Clinical use of whole exome sequencing in children with developmental delay/intellectual disability.

BACKGROUND: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. METHODS: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. RESULTS: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. CONCLUSION: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Adult height in girls with central precocious puberty without gonadotropin-releasing hormone agonist treatment: a retrospective case-control study.

BACKGROUND: The primary aim of this study was to investigate the final adult height (FAH) of girls diagnosed with central precocious puberty (CPP) who were untreated. METHODS: We retrospectively analyzed the medical records of 36 girls diagnosed with CPP between 8 and 9 years of age who did not receive treatment, and 206 girls diagnosed with CPP within the same age range who received gonadotropin-releasing hormone (GnRH) agonist treatment. Midparental height (MPH), predicted adult height (PAH) obtained using height and bone age (BA) at the time of diagnosis (PAH for BA), and PAH obtained using the Bayley-Pinneau method (PAH by BP) were calculated. Additionally, height at the time of growth completion was compared with the predicted height. RESULTS: The FAHs were 160.71±4.56 cm in the untreated group and 159.31±4.26 cm in the treated group. In the untreated group, the FAH was 0.99±4.50 cm shorter than the MPH but 4.29±3.33 cm and 3.46±3.93 cm greater than the PAH for BA and PAH by BP, respectively. CONCLUSION: In children diagnosed with CPP between 8 and 9 years of age who were untreated, FAH was greater than PAH for BA and PAH by BP at the time of diagnosis, indicating that the prognosis of FAH was not poor. Therefore, for girls diagnosed with CPP, it is recommended to consider various conditions, such as pubertal onset, height at diagnosis, BA, peak luteinizing hormone level, predicted height, and speed of puberty, when deciding whether to administer GnRH agonists.

Contact Investigations With a Single Tuberculin Skin Test on Infants Exposed to Tuberculosis in a Postpartum Care Center During the Neonatal Period.

BACKGROUND: Tuberculosis (TB) exposure in congregate settings related to neonates is a serious medical and social issue. TB exposure happens during the neonatal period, but contact investigations for exposed infants are usually conducted after the neonatal period. Generally, recommendations for screening and managing close contact are different for neonates and children. Thus, there are challenges in contact investigations. We aimed to report contact investigations with a single tuberculin skin test (TST) on infants exposed to infectious TB in a postpartum care center. METHODS: The index case was a healthcare worker with active pulmonary TB: sputum acid-fast bacilli smear negative, culture positive, and no cavitary lesion. All exposed infants underwent medical examinations and chest X-ray. After TB disease was ruled out, contacts received window period prophylaxis with isoniazid (INH) until three months after the last exposure. TST was performed only once after completing the prophylaxis. RESULTS: A total of 288 infants were selected as high-priority contacts. At the initial contact investigation, the age of infants ranged from 8 to 114 days. None of these exposed infants had TB disease. The prevalence of latent TB infection (LTBI) was 25.3% (73/288; 95% confidence interval [CI], 20.7-30.7). There were no serious adverse events related to the window period prophylaxis or LTBI treatment with INH. During the 1-year follow-up period, no infants progressed to overt TB disease. The size of TST induration in infants vaccinated with percutaneous Bacillus Calmette-Guérin (BCG) vaccine was significantly larger than that of infants vaccinated with intradermal BCG vaccine (median, 8 mm vs. 5 mm; P = 0.002). In multiple logistic regression analysis, independent factors associated with TST positivity (≥ 10 mm induration) were male (adjusted odds ratio [aOR], 2.98; 95% CI, 1.6-5.64), percutaneous BCG vaccination (aOR, 3.30; 95% CI, 1.75-6.48), TST reading between 60 and 72 hours after injecting purified protein derivative (aOR, 2.87; 95% CI, 1.53-5.49), and INH prophylaxis more than four weeks (aOR, 0.49; 95% CI, 0.25-0.94). CONCLUSION: A single TST at three months after the last TB exposure with INH prophylaxis could be used as a main protocol in contact investigations for infants exposed to infectious TB during the neonatal period in congregate settings in Korea.

