina at Chapel Hill Chapel Hill, N C 27599-7220 REFERENCES
1. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J PEDIATR 1991; 119:478-83. 2. Youlton R, Kaplan SL, Grumbach MM. Growth and growth hormone. IV. Limitations of the growth hormone response to insulin and arginine and the immunoreactive insulin response to arginine in the assessment of growth hormone deficiency in children. Pediatrics 1969;43:989-1004. 3. Shulman D, Zamanillo J, Lowitt S. Effect of clonidine upon anterior pituitary function and plasma cateeholamine concentrations in short children and adolescents. J Pediatr Endoerinol 1985;4:211-6. 4. Ad Hoc Committee on Growth Hormone Usage, Lawson Wilkins Pediatric Endocrine Society, and Committee on Drugs, American Academy of Pediatrics. Growth hormone in the treatment of children with short stature. Pediatrics 1983; 72:891-4. 5. Fisher DA, Job J-C, Preece M, Underwood LE. Growth hormone deficiency, human growth hormone and the occurrence of leukemia. Lancet 1988;l:1159-60.
Reply To the Editor." Dr. Underwood suggests that the evidence of growth hormone (GH) deficiency in the 13 children whom we treated with recombinant human growth hormone (hGH) is weak. We disagree because we tested all 13 children for hGH deficiency (height
Editorial correspondence
immune response with long-standing and easily detectable levels of specific EBV antibodies, especially to VCA but also to the early antigen complex. 3 Variation in specific EBV antibody titers may be due to reactivation of latent virus, infection with heterologous virus with development of cross-reactive antibodies, selective stimulation of memory B cells by related antigens, or polyclonal B cell stimulation.5 These important differences from most other infectious agents and the high prevalence of past EBV infection have led to innumerable case reports in which EBV has been implicated on the basis of serologic findings alone as a cause of a variety of illnesses. 6 We must be cognizant of the nuances of serologic tests for latent viruses and circumspect in using serologic testing as the sole means of establishing a causal relationship between infection and clinical Illness.
Hal B. Jenson, MD Departments of Pediatrics and Microbiology Ciro V. Sumaya, MD Departments of Pediatrics and Pathology University of Texas Health Science Center San Antonio, TX 78284-7811 REFERENCES
I. Kinoshita S, Yoshioka K, Kasahara M, Osamu T. Acquired yon Willebrand disease after Epstein-Barr virus infection. J PEDIATR 1991;119:595-8. 2. Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children. 11. Heterophile antibody and viral-specific responses. Pediatrics 1985;75:1011-9. 3. Horwitz CA, Henle W, Henle G, Rudnick G, Latts E. Longterm serological follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect Dis 1985;151:1150-3. 4. Henle G, Henle W, Horwitz CA. Antibodies to Epstein-Barr virus-associated nuclear antigen in infectious mononucleosis. J Infect Dis 1974;130:231-9. 5. Linde A, Fridell E, Dahl H, Andersson J, Biberfeld P, Wahren B. Effect of primary Epstein-Barr virus infection on human herpesvirus 6, cytomegalovirus, and measles virus immunoglobulin G titers. J Clin Microbiol 1990;28:211-5. 6. Andiman WA. Epstein-Barr virus-associated syndromes: a critical reexamination. Pediatr Infect Dis 1984;3:198-203.
Reply To the Editor: Drs. Jenson and Sumaya comment that the febrile illness with rash that occurred 2 weeks before the onset of von Willebrand disease was not due to a primary Epstein-Barr virus (EBV) infection. We agree because of the persistent presence of antibodies to EBV nuclear antigen and the lack of IgM antibodies, so we did not call it a "primary infection." Because of the persistent presence of antibodies to EBV nuclear antigen, the increase in IgG antibodies to viral capsid antigen (VCA) was explained by reactivation of or reinfection with EBV. In this patient the Paul-Bunnell heterophil antibody titer was 256, which was not reported in the article because it was thought to be a nonspecific antibody and was assayed only once. However, the high level of Paul-Bunnell heterophil an-
The Journal of Pediatrics May 1992
tibody may suggest reinfection with EBV rather than reactivation. Viral antibodies, including those against the influenza and parainfluenza viruses, respiratory syncytial virus, adenovirus, herpes simplex virus, varicella-zoster virus, rubella and measles viruses, mumps virus, cytomegalo virus, rota virus, echovirus, coxsackievirus, and poliovirus, were examined; there was no significant increase in antibody titers in paired samples during the period. Although human herpesvirus type 6 was not examined (because the episode had occurred 5 years previously), only the EBV-VCA (IgG) antibody increased from 80 to 1280. We believe that a significant increase in EBV-VCA (IgG) antibody titer might have been caused by EBV reactivation and possibly EBV reinfection, although there is no certain proof of reinfection. We agree that the exact state of EBV infection cannot be identified by the serologic tests alone, and it is difficult to tell the precise relationship between the presence of EBV infection and the development of clinical illness. Whether EBV infection causes yon Wiflebrand disease should be further studied in additional similar cases.
