Hemolytic anemia associated with intravenous immunoglobulin in Kawasaki disease.

BACKGROUND: The administration of high-dose intravenous immunoglobulin (IVIG) is a standard treatment for the management of Kawasaki disease (KD). IVIG is known to be a highly effective and safe treatment. CASE PRESENTATION: We report the development of hemolytic anemia in seven children receiving repeated doses of IVIG. The children were aged 3-44 months and included 4 girls and 3 boys. All children received 10% IVIG and a second course of immunoglobulin because they did not respond to the first course of immunoglobulin. Two received high-dose aspirin (50 mg/kg), and five received low-dose aspirin (5 mg/kg). Two patients required additional methylprednisolone pulse therapy (30 mg/kg) after the second dose of immunoglobulin, and three patients received oral prednisolone therapy for defervescence. Three patients showed coronary artery dilation during hospitalization and normalized within two months. Pretreatment hemoglobin averaged 11.3-14.2 g/dL, and post-hemolytic anemia hemoglobin ranged from 7.4 to 9.6 g/dL, with a difference of 1.7-6.8 g/dL. Reticulocytes were increased to 3.3-13.2%. Peripheral blood smears showed normochromic normocytic anemia, and anisopoikilocytosis. All children were positive for warm-type antibodies with IgG+, C3d- in direct antiglobulin test, and the blood group was A + in five and B + in two. None of the patients received immunomodulatory therapy or red blood cell transfusions. They were followed for a year and all recovered. CONCLUSION: Especially, in non-O blood group KD patients who are refractory to initial IVIG and require a second dose of IVIG or 10% formulation the possibility of immune hemolytic anemia should be carefully considered, and close follow-up should be maintained after therapy.

Parental metabolic syndrome and elevated liver transaminases are risk factors for offspring, even in children and adolescents with a normal body mass index.

Introduction: The parent-child correlation in metabolic syndrome (MetS) and elevated transaminases is sparsely researched. We assessed the correlation of parental MetS and elevated transaminase status with these conditions in their children. Methods: Data of 4,167 youths aged 10-18 years were analyzed in a population-based survey, and the parental characteristics were stratified by the presence or absence of MetS or alanine aminotransferase (ALT) elevation in their children. The prevalence of these conditions in children was analyzed according to their parents' status. Logistic regression analyses were performed with MetS and ALT elevation in youth as the dependent variables. Results: The proportions of MetS and ALT elevation were higher in parents of children with MetS and ALT elevation than in those without, even among youths without obesity. In logistic regression analyses, age, body mass index-standard deviation score (BMI-SDS), and ALT elevation were positively associated with MetS, whereas age, male sex, BMI-SDS, protein intake, and MetS were positively associated with ALT elevation. Higher protein intake was related to ALT elevation, whereas metabolic components and nutritional factors were closely related in parents and their children. Odds ratios (OR) of ALT elevation for MetS was 8.96 even after adjusting nutritional factors in the children. The OR was higher for ALT elevation in the children of parents with MetS and ALT elevation compared to those without. ORs for MetS and ALT elevation in the children of parents with MetS were higher than those of children of parents without MetS, even after adjusting for nutritional intake. ORs for ALT elevation were higher in the children of parents with ALT elevation than those without, even after adjusting for nutritional intake and BMI of parents as well as the nutritional intake, age, sex, and BMI-SDS of the children. Conclusion: MetS and elevated liver transaminase statuses in children were associated with those of their parents even after adjusting for nutritional factors, and the relationships were more prominent in the youth without obesity.

The influence of pituitary volume on the growth response in growth hormone-treated children with growth hormone deficiency and idiopathic short stature.