Two Years of Experience and Methodology of Korean COVID-19 Living Clinical Practice Guideline Development.

BACKGROUND: In Korea, during the early phase of the coronavirus disease 2019 (COVID-19) pandemic, we responded to the uncertainty of treatments under various conditions, consistently playing catch up with the speed of evidence updates. Therefore, there was high demand for national-level evidence-based clinical practice guidelines for clinicians in a timely manner. We developed evidence-based and updated living recommendations for clinicians through a transparent development process and multidisciplinary expert collaboration. METHODS: The National Evidence-based Healthcare Collaborating Agency (NECA) and the Korean Academy of Medical Sciences (KAMS) collaborated to develop trustworthy Korean living guidelines. The NECA-supported methodological sections and 8 professional medical societies of the KAMS worked with clinical experts, and 31 clinicians were involved annually. We developed a total of 35 clinical questions, including medications, respiratory/critical care, pediatric care, emergency care, diagnostic tests, and radiological examinations. RESULTS: An evidence-based search for treatments began in March 2021 and monthly updates were performed. It was expanded to other areas, and the search interval was organized by a steering committee owing to priority changes. Evidence synthesis and recommendation review was performed by researchers, and living recommendations were updated within 3-4 months. CONCLUSION: We provided timely recommendations on living schemes and disseminated them to the public, policymakers and various stakeholders using webpages and social media. Although the output was successful, there were some limitations. The rigor of development issues, urgent timelines for public dissemination, education for new developers, and spread of several new COVID-19 variants have worked as barriers. Therefore, we must prepare systematic processes and funding for future pandemics.

Clinical characteristics and outcomes in febrile infants aged 29-90 days with urinary tract infections and cerebrospinal fluid pleocytosis.

Introduction: Fever without a focus is a common reason for medical evaluations, hospitalizations, and the antimicrobial treatment of infants younger than 90 days. The presence of cerebrospinal fluid (CSF) pleocytosis could be challenge for clinicians who treat febrile young infants with urinary tract infection (UTI). We evaluated the factors associated with sterile CSF pleocytosis and the clinical outcomes of the patients. Methods: A retrospective review of patients aged 29-90 days with febrile UTIs who underwent a non-traumatic lumbar puncture (LP) at Pusan National University Hospital from January 2010 to December 2020 was conducted. CSF pleocytosis was defined as white blood cell (WBC) counts ≥9/mm3. Results: A total of 156 patients with UTI were eligible for this study. Four (2.6%) had concomitant bacteremia. However, no patients had culture-proven bacterial meningitis. In correlation analysis, although weak strength, CSF WBC counts were positively correlated with C-reactive protein (CRP) level (Spearman r = 0.234; P = 0.003). Thirty-three patients had CSF pleocytosis [21.2%; 95% confidential interval (CI), 15.5-28.2]. The time from fever onset to the hospital visit, peripheral blood platelet counts, and CRP level at admission were statistically significant in patients with sterile CSF pleocytosis compared to those without CSF pleocytosis. In the multiple logistic regression, only CRP was independently associated with sterile CSF pleocytosis (cutoff, 3.425 mg/dl; adjusted odds ratio, 2.77; 95% CI, 1.19-6.88). The proportion of fever defervescence by hospital day 2 was 87.9% in patients with CSF pleocytosis and 89.4% in those without CSF pleocytosis (P = 0.759). There was no statistical difference in the fever defervescence curves between the two patient groups (P = 0.567). No patients had neurological manifestations or complications. Conclusions: Coexisting sterile CSF pleocytosis among febrile infants with UTIs suggest a systemic inflammatory response. However, the clinical outcomes between the two groups were similar. A selective LP should be considered in young infants with evidence of UTI, and inappropriate antibiotic therapy for sterile CSF pleocytosis should be avoided.

