Efficacy and safety of LB03002, a once-weekly sustained-release human GH for 12-month treatment in Korean children with GH deficiency.

PURPOSE: The purpose of this study was to investigate the efficacy and safety of LB03002, a sustained-release human GH (SR-hGH), compared with that of daily rhGH for 12 months in children with GH deficiency (GHD). METHODS: A total of 73 children with GHD were screened and 63 eligible subjects were randomized in a 1:1 ratio of LB03002 (SR-hGH) to daily rhGH treatment group. LB03002 was administered once weekly at a dose of 0.5 mg/kg while daily rhGH was administered for 6 consecutive days with equally divided doses to make a total of 0.21 mg/kg per week. Treatments were given for 12 months by s.c. injections. Injection site reactions and adverse events were investigated throughout the study period. RESULTS: The mean (S.D.) height velocity (HV) SHOWED a clinically significant increase after the 6-month treatment: 3.00 (1.15) cm/year at screening to 9.78 (1.98) cm/year at 6 months in the LB03002 group; 2.39 (1.63) cm/year at screening to 10.56 (2.65) cm/year at 6 months in the daily rhGH group. The increased HV at 12 months was still maintained in both the groups: 9.06 (1.63) cm/year at 12 months in the LB03002 group; 9.72 (2.32) cm/year at 12 months in the daily rhGH group. Most of the adverse drug reactions were mild and tolerable. No subjects were withdrawn due to adverse events. CONCLUSION: Weekly injection of LB03002 at a dose of 0.5 mg/kg per week was confirmed to have comparable efficacy to daily injection of rhGH at a dose of 0.21 mg/kg per week. Both formulations were well tolerated.

Reference values for serum levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Korean children and adolescents.

OBJECTIVE: Measurements of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) are utilized in the diagnostic work-up and clinical management of children with growth disorders. We designed this study to establish the reference values of serum IGF-I and IGFBP-3 levels according to age, sex and pubertal stage in Korean children and adolescents. METHODS: For the study, 1378 healthy Korean children and adolescents aged 0 to 17 years (722 boys, 656 girls) were randomly selected. Blood samples were collected, and the stored sera were assayed for IGF-I and IGFBP-3 using immunoradiometric assay (IRMA, Immunotech). The R 2.8.1 program (Bell Laboratories) was used to generate reference percentile curves for IGF-I and IGFBP-3 according to age, sex, and pubertal stage RESULTS: Serum IGFBP-3 level was higher in girls compared to that in boys of the same ages throughout the pubertal period, whereas IGF-I was only higher for girls younger than 13 years of age. Serum levels of IGF-I and IGFBP-3 increased steadily with age in the prepubertal stage, followed by a progressive decline thereafter. Peak levels of serum IGF-I and IGFBP-3 were observed two years earlier in girls compared to those in boys (13 vs. 15 years of age, respectively). Serum IGF-I and IGFBP-3 concentrations were highest at Tanner stage IV in boys and girls, with a subsequent decline. CONCLUSIONS: Our reference value model based on age, sex, and pubertal stage can improve the diagnostic utility of IGF-1 and IGFBP-3 levels in the evaluation and management of Korean children and adolescents with growth disorders.

Blockade of Vascular Endothelial Growth Factor (VEGF) Aggravates the Severity of Acute Graft-versus-host Disease (GVHD) after Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT).

BACKGROUND: Recent clinical observation reported that there was a significant correlation between change in circulating vascular endothelial growth factor (VEGF) levels and the occurrence of severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the action mechanisms of VEGF in GVHD have not been demonstrated. METHODS: This study investigated whether or not blockade of VEGF has an effect on acute GVHD in a lethally irradiated murine allo-HSCT model of B6 (H-2(b))→B6D2F1 (H-2(b/d)). Syngeneic or allogeneic recipient mice were injected subcutaneously with anti-VEGF peptides, dRK6 (50 µg/dose) or control diluent every other day for 2 weeks (total 7 doses). RESULTS: Administration of the dRK6 peptide after allo-HSCT significantly reduced survival with greaterclinical GVHD scores and body weight loss. Allogeneic recipients injected with the dRK6 peptide exhibited significantly increased circulating levels of VEGF and expansion of donor CD3(+) T cells on day +7 compared to control treated animals. The donor CD4(+) and CD8(+) T-cell subsets have differential expansion caused by the dRK6 injection. The circulating VEGF levels were reduced on day +14 regardless of blockade of VEGF. CONCLUSION: Together these findings demonstrate that the allo-reactive responses after allo-HSCT are exaggerated by the blockade of VEGF. VEGF seems to be consumed during the progression of acute GVHD in this murine allo-HSCT model.

Association of cytotoxic T lymphocyte antigen-4 gene polymorphisms and HLA class II alleles with the development of type 1 diabetes in Korean children and adolescents.

We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.

Endocrine complications after hematopoietic stem cell transplantation during childhood and adolescence.