Purpose: Magnetic resonance imaging (MRI) can be used for assessing the morphology of pituitary gland. The purpose of this study was 1) to determine whether the pituitary volume (PV) distinguish growth hormone (GH) deficiency from idiopathic short stature (ISS) and 2) to validate an association between PV and severity of GH deficiency and 3) to compare the PV between good and poor response groups in children with GH deficiency and ISS. Methods: Data were collected from the medical records of 152 children with short stature who underwent GH stimulation test, sella MRI, and GH treatment. Estimated PV were calculated using the formula of an ellipsoid. We compared the PV in patients with GH deficiency with that of patients with ISS. In addition, we assessed the association between PV and severity of GH deficiency, and growth response after treatment. Results: No difference was observed in the PV between patients with GH deficiency and ISS. The PV seemed to be smaller as the degree of GH deficiency was severe (P=0.082). The PV in good response group was smaller than that in poor response group in patients with GH deficiency (P< 0.005). The PV showed no association with responsiveness to GH treatment in patients with ISS (P=0.073). Conclusions: The measurement of PV cannot be used for differential diagnosis between GH deficiency and ISS. In patients with GH deficiency, the PV tend to be smaller as the severity of GH deficiency even though no statistical significance, and may be a good response predictor for GH treatment.

Bone Age Estimation and Prediction of Final Adult Height Using Deep Learning.

PURPOSE: The appropriate evaluation of height and accurate estimation of bone age are crucial for proper assessment of the growth status of a child. We developed a bone age estimation program using a deep learning algorithm and established a model to predict the final adult height of Korean children. MATERIALS AND METHODS: A total of 1678 radiographs from 866 children, for which the interpretation results were consistent between two pediatric endocrinologists, were used to train and validate the deep learning model. The bone age estimation algorithm was based on the convolutional neural network of the deep learning system. The test set simulation was performed by a deep learning program and two raters using 150 radiographs and final height data for 100 adults. RESULTS: There was a statistically significant correlation between bone age interpreted by the artificial intelligence (AI) program and the reference bone age in the test set simulation (r=0.99, p<0.001). In the test set simulation, the AI program showed a mean absolute error (MAE) of 0.59 years and a root mean squared error (RMSE) of 0.55 years, compared with reference bone age, and showed similar accuracy to that of an experienced pediatric endocrinologist (rater 1). Prediction of final adult height by the AI program showed an MAE of 4.62 cm, compared with the actual final adult height. CONCLUSION: We developed a bone age estimation program based on a deep learning algorithm. The AI-derived program demonstrated high accuracy in estimating bone age and predicting the final adult height of Korean children and adolescents.

Comparison of growth response and adverse reaction according to growth hormone dosing strategy for children with short stature: LG Growth Study.

OBJECTIVE: Growth hormone (GH) dosage in children is conventionally determined either by body weight (BW) or body surface area (BSA). However, there is no consensus on the calculation method for proper GH treatment dose. We aimed to compare growth response and adverse reactions between BW- and BSA-based GH treatment doses for children with short statures. DESIGN: Data from 2284 GH-treated children were analyzed. Distributions of BW- and BSA-based GH treatment doses and their association with growth response parameters, including changes in height, height standard deviation score (SDS), body mass index (BMI), and safety parameters, such as changes in insulin-like growth factor (IGF)-I SDS and adverse events, were investigated. RESULTS: The mean BW-based doses were close to the recommended dose's upper limit in participants with GH deficiency and idiopathic short stature, while they were below the recommended dose in patients with Turner syndrome (TS). As age and BW increased, BW-based dose decreased, whereas BSA-based dose increased. Gain in height SDS was positively associated with BW-based dose in the TS group and negatively associated with BW in all groups. Despite having a lower BW-based dose, the overweight/obese groups had a higher BSA-based dose and higher frequencies of children with high IGF-I and adverse events than those of the normal-BMI group. CONCLUSIONS: In children of older age or with high BW, BW-based doses can be overdosed in terms of BSA. and BW-based dose positively correlated with height gain only in the TS group. BSA-based doses represent an alternative dosing strategy in children who are overweight/obese.

Association between early glycemic management and diabetes complications in type 1 diabetes mellitus: A retrospective cohort study.