Effect of gonadotropin-releasing hormone agonist treatment on near final height in girls with central precocious puberty and early puberty.

PURPOSE: The aim of this study was to examine whether gonadotropin-releasing hormone (GnRH) agonist treatment is effective in preserving final height in patients with central precocious puberty (CPP) or early puberty (EP). METHODS: The medical records of 40 patients with CPP and 206 patients with EP who completed GnRH agonist treatment following diagnosis were analyzed retrospectively. Height and height standard deviation (height SDS) scores based on bone age (BA) were measured and calculated at baseline, after treatment completion, and at final follow-up to compare changes within and between groups. Predicted adult height (PAH) was estimated by the height corresponding to height SDS for BA in girls at 18 years 11 months of age based on the growth chart. RESULTS: PAH at baseline did not differ significantly between the CPP group (153.67±4.95) and the EP group (154.77±3.72). In the CPP group, PAH significantly increased at treatment completion (156.01±4.61) and at final follow-up (158.52±6.04) compared to baseline. In the EP group, PAH significantly increased at treatment completion (157.7±3.60) and at final follow-up (159.31±4.26) compared to baseline. The increase in PAH at all timepoints compared to baseline did not significantly differ between the CPP and EP groups. CONCLUSION: Both CPP and EP groups had significantly greater PAH after treatment, with no difference in the amount of increase between groups. These results show that GnRH agonist treatment can help increase final height even in patients diagnosed with EP after the age of 8 years.

Clinical Characteristics and Outcomes of Children With SARS-CoV-2 Infection During the Delta and Omicron Variant-Dominant Periods in Korea.

BACKGROUND: Data on the clinical characteristics of pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection are limited. We aimed to evaluate the clinical features and outcomes of children with SARS-CoV-2 infection before and after omicron variant dominance in Korea. METHODS: A multicenter retrospective cohort study was conducted in hospitalized patients aged ≤ 18 years with laboratory-confirmed SARS-CoV-2 infection at five university hospitals in South Korea. The study periods were divided into the delta (from August 23, 2021 to January 2, 2022) and omicron (from January 30 to March 31, 2022). RESULTS: In total, 612 hospitalized patients were identified (211, delta; 401, omicron). During the omicron and delta periods, the proportions of individuals with serious illness (moderate, severe, and critical severity) were 21.2% and 11.8%, respectively (P = 0.034). Compared with the delta period, the proportions of patients with moderate illness increased significantly in the age groups of 0-4 years (14.2% vs. 3.4%) and 5-11 years (18.6% vs. 4.2%) during the omicron period. During the two periods, the proportions of patients with complex chronic diseases (delta, 16.0% vs. 4.3%, P = 0.040; omicron, 27.1% vs. 12.7%; P = 0.002), respiratory diseases except for asthma (delta, 8.0% vs. 0.0%, P = 0.013; omicron, 9.4% vs. 1.6%; P = 0.001), and neurologic diseases (delta, 28.0% vs. 3.2%, P < 0.001; omicron, 40.0% vs. 5.1%, P < 0.001) were significantly higher in patients with serious illness than in those with non-serious illness. During the delta period, the risk for serious illness was higher among patients with obesity (adjusted odds ratio [aOR], 8.18; 95% confidence interval [CI], 2.80-27.36) and neurologic diseases (aOR, 39.43; 95% CI, 6.90-268.3) and aged 12-18 years (aOR, 3.92; 95% CI, 1.46-10.85). However, the presence of neurologic disease (aOR, 9.80; 95% CI, 4.50-22.57) was the only risk factor for serious illness during the omicron period. During the omicron period, the proportions of patients with croup (11.0% vs. 0.5%) and seizures (13.2% vs. 2.8%) increased significantly compared with the delta period. CONCLUSION: Compared with the delta period, the proportions of young children and patients with complex comorbidities were higher during the omicron period in Korea. Patients with complex chronic diseases, especially neurologic diseases, had a high risk of severe coronavirus disease 2019 in the two distinct variant-dominant periods.