Long-term survivors of hematopoietic stem cell transplantation (HSCT) during childhood and adolescence are at risk of developing endocrine complications. The purpose of this study was to evaluate the long-term endocrine complications and their associated risk factors among such patients. We reviewed the data from 111 patients (59 males and 52 females) who underwent HSCT at the mean age of 8.3+/-4.1 yr. Thirty patients (27.0%) had growth impairment, and seven (21.2%) out of 33 patients who attained final height reached final height below 2 standard deviation (SD). The final height SD score of the patients conditioned with total body irradiation (TBI) was significantly lower than that of the patients conditioned without TBI (-1.18+/-1.14 vs. -0.19+/-0.78, P=0.011). Thirteen patients (11.7%) developed hypothyroidism (11 subclinical, 2 central) 3.8+/-1.8 (range 1.6-6.2) yr after HSCT. Nineteen (65.5%) out of 29 females had evidence of gonadal dysfunction, and 18 (64.3%) out of 28 males had evidence of gonadal dysfunction. The risk for gonadal dysfunction was significantly higher in females conditioned with busulfan/cyclophosphamide (P=0.003). These results suggest that the majority of patients treated with HSCT during childhood and adolescence have one or more endocrine complications. Therefore, multiple endocrine functions should be monitored periodically after HSCT until they reach adult age.

The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis.

Familial hypokalemic periodic paralysis (HOPP) is a rare autosomal-dominant disease characterized by reversible attacks of muscle weakness occurring with episodic hypokalemia. Mutations in the skeletal muscle calcium (CACNA1S) and sodium channel (SCN4A) genes have been reported to be responsible for familial HOPP. Fifty-one HOPP patients from 20 Korean families were studied to determine the relative frequency of the known mutations and to specify the clinical features associated with the identified mutations. DNA analysis identified known mutations in 12 families: 9 (75%) were linked to the CACNA1S gene and 3 (25%) to the SCN4A gene. The Arg528His mutation in the CACNA1S gene was found to be predominant in these 12 families. Additionally, we have detected one novel silent exonic mutation (1950C>T) in the SCN4A gene. As for a SCN4A Arg669His mutation, incomplete penetrance in a woman was observed. Characteristic clinical features were observed both in patients with and without mutations. This study presents comprehensive data on the genotype and phenotype of Korean families with HOPP.

The changing epidemiology of hospitalized pediatric patients in three measles outbreaks.

OBJECTIVES: To assess the demographic and clinical findings of measles patients during three epidemics from 1989 to 2001. METHODS: A total 520 medical records of measles patients were analyzed retrospectively and divided into three groups; those who were admitted during 1989-1990 (group I, 116 patients), those admitted during 1993-1994 (group II, 127 patients), and those admitted during 2000-2001 (group III, 277 patients). RESULTS: For the age distribution, there was no difference in the proportion of < 2 years of age (61%, 58% and 57%, respectively) for the three groups. However, in each outbreak, there were significant differences in the distribution of > or = 2 years children who had mostly received one-dose measles-mumps-rubella (MMR) vaccination. The age distribution had changed with a significant increase in older children in subsequent outbreaks. In the last 2000-2001 outbreak, there was a pattern for increased attack rates with increasing interval since the initial vaccination. There was no statistical difference between the three groups in gender ratio, MMR vaccination rate in > or = 2 years of age, duration of fever, and complications. No difference was found in all the clinical and laboratory parameters between the anti-measles IgM antibody negative patients and the positive patients. CONCLUSIONS: The age distribution of admitted children with measles in each outbreak has changed over time since the introduction of one-dose MMR vaccination. This finding suggests that the secondary vaccine failure may have played a large role in the last measles outbreak.

Features of Kawasaki disease at the extremes of age.

AIM: The diagnosis of Kawasaki disease (KD) in those outside the typical age range (6 months-4 years) is often delayed, potentially worsening prognosis. The features of KD in childrenor=5 years were compared with those presenting within the more typical age distribution. METHODS: Korean children with complete diagnostic criteria for KD were grouped according to their age at presentation: Group A (or=5 years). The clinical features, laboratory findings and outcome in each group were compared. RESULTS: Of 136 children presenting to a single centre between 1999 and 2003, 10 children were in Group A, 114 in Group B and 12 in Group C. The mean total fever duration was 8 days in Group C and 6.2 days in Group A (P=0.03). All children in Group C had cervical lymphadenopathy, compared with 50% of Group A and 64% of Group B (P=0.01). Coronary artery lesions were commoner in older children (Group C, 42%) compared with Group B (17%, P=0.05). All children had an equivalent leukocytosis, but Group C had significantly higher neutrophil counts (P=0.001). Group A had significantly lower mean haemoglobin (P=0.003) and total protein (P=0.002) at presentation and a more marked thrombocytosis 1 week after intravenous immunoglobulin therapy (P<0.05). CONCLUSION: The clinical and laboratory phenotype of KD varies with age. Older children may have a more marked inflammatory response and worse outcome. Younger children who are treated appropriately may not have a chance to higher risk of coronary artery lesions.

Role of prednisolone treatment in severe Mycoplasma pneumoniae pneumonia in children.