AIMS: To investigate the association between early HbA1c levels near diagnosis and future glycemic management, and analyzed risk factors of complications in people with T1DM. METHODS: This retrospective cohort study included 201 children and adolescents with T1DM. Patient data including sex, age at diagnosis, duration of disease, HbA1c levels, HbA1c variability during the follow-up period, and diabetes complications and comorbidities were collected. RESULTS: The mean follow-up period of patients was 16.4 years. HbA1c levels in all three examined time points after diagnosis (first year, second year, and first two years) were significantly associated with recent HbA1c level, and second-year HbA1c was most closely correlated with recent HbA1c level. Elevated second-year HbA1c was a risk factor of diabetic ketoacidosis (DKA) and retinopathy, and increased variability of HbA1c was significantly related to various microvascular complications. When HbA1c is stratified into quartiles, the subjects of each quartile trend to stay within that quartile over the follow-up period. CONCLUSIONS: Early HbA1c levels were closely associated with recent HbA1c levels and diabetes complications in patients with T1DMs. Strict glucose management after diagnosis and reducing variability of HbA1c may prevent future diabetes complications and comorbidities.

A decision tree model for predicting intravenous immunoglobulin resistance and coronary artery involvement in Kawasaki disease.

OBJECTIVES: This study aims to develop a new algorithm for predicting intravenous immunoglobulin (IVIG) resistance and coronary artery involvement in Kawasaki disease (KD) through decision tree models. METHODS: Medical records of children hospitalized for KD were analysed retrospectively. We compared the clinical characteristics, and the laboratory data in the groups with IVIG resistance and coronary artery dilatations (CADs) in KD patients. The decision tree models were developed to predict IVIG resistance and CADs. RESULTS: A total 896 patients (511 males and 385 females; 1 month-12 years) were eligible. IVIG resistance was identified in 111 (12.3%) patients, and CADs were found in 156 (17.4%). Total bilirubin and nitrogen terminal- pro-brain natriuretic peptide (NT-proBNP) were significantly higher in IVIG resistant group than in IVIG responsive group (0.62 ± 0.8 mg/dL vs 1.38 ± 1.4 mg/dL and 1231 ± 2136 pg/mL vs 2425 ± 4459 mL, respectively, P < 0.01). Also, CADs were more developed in the resistant group (39/111; 14.9% vs. 117/785; 35.1%, P < 0.01). The decision tree for predicting IVIG resistance was classified based on total bilirubin (0.7 mg/mL, 1.46 mg/dL) and NT-proBNP (1561 pg/mL), consisting of two layers and four nodes, with 86.2% training accuracy and 90.5% evaluation accuracy. The Receiver Operating Characteristic (ROC) evaluated the predictive ability of the decision tree, and the area under the curve (AUC) (0.834; 95% confidence interval, 0.675-0.973; P < 0.05) showed relatively higher accuracy. The group with CADs had significantly higher total bilirubin and NT-proBNP levels than the control group (0.64 ± 0.82 mg/dL vs 1.04 ± 1.14 mg/dL and 1192 ± 2049 pg/mL vs 2268 ± 4136 pg/mL, respectively, P < 0.01). The decision trees for predicting CADs were classified into two nodes based on NT-proBNP (789 pg/mL) alone, with 83.5% training accuracy and 90.3% evaluation accuracy. CONCLUSION: A new algorithm decision tree model presents for predicting IVIG resistance and CADs in KD, confirming the usefulness of NT-proBNP as a predictor of KD.

Next-generation sequencing-based mutational analysis of idiopathic short stature and isolated growth hormone deficiency in Korean pediatric patients.