Incidence of congenital hypothyroidism by gestational age: a retrospective observational study.

BACKGRUOUND: Congenital hypothyroidism (CH) is the leading cause of preventable physical and intellectual disabilities. This study aimed to assess the incidence and clinical characteristics of CH in newborns. METHODS: We retrospectively reviewed the medical records of all newborns delivered at the Pusan National University Hospital between January 2011 and March 2021. The incidence of CH was compared according to gestational age, birth weight, and small for gestational age (SGA). The patients aged ≥3 years who could not maintain normal thyroid function and required levothyroxine treatment were diagnosed with permanent CH. Logistic regression analysis was performed to compare CH risks. RESULTS: Of 3,722 newborns, 40 were diagnosed with CH (1.07%). Gestational age and birth weight were significantly associated with CH incidence. The odds ratios (ORs) of CH in infants delivered at 32-37, 28-31, and <28 weeks were 2.568 (95% confidence interval [CI], 1.141-5.778), 5.917 (95% CI, 2.264-15.464), and 7.441 (95% CI, 2.617-21.159) times higher, respectively, than those delivered at term. The ORs of CH in infants weighing 1,500-2,499 g, 1,000-1,499 g, and <1,000 g were 4.664 (95% CI, 1.928-11.279), 11.076 (95% CI, 4.089-29.999), and 12.544 (95% CI, 4.350-36.176) times greater, respectively, than those in infants weighing ≥2,500 g. The OR of CH was 6.795 (95% CI, 3.553-13.692) times greater in SGA than in non-SGA infants. CONCLUSION: The CH incidence in South Korea has increased significantly compared with that in the past. Gestational age, birth weight, and SGA were significantly associated with CH incidence.

SARS-CoV-2-Naïve Korean Children and Adolescents Hospitalized With COVID-19 in 2021.

BACKGROUND: The risk of severe outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant remains low in children and adolescents, but less is known about its effect on the SARS-CoV-2-naïve population. This study evaluated clinical manifestations and risk factors for moderate-to-critical coronavirus disease 2019 (COVID-19) in mostly SARS-CoV-2-naïve children and adolescents in 2021. METHODS: This multicenter retrospective study included patients aged 0-18 years who were hospitalized with COVID-19 at 8 referring hospitals in South Korea during the predelta-predominant and delta-predominant periods in 2021. Each case was labeled as either hospitalization with medical needs or for isolation. Severity was categorized as mild, moderate, severe, or critical with regard to pneumonia presence and illness severity. RESULTS: Among 753 cases, most (99.5%) had no prior history of COVID-19 or vaccination against COVID-19. The proportions of hospitalization with medical needs (3.5% vs. 19.7%), moderate illness (0.9% vs. 4.0%), and severe/critical illness (0.8% vs. 5.3%) increased during delta predominance. The risk of moderate-to-critical COVID-19 among hospitalizations with medical needs was higher among patients aged 12-18 years (adjusted odds ratio [aOR], 4.1; 95% confidence interval [CI], 1.5-11.8) and with obesity (aOR, 6.9; 95% CI, 2.4-19.6) but not among patients infected during delta predominance. However, children with obesity experienced more severe COVID-19 during delta predominance (aOR, 6.1; 95% CI, 1.2-29.6). CONCLUSION: Despite its similar severity among most SARS-CoV-2-naïve children and adolescents, the delta variant may affect COVID-19 severity in those with high-risk underlying medical conditions. Underlying conditions, particularly obesity, may cause severe COVID-19 in children and adolescents, warranting strong consideration for vaccinating high-risk children.

Shift in Clinical Epidemiology of Human Parainfluenza Virus Type 3 and Respiratory Syncytial Virus B Infections in Korean Children Before and During the COVID-19 Pandemic: A Multicenter Retrospective Study.