Mycoplasma pneumoniae pneumonia (MP) is responsible for 10-40% of cases of pediatric community-acquired pneumonia. Occasionally, progression to severe pneumonia occurs despite appropriate antibiotic therapy. We retrospectively evaluated the effect of prednisolone in 15 children with MP whose clinical and radiographic course worsened despite broad-spectrum antibiotics, including appropriate macrolides. The mean ( +/- SD) age was 6.1 +/- 1.9 years, and 10 were boys. All children had received macrolides at presentation, but they had persistent fever and progressively worsening radiographic findings. In addition to broad-spectrum antimicrobial therapy, we added prednisolone (1 mg/kg for 3-7 days, then tapered over 7 days) on day 6 (+/-1.5 days) of admission. Fourteen children became afebrile within 24 hr, and their clinical status and radiographic findings improved over several days. The white blood cell count at presentation was 7,500 +/- 2,000/mm3, with a proportion demonstrating lymphopenia (lymphocyte differential, 19.7 +/- 5.7%). In conclusion, corticosteroid treatment appeared to be temporally associated with clinical and radiographic improvement, and may be helpful for reducing morbidity in children with macrolide-nonresponsive severe MP. Further studies may be warranted.

The changing epidemiology of pediatric aseptic meningitis in Daejeon, Korea from 1987 to 2003.

BACKGROUND: Aseptic meningitis is a relatively frequent childhood disease and virologic data suggest that enteroviruses are the commonest etiologic agents. We evaluated the epidemiologic characteristics of aseptic meningitis in Daejeon, South Korea from 1987 to 2003. METHODS: 2201 medical records of children with aseptic meningitis admitted to The Catholic University of Korea, Daejeon St Mary's Hospital were retrospectively analyzed. RESULTS: Outbreaks of aseptic meningitis were observed in 1990, 1993, 1996, 1997, 2001 and 2002. The age distribution of cases was relatively uniform, with a higher incidence in those aged < 1 year and 4-7 years. The male-to-female ratio was 2:1. There was a higher incidence of disease in the summer (May to August, 74.1% of total). Comparison of the largest epidemics in 1997 and 2002 showed significant differences in the incidence in those < 1 year (11.8% vs. 4.4%, respectively; P = 0.001). Neurologic sequelae were observed in 0.7% of the patients. CONCLUSION: Aseptic meningitis, rare before the 1980s in Korea, has since become a common clinical entity. Since 1990, outbreaks of aseptic meningitis have occurred every 1 to 3 years in Daejeon in keeping with Korea-wide epidemics. The frequency of disease affecting children less than one year of age may reflect herd immunity to the epidemic strain.

Clinical features of measles according to age in a measles epidemic.

The purpose of this study was to retrospectively investigate the relationship between age and clinical manifestations and laboratory findings in patients with measles. The study included 216 patients admitted to a hospital in Daejeon, 1 of the largest cities in South Korea, during the 2000-2001 measles outbreak: very young children (<2 y old; 159 patients), school age children (9-11 y old; 34 patients), and young adults (>16 y old; 23 patients). Few of the very young children (9%), but most of the older children (86%) had a history of a prior measles-mumps-rubella vaccination. There were no statistical differences between the 3 groups in terms of the total duration of fever, length of hospitalization, occurrence of complications (defined as hospitalization for more than 7 d) or anti-measles IgM positivity. A reduction in the number of white blood cells and lymphocytes was observed in all age groups. The levels of C-reactive protein were not different between very young children and older children, but hepatic involvement was more prevalent in young adults. In conclusion, the clinical course including the complications experienced was similar in all the measles patients regardless of age.

Kikuchi-Fujimoto disease with prolonged fever in children.

We reviewed 12 patients who had Kikuchi-Fujimoto disease (KFD) and presented with prolonged fever and lymphadenopathy. The clinical and laboratory aspects of the patients confirmed by excisional lymph node biopsy were analyzed. The mean age of the children was 11.0 +/- 3.0 years (range: 6-15 years). The male-to-female ratio was 1.4:1. The median duration of fever before admission and the total duration of fever was 13 days (range: 7-65 days) and 19.5 days (range: 9-75 days), respectively. One patient had supraclavicular lymphadenopathy, 10 had cervical involvement, and 1 had axillary lymphadenopathy. All of the histologic findings of the lymph node biopsies showed the characteristic findings consistent with KFD, such as paracortical necrosis with karyorrhexis and an increase in the number of phagocytic histiocytes and atypical lymphocytes. As for the laboratory findings, leukopenia (3600 +/- 900 per mm3), anemia (hemoglobin 11.4 +/- 1.2 g/dL), an elevated erythrocyte sedimentation rate (44 +/- 18 mm/hour), and a relatively low C-reactive protein level (1.3 +/- 1.1 mg/dL) were noted. Eight patients received conservative therapy with antipyretics, and 3 patients were treated with prednisolone. KFD is a rare disease yet should be considered in the differential diagnosis for older children with prolonged fever and lymphadenopathy.