We investigated the distribution of short stature-associated mutations in Korean pediatric patients with idiopathic short stature (ISS) and isolated growth hormone deficiency (IGHD) via targeted next-generation sequencing (TNGS). We employed a 96-gene TNGS panel for short stature in a total of 144 patients (5-19 years-old) previously diagnosed with ISS or IGHD and identified heterozygous pathogenic or likely pathogenic genetic variants in 14 (10%) patients. Of the mutated genes, PROKR2 (n = 3) is associated with gonadotropin-releasing hormone deficiency or hypopituitarism, while FGFR1 (n = 1) and NPR2 (n = 3) encode growth plate paracrine factors. FBN1 (n = 1), COL9A1 (n = 1), MATN3 (n = 1), and ACAN (n = 3) regulate the cartilage extracellular matrix, while PTPN11 (n = 1) controls intracellular pathways. Six patients had IGHD, and eight patients had ISS. The current findings highlight the utility of TNGS for determining the genetic etiology in these patients.

Testosterone Levels in Adolescents and Young Men with Type 1 Diabetes and Their Association with Diabetic Nephropathy.

The association between serum testosterone levels and type 1 diabetes (T1D), especially in adolescents and young adults, has not been fully investigated. We aimed to compare testosterone levels between adolescents/young men with T1D and controls and to determine the factors affecting testosterone levels. We enrolled 47 men with T1D and 32 controls aged 15-29 years. We evaluated anthropometric measurements, lipid profiles, diabetic complications, and levels of serum luteinizing hormone, follicle-stimulating hormone, hemoglobin A1c, 24-h urine albumin, insulin autoantibody, and total serum testosterone. We assessed the correlation between serum testosterone levels and clinical characteristics. Total testosterone levels were higher in T1D patients than in controls (694.6 ± 182.2 vs. 554.1 ± 147.3 ng/dL, p = 0.001), and 24-h urine albumin level positively correlated with total testosterone levels (correlation coefficient 0.415, p = 0.004). T1D patients with nephropathy showed higher total testosterone levels than those without nephropathy (778.4 ± 198.9 vs. 655.4 ± 162.5 ng/dL, p = 0.029). However, diabetic nephropathy and testosterone levels were not significantly associated after adjusting for confounders (ß ± SE 77.5 ± 55.2, p = 0.169). Further longitudinal studies are imperative to confirm a causal relationship between testosterone levels and T1D.

Management of Central Precocious Puberty in Children with Hypothalamic Hamartoma.

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children's Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.

Prediction of Insulin Resistance by Modified Triglyceride Glucose Indices in Youth.

The triglyceride glucose (TyG) index, derived from a combination of fasting glucose and triglycerides, has been suggested as a useful marker for insulin resistance (IR), in addition to modified TyG indices that combine obesity parameters. This study investigated the association and utility of TyG and modified TyG indices for IR prediction in youth. Based on the Korea National Health and Nutritional Examination Survey, the data of 3728 youth aged 10-19 years were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) of tertiles 2 and 3 for each parameter were calculated and compared with tertile 1 as a reference. To compare the parameters for identifying IR, receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. The ORs and 95% CIs for insulin resistance (IR) progressively increased across tertiles of each parameter. Overall, all modified TyG indices presented higher ORs and AUC than the TyG index. The TyG-body mass index standard deviation score showed the largest AUC for IR detection in all subjects. In conclusion, TyG and modified TyG indices could be used as valuable markers for the prediction of IR in youth. Moreover, modified TyG indices had better diagnostic accuracy than the TyG index.

Ten-Year Trends of Metabolic Syndrome Prevalence and Nutrient Intake among Korean Children and Adolescents: A Population-Based Study.