BACKGROUND: Parainfluenza virus type 3 (PIV3) and respiratory syncytial virus (RSV) B epidemics occurred in South Korea in late 2021. We investigated epidemiological changes of PIV3 and RSV B infections in Korean children before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In this multicenter retrospective study, we enrolled patients aged less than 19 years with PIV3 or RSV infection in four university hospitals from January 2018 to January 2022. Demographic and clinical data were extracted from the subject's medical records and analyzed for each virus. RESULTS: A total of 652 children with PIV3 were identified including three epidemics: 216 in 2018, 260 in 2019, and 167 in 2021. Among 627 RSV B cases, 169 were identified in 2017/2018, 274 in 2019/2020, and 115 in 2021/2022. The peak circulation of PIV3 and RSV B epidemics were delayed by 6 and 2 months, respectively, in 2021, compared with those in the pre-COVID-19 period. The median age of PIV3 infections increased in 2021 (21.5 months in 2021 vs. 13.0-14.0 in 2018-2019; P < 0.001), whereas that of RSV B infections remained unchanged (3.6-4.0 months). During the COVID-19 pandemic, less frequent hospitalization rates were observed for both PIV3 and RSV B infections, but more children needed respiratory assistance for RSV B infection in 2021/2022 epidemic (32.5%) than before (14.7-19.4%, P = 0.014). CONCLUSION: We observed changes in the epidemiology and clinical presentation of PIV3 and RSV B infections in Korean children during the COVID-19 pandemic.

The Changes in Epidemiology of Imipenem-Resistant Acinetobacter baumannii Bacteremia in a Pediatric Intensive Care Unit for 17 Years.

BACKGROUND: Acinetobacter baumannii infections cause high morbidity and mortality in intensive care unit (ICU) patients. However, there are limited data on the changes of long-term epidemiology of imipenem resistance in A. baumannii bacteremia among pediatric ICU (PICU) patients. METHODS: A retrospective review was performed on patients with A. baumannii bacteremia in PICU of a tertiary teaching hospital from 2000 to 2016. Antimicrobial susceptibility tests, multilocus sequence typing (MLST), and polymerase chain reaction for antimicrobial resistance genes were performed for available isolates. RESULTS: A. baumannii bacteremia occurred in 27 patients; imipenem-sensitive A. baumannii (ISAB, n = 10, 37%) and imipenem-resistant A. baumannii (IRAB, n = 17, 63%). There was a clear shift in the antibiogram of A. baumannii during the study period. From 2000 to 2003, all isolates were ISAB (n = 6). From 2005 to 2008, both IRAB (n = 5) and ISAB (n = 4) were isolated. However, from 2009, all isolates were IRAB (n = 12). Ten isolates were available for additional test and confirmed as IRAB. MLST analysis showed that among 10 isolates, sequence type 138 was predominant (n = 7). All 10 isolates were positive for OXA-23-like and OXA-51-like carbapenemase. Of 27 bacteremia patients, 11 were male (41%), the median age at bacteremia onset was 5.2 years (range, 0-18.6 years). In 33% (9/27) of patients, A. baumannii was isolated from tracheal aspirate prior to development of bacteremia (median, 8 days; range, 5-124 days). The overall case-fatality rate was 63% (17/27) within 28 days. There was no statistical difference in the case fatality rate between ISAB and IRAB groups (50% vs. 71%; P = 0.422). CONCLUSION: IRAB bacteremia causes serious threat in patients in PICU. Proactive infection control measures and antimicrobial stewardship are crucial for managing IRAB infection in PICU.

Therapeutics for the treatment of coronavirus disease 2019 in children and adolescents.