Seiji Kinoshita, MD Keiichiro Yoshioka, MD Motoko Kasahara Osamu Takamiya Department of Pediatrics and Clinical Laboratory Osaka National Hospital 2-1-14, Hoenzaka, Chuo-ku Osaka 540, Japan
Growth hormone therapy in children with Down syndrome To the Editor: The article by Torrado et al. 1 showed that children with Down syndrome can respond to treatment with recombinant human growth hormone by increasing their annual rate of growth. In a small group they showed that there were no significant short-term side effects. They concluded, by analogy to Turner syndrome, that these children should be treated with growth hormone. Missing from the discussion of the ethical aspects of treating children who have Down syndrome with growth hormone was a clear statement of the benefits of the treatment for these patients. In what way do the authors, the patients, and their parents believe that these children will benefit by being taller? Do these benefits outweigh any inconvenience and discomfort from the treatment? Do the authors believe that it is obligatory to treat all children who have Down syndrome with growth hormone? Is treatment required if it is against the wishes of the parents? Who should be required to pay for the treatment? Before patients are treated with this or any other therapy, a clearly defined benefit should be seen to outweigh the risks of therapy, including those risks that cannot be foreseen at present.
Nancy D. Binder, MD, PhD Oregon Health Sciences University Portland, OR 97201
Volume 120 Number 5
REFERENCE
1. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J PEDIATR 1991;119:478-83.
To the Editor." Torrado et al. I concluded that it is appropriate to treat children who have Down syndrome with growth hormone (GH) because the authors believe that these children are GH deficient. The evidence for this belief is weak. Of the 13 treated patients, 7 had endogenous serum GH responses > 10 ng/ml in response to at least one provocative test. Such responses do not exclude GH deficiency, nor can they be used to make the diagnosis. The authors based their belief that GH deficiency is present on speculation by Youlton et al. 2 that disparate GH responses might indicate GH deficiency, and on the suggestion by Shulman et al. 3that elonidine might differ from other provocative stimuli by giving false-positive results in some GH-deficient children. Neither of these points is widely accepted as valid. Likewise, "GH neurosecretory dysfunction" is not widely accepted as a definable entity. The guidelines for therapeutic use of GH, suggested in 1983 by the American Academy of Pediatrics and the Lawson Wilkins Pediatric Endocrine Society,4 encourage physicians to doeument GH deficiency before recommending GH therapy. This recommendation was not followed in the study by Torrado et al. The investigators leave the reader with the implication that increased head circumference during GH therapy provides some special benefit to the patient, but they did not show that increased head size related to improved intellectual performance. It is probable that some parents of children with Down syndrome might assume that increased head circumference can be equated with improved intellectual capacity and might pursue GH therapy for their child for inappropriate reasons. It seems likely from the limited information presented that some patients did not meet reasonable criteria (or the criteria proposed by the investigators) for treatment with GH. The mean height standard deviation score was -2.2 _+ 0.8 (SD). The 3rd percentile is approximately -1.8 SD below the mean; the reader must infer that several of the patients were not short. It is inappropriate to use a pretreatment growth velocity that is "less than normal" as a criterion for therapy; the authors should have defined "less than normal" as less than the 50th percentile or less than the 3rd percentile for age. The mean growth velocity of their patients before treatment was 5.4 _+ 1.6 cm/yr, suggesting that some of these children were growing at a normal rate. It is not my purpose to propose that patients with Down syndrome should never be treated with GH. It is important, however, not to Undertake treatments that are difficult and expensive if the patient does not benefit or is harmed. The investigators focus on lack of development of carbohydrate intolerance in their treated patients but fail to express concern about reports of leukemia in GH-deficient children treated with GH. 5 This is particularly pertinent in Down syndrome because these patients have a predisposition to leukemia.
Editorial correspondence
833
Physicians and parents of children with Down syndrome should be wary about treating these children with GH before controlled studies are completed. These studies should include assessment of the child's biologic and psychologic need for GH, the potential benefits to the child, and the potential physical and psychologic risks of treatment, some of which may be unique to patients with Down syndrome. The matter of informed consent is especially pertinent because many of these children are limited in their ability to understand the complex issues involved in GH treatment. We might serve the needs of children with Down syndrome better by questioning the assumption that "taller is more desirable" and by committing the resources that would have been applied toward GH therapy to meeting their other needs.
Louis E. Underwood, MD Professor of Pediatrics University of North Carolina at Chapel Hill Chapel Hill, N C 27599-7220 REFERENCES
1. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J PEDIATR 1991; 119:478-83. 2. Youlton R, Kaplan SL, Grumbach MM. Growth and growth hormone. IV. Limitations of the growth hormone response to insulin and arginine and the immunoreactive insulin response to arginine in the assessment of growth hormone deficiency in children. Pediatrics 1969;43:989-1004. 3. Shulman D, Zamanillo J, Lowitt S. Effect of clonidine upon anterior pituitary function and plasma cateeholamine concentrations in short children and adolescents. J Pediatr Endoerinol 1985;4:211-6. 4. Ad Hoc Committee on Growth Hormone Usage, Lawson Wilkins Pediatric Endocrine Society, and Committee on Drugs, American Academy of Pediatrics. Growth hormone in the treatment of children with short stature. Pediatrics 1983; 72:891-4. 5. Fisher DA, Job J-C, Preece M, Underwood LE. Growth hormone deficiency, human growth hormone and the occurrence of leukemia. Lancet 1988;l:1159-60.
Reply To the Editor." Dr. Underwood suggests that the evidence of growth hormone (GH) deficiency in the 13 children whom we treated with recombinant human growth hormone (hGH) is weak. We disagree because we tested all 13 children for hGH deficiency (height