PURPOSE: Metabolic syndrome (MetS) comprises a cluster of risk factors for future cardiovascular and metabolic diseases. Only a few recent studies have reported the trend in the prevalence of MetS in youth. This study aimed to analyze trends in the prevalence of MetS and nutrient intake in the last 10 years and investigate the changes in MetS components among Korean children and adolescents. MATERIALS AND METHODS: We analyzed the data of 9513 children and adolescents aged 10-19 years from the 2008-2017 Korean National Health and Nutrition Examination Surveys. Diagnosis of MetS was based on the International Diabetes Federation (IDF) and modified National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. RESULTS: Based on the IDF criteria, MetS prevalence increased from 1.53% in 2008 to 3.19% in 2017 (p=0.007). Based on the NCEP-ATP III criteria, MetS prevalence increased from 2.18% in 2008 to 3.19% in 2017; however, the increase was not statistically significant. Daily calorie and fat intakes increased significantly during the study period. Among the risk factors that MetS comprises, the prevalence rates of central obesity, low high-density lipoprotein cholesterol levels, and high fasting glucose levels increased significantly. CONCLUSION: Over the last 10 years, the prevalence of MetS has grown significantly with increasing calorie and fat intake in Korean children and adolescents. Central obesity and high-density lipoprotein cholesterol and fasting glucose levels have worsened. Therefore, active support and close monitoring are required to control MetS and prevent further increase in the prevalence of cardiovascular diseases.

Vitamin D status is associated with bone mineral density in adolescents: Findings from the Korea National Health and Nutrition Examination Survey.

Vitamin D is a factor that regulates calcium and bone metabolism. However, the clinical effect of vitamin D on bone mineral density (BMD) remains controversial. We hypothesized that sufficient vitamin D is required to maintain optimal BMD in adolescents. Based on the Korea National Health and Nutritional Examination Survey, data of 1063 adolescents aged 12 to 18 years were analyzed. The association of vitamin D status and other variables, such as body mass index (BMI), calcium intake, physical activity, lean mass, and fat mass, with BMD Z-scores in the lumbar spine, whole body, total femur, and femur neck were examined. We defined vitamin D deficiency as < 12 ng/mL, vitamin D insufficiency as 12 to 20 ng/mL, and sufficiency as > 20 ng/mL according to the 25-hydroxyvitamin D (25-OHD) level. The mean 25-OHD concentration of subjects was below normal, at 16.28 ng/mL. Subjects with vitamin D deficiency, insufficiency, and sufficiency comprised 20.5%, 58.6%, and 20.9% of all subjects, respectively. The vitamin D sufficient group had higher BMD Z-scores compared to the insufficient group, and the insufficient group had higher BMD Z-scores compared to the deficient group. In linear regression analysis, 25-OHD level, BMI, calcium intake, physical activity, lean mass, and fat mass were positively associated with BMD Z-scores. 25-OHD level was positively associated with BMD Z-scores, even after adjusting for other factors. This study suggests that vitamin D status is positively associated with BMD in adolescents; therefore, maintaining sufficient vitamin D levels during adolescence is crucial to prevent low BMD.

Sex Hormone-Binding Globulin Is Associated with Obesity and Dyslipidemia in Prepubertal Children.

Sex hormone-binding globulin (SHBG) is associated with age, sex, and puberty. The association of SHBG with various diseases has been suggested nowadays, however, the relationships in prepubertal children have not been sufficiently investigated. This study analyzed the relationship of SHBG with body mass index (BMI) and plasma lipid levels in prepubertal children. We evaluated the association of SHBG with BMI among the 693 prepubertal children subdivided into normal, overweight, and obese groups, with plasma lipid levels among the children subdivided into normal and dyslipidemia groups. The obese and overweight group had lower SHBG levels than the normal BMI group in both sexes. The dyslipidemia group included subjects with low high-density lipoprotein cholesterol (HDL-C), high triglycerides (TG), or a high atherogenic index of plasma (AIP); this group had lower SHBG than the normal lipid group. SHBG was positively correlated with HDL-C, and negatively correlated with TG and AIP. After adjusting for BMI, SHBG was positively correlated with HDL-C and negatively correlated with TG and AIP in all groups. In conclusion, SHBG levels are closely correlated with BMI in prepubertal children. SHBG may play a meaningful role in the decrease in HDL-C and increase in TG during prepubertal age.

Mannitol Enhances the Antinociceptive Effects of Diphenhydramine as an Alternative Local Anesthetic.