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory illness in most children and adolescents, but a small proportion develop severe or critical illness. Although pediatric clinical trials for the treatment of COVID-19 are sparse, there are some available drugs for children and adolescents with severe COVID-19. This review summarizes clinical data focusing on antiviral agents and immunomodulators for COVID-19 treatment. Additionally, the current recommendations for therapeutics for children and adolescents with COVID-19 are discussed. Remdesivir is suggested for pediatric patients with COVID-19 in the following cases: children and adolescents with severe COVID-19 who need supplemental oxygen without mechanical ventilation; adolescents aged ≥12 years and weight of at least 40 kg with COVID-19 who do not require supplemental oxygen and are within 7 days of symptom onset and are at high risk of progression to severe illness. Nirmatrelvir/ritonavir is considered for adolescents aged ≥12 years and weighing at least 40 kg who do not require supplemental oxygen and are within 5 days of symptom onset and are at high risk of progression to severe disease. Corticosteroids are not recommended in children and adolescents with mild to moderate COVID-19. Corticosteroids are recommended in children and adolescents with severe to critical COVID-19.

Epidemiology and Clinical Characteristics of Human Coronaviruses-Associated Infections in Children: A Multi-Center Study.

Background: Human coronaviruses (HCoVs) are associated with upper respiratory tract infections. Although studies have analyzed the clinical and epidemiological characteristics of HCoV-associated infections, no multi-center studies have been conducted in Korean children. We aimed to describe the epidemiology and clinical characteristics of HCoV-associated infection in children. Methods: We retrospectively reviewed medical records of children in whom HCoVs were detected using multiplex reverse transcriptase-polymerase chain reaction amplification in five centers from January 2015 to December 2019. Results: Overall, 1,096 patients were enrolled. Among them, 654 (59.7%) patients were male. The median age was 1 year [interquartile range (IQR), 0-2 years]. HCoVs were identified mainly in winter (55.9%). HCoV-229E, HCoV-OC43, and HCoOV-NL63 were detected mainly in winter (70.9, 55.8, and 57.4%, respectively), but HCoV-HKU1 was mainly identified in spring (69.7%). HCoV-OC43 (66.0%) was detected most frequently, followed by HCoV-NL63 (33.3%), and HCoV-229E (7.7%). Two different types of HCoVs were co-detected in 18 samples, namely. Alphacoronavirus-betacoronavirus co-infection (n = 13) and, alphacoronavirus-alphacoronavirus co-infection (n = 5). No betacoronavirus-betacoronavirus co-infection was detected. Patients were diagnosed with upper respiratory tract infection (41.4%), pneumonia (16.6%), acute bronchiolitis (15.5%), non-specific febrile illness (13.1%), croup (7.3%), and acute gastroenteritis (5.1%). There were 832 (75.9%) hospitalized patients with a median duration of hospitalization of 4 days (IQR, 3-5 days); 108 (9.9%) patients needed supplemental oxygen with 37 (3.4%) needing high-flow nasal cannula or mechanical ventilation. There were no deaths. Conclusion: HCoV-associated infections exhibit marked seasonality with peaks in winter. Patients with lower respiratory tract infection, a history of prematurity, or underlying chronic diseases may progress to a severe course and may need oxygen therapy.

Analysis of Novel Drug-Resistant Human Cytomegalovirus DNA Polymerase Mutations Reveals the Role of a DNA-Binding Loop in Phosphonoformic Acid Resistance.

The appearance of drug-resistant mutations in UL54 DNA polymerase and UL97 kinase genes is problematic for the treatment of human cytomegalovirus (HCMV) diseases. During treatment of HCMV infection in a pediatric hematopoietic cell transplant recipient, H600L and T700A mutations and E576G mutation were independently found in the UL54 gene. Foscarnet (FOS; phosphonoformic acid) resistance by T700A mutation is reported. Here, we investigated the role of novel mutations in drug resistance by producing recombinant viruses and a model polymerase structure. The H600L mutant virus showed an increase in resistance to ganciclovir (GCV) by 11-fold and to FOS and cidofovir (CDV) by 5-fold, compared to the wild type, while the E756G mutant virus showed an increase in resistance to FOS by 9-fold and modestly to CDV by 2-fold. With the FOS-resistant T700A mutation, only H600L produced increased FOS resistance up to 37-fold, indicating an additive effect of these mutations on FOS resistance. To gain insight into drug resistance mechanisms, a model structure for UL54 polymerase was constructed using the yeast DNA polymerase as a template. In this model, HCMV DNA polymerase contains a long palm loop domain of which H600 and T700 are located on each end and T700 interacts with the FOS binding pocket. Our results demonstrate that H600L and E756G mutations in UL54 polymerase are novel drug-resistant mutations and that the acquisition of both H600L and T700A mutations in the DNA-binding loop confers increased resistance to FOS treatment, providing novel insights for the mechanism acquiring foscarnet resistance.

Risk Factors for Severe COVID-19 in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been the most important global issue since December 2019. Although the clinical course of COVID-19 is known to be milder in children than in adults, associated hospitalizations among children have increased since the emergence of contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the achievement of a high vaccination rate in adults. Considering these global and domestic situations, we believe that risk stratification in children with COVID-19 is urgently needed for decision making regarding hospitalization priority in children infected with SARS-CoV-2 and vaccination priority against COVID-19. METHODS: This systematic review and meta-analysis was performed by comprehensively searching the PubMed, EMBASE, Scopus and KoreaMed databases through August 25, 2021. The criteria for enrollment were "severe COVID-19" as poor outcomes (intensive care unit admission, invasive mechanical ventilation, and/or death) and underlying comorbidities before SARS-CoV-2 infection. RESULTS: Among 872 screened studies, 17 articles were included in the systematic review, and 10 articles were included in the meta-analysis. Neonate (risk ratio [RR], 2.69; 95% confidence interval [CI], 1.83-3.97), prematurity in young infants (RR, 2.00; 95% CI, 1.63-2.46), obesity (RR, 1.43; 95% CI, 1.24-1.64), diabetes (RR, 2.26; 95% CI, 1.95-2.62), chronic lung disease (RR, 2.62; 95% CI, 1.71-4.00), heart disease (RR, 1.82; 95% CI, 1.58-2.09), neurologic disease (RR, 1.18; 95% CI, 1.05-1.33), and immunocompromised status (RR, 1.44; 95% CI, 1.01-2.04) were significant risk factors for severe COVID-19 in children. In the subgroup analysis, age younger than 3 months (RR, 0.26; 95% CI, 0.11-0.66), asthma (RR, 1.08; 95% CI, 0.98-1.20), and neurodevelopmental disorders (RR, 0.88; 95% CI, 0.75-1.04) were not risk factors for severe COVID-19. CONCLUSION: Children with comorbidities such as obesity, diabetes, heart disease, chronic lung diseases other than asthma, seizure disorders, and an immunocompromised status had a high prevalence of severe COVID-19. Neonate and premature infants had a high risk of severe COVID-19. Defining the high-risk group for severe COVID-19 could help to guide hospital admission and priority for vaccination against SARS-CoV-2.

Antibiotic Prescribing Practices and Clinical Outcomes of Pediatric Patients with Campylobacter Enterocolitis.