Mannitol has recently been reported to be effective in enhancing the antinociceptive efficacy of lidocaine. No single study to date, however, has compared diphenhydramine with and without mannitol for nociceptive processing as an alternative local anesthetic. In this study, we examined the antinociceptive efficacy enhancements of diphenhydramine when combined with mannitol. Male Sprague-Dawley rats weighing 230-260 g were used in a hot plate test to evaluate the antinociceptive effects of diphenhydramine. All chemicals were dissolved in isotonic normal saline and administered subcutaneously into the plantar surface of the right hind paw at 10 min before the hot plate test. A subcutaneous injection of 0.5% or 1% diphenhydramine produced significant inhibition of the withdrawal latency time compared with the vehicle treatment. Antinociceptive effects appeared 10 min after the diphenhydramine injections and persisted for over 30 min. The antinociceptive effects of 1% diphenhydramine were not statistically different from those of 1% lidocaine. Although a subcutaneous injection of a 0.5 M mannitol solution alone did not affect the withdrawal latency time, 1% diphenhydramine with 0.5 M mannitol significantly enhanced antinociception. A subcutaneous injection of 1% diphenhydramine with epinephrine (1 : 100,000) solution did not increase the antinociceptive effect of the diphenhydramine. These results suggest that diphenhydramine with mannitol can be used as an alternative local anesthetic.

Association of Vitamin D Status and Physical Activity with Lipid Profile in Korean Children and Adolescents: A Population-Based Study.

Dyslipidemia is one of the important influencing factors of cardiovascular health in the youth, and thus, assessment of its etiology is important. We aimed to investigate the association of dyslipidemia with vitamin D and physical activity in Korean children and adolescents. Data of 3183 subjects aged 12-18 years in the Korea National Health and Nutrition Examination Survey were analyzed. Participants were divided into subgroups according to sex, body mass index, 25-hydroxyvitamin D levels, and lipid profile. The mean 25-hydroxyvitamin D level was 16.15 ng/mL, which was below normal. In total, 79.3% of the subjects had vitamin D deficiency. Females had lower vitamin D levels and a higher incidence of dyslipidemia compared to males. Vitamin D deficiency was significantly associated with high density lipoprotein cholesterol (HDL-C) levels. The low HDL-C group consisted of a higher proportion of subjects with vitamin D deficiency and low physical activity. This study suggests that vitamin D deficiency is prevalent in Korean children and adolescents. Vitamin D deficiency and low physical activity are related with low HDL-C levels. Maintaining sufficient vitamin D levels and physical activity may help prevent dyslipidemia.

The Relationships between Respiratory Virus Infection and Aminotransferase in Children.

PURPOSE: We sought to examine the relationship between the clinical manifestations of nonspecific reactive hepatitis and respiratory virus infection in pediatric patients. METHODS: Patients admitted to the pediatric unit of Konyang University Hospital for lower respiratory tract disease between January 1, 2014 and December 31, 2014 and who underwent reverse transcriptase polymerase chain reaction tests were examined. The patients were divided into those with increased levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and those with normal ALT or AST levels. Further, patients with increased ALT and AST levels were individually compared with patients in the normal group, and the blood test results were compared according to the type of respiratory virus. RESULTS: Patients with increased ALT or AST levels had one more day of hospital stay, on average, compared with patients in the normal group (5.3±3.1 days vs. 4.4±3.0 days, p=0.019). Patients in the increased ALT level group were younger and had a longer mean hospital stay, compared with patients in the normal group (p=0.022 and 0.003, respectively). The incidences of increased ALT or AST were the highest in adenovirus infections (6/24, 25.0%), followed by enterovirus (2/11, 18.2%) and respiratory syncytial virus A (21/131, 16.0%) infections. CONCLUSION: Nonspecific reactive hepatitis is more common among patients with adenovirus, enterovirus and respiratory syncytial virus infection, as well as among those infected at a younger age. Compared with AST levels, ALT levels are better indicators of the severity of nonspecific reactive hepatitis.