Antibiotics are not routinely recommended for patients with Campylobacter enterocolitis. We conducted a retrospective review of hospitalized patients younger than 18 years diagnosed with Campylobacter enterocolitis from July 2015 to December 2019. This study aimed to investigate antibiotic prescribing practices and the clinical outcomes and to evaluate the factors associated with antibiotic use. A total of 157 patients (median age, 10.7 years) were included in this study. Most patients (93.0%) had a fever, and a quarter of the patients complained of bloody diarrhea. The overall antibiotic prescribing rate was 36.7% (57/157), 91.2% of the patients received antibiotics within hospital day 2. The semi-annual antibiotic prescribing rate ranged from 16.7 to 50.0%. There were no increasing or decreasing trends in antibiotic prescribing rates. Cephalosporins were the most prescribed antibiotics for initial antibiotic therapy. Azithromycin use increased significantly during the study period. The independent factors associated with early antibiotic therapy were leukocytosis (adjusted odds ratio (aOR), 3.95; 95% confidence interval (CI), 1.76-9.27), C-reactive protein ≥50 mg/L (aOR, 4.19; 95% CI, 1.84-10.21), and performing abdominal imaging studies (aOR, 3.44; 95% CI, 1.55-7.99). There was no significance in defervescence between the early and no-antibiotic therapy groups (p = 0.232). A careful assessment of the need for antibiotic therapy in patients with acute diarrhea should be conducted to avoid unnecessary use. After identifying the causative pathogens, the appropriateness of antibiotic prescription should be evaluated.

Chromosomal Microarray in Children With Developmental Delay: The Experience of a Tertiary Center in Korea.

Background and Objectives: Chromosomal microarray (CMA) is a first-tier genetic test for children with developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), and multiple congenital anomalies (MCA). In this study, we report our experiences with the use of CMA in Korean children with unexplained DD/ID. Methods: We performed CMA in a cohort of 308 children with DD/ID between January 2010 and September 2020. We also retrospectively reviewed their medical records. The Affymetrix CytoScan 750 K array with an average resolution of 100 kb was used to perform CMA. Results: Comorbid neurodevelopmental disorders were ASD (37 patients; 12.0%), epilepsy (34 patients; 11.0%), and attention deficit hyperactivity disorders (12 patients; 3.9%). The diagnostic yield was 18.5%. Among the 221 copy number variants (CNVs) identified, 70 CNVs (57 patients; 18.5%) were pathogenic. Deletion CNVs were more common among pathogenic CNVs (PCNVs) than in non-PCNVs (P < 0.001). The size difference between PCNVs and non-PCNVs was not significant (P = 0.023). The number of included genes within CNV intervals was significantly higher in PCNVs (average 8.6; 0-347) than in non-PCNVs (average 47.5; 1-386) (P < 0.001). Short stature and hearing difficulty were also more common in the PCNV group than in the non-PCNV group (P = 0.010 and 0.070, respectively). Conclusion: This study provides additional evidence for the usefulness of CMA in genetic testing of children with DD/ID in Korea. The pathogenicity of CNVs correlated with the number of included genes within the CNV interval and deletion type of the CNVs, but not with CNV size.

Positive Rate of Tests for Group a Streptococcus and Viral Features in Children with Acute Pharyngitis.

Group A streptococcus (GAS) is an important cause of acute pharyngitis. We investigated the positive rate of GAS tests and clinical viral features in children with acute pharyngitis. A retrospective review was conducted for patients <15 years old with both rapid antigen detection test (RADT) and throat culture results. Patients were excluded if they were diagnosed with influenza or had received antibiotics within two weeks before these tests. A total of 377 patients were eligible. The median age of patients was 3.5 years, and 45.4% of total patients were <3 years old. Among all patients, 68.7% had at least one viral feature, and 39% had more than two. The overall positiv rate for GAS was 11.4%. The GAS positive rate was significantly lower in patients <3 years old than in older patients (1.8% vs. 19.4%, p < 0.0001). The overall sensitivity and specificity of RADT were 75.0% (95% CI: 57.8-87.9) and 97.9% (95% CI: 95.8-99.2), respectively. The GAS positive rate was not significantly different between patients with and without viral features (12.4% vs. 9.3%, p = 0.4854). In patients aged 3-14 years, the GAS positive rate was not associated with the modified Centor score or the frequency of clinical viral features. Despite a low prevalence of GAS pharyngitis, testing for GAS was frequently performed in children <3 years old in this study. Appropriate use of laboratory testing for GAS pharyngitis and judicious prescription of antibiotics were imperative.