The Impact of an Antimicrobial Stewardship Program on Days of Therapy in the Pediatric Center: An Interrupted Time-Series Analysis of a 19-Year Study.

BACKGROUND: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients. METHODS: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ². RESULTS: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period (P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period (P = 0.881). CONCLUSION: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia.

Myocarditis and Pericarditis are Temporally Associated with BNT162b2 COVID-19 Vaccine in Adolescents: A Systematic Review and Meta-analysis.

The incidence of myocarditis and pericarditis has been documented in adolescents after COVID-19 vaccinations. This study aims to assess the risk of myopericarditis in adolescents following COVID-19 vaccination, using a meta-analysis of the published cases. We performed a comprehensive literature search of the following databases on July 5, 2023: MEDLINE, EMBASE, PubMed, and the Cochrane Library. We performed a meta-analysis using a random-effects model to estimate the incidence of myopericarditis per million of administered COVID-19 vaccine doses or COVID-19 infections. A total of 33 studies were included in the meta-analysis. The incidence of myopericarditis per million COVID-19 infections (1583.9 cases, 95% CI 751.8-2713.8) was approximately 42 times higher than that for COVID-19 vaccine administrations (37.6 cases, 95% CI 24.2-53.8). The risk of myopericarditis after COVID-19 vaccination was particularly high among the 16-19 age group (39.5 cases per million, 95% CI 25.8-56.0), males (43.1 cases per million, 95% CI 21.6-71.9), and those who received the second dose (47.7 cases per million, 95% CI 22.2-82.2). There were no significant differences in the incidence of myopericarditis per million COVID-19 vaccine administrations between Europe, the Western Pacific, and the Americas (p = 0.51). Adolescents faced a potential risk of myopericarditis after COVID-19 vaccination, but this risk is less harmful than that of myopericarditis following COVID-19 infection.

Complications of the Central Nervous System in Pediatric Patients With Common Cold Coronavirus Infection During 2014-2019.

BACKGROUND: In pediatric patients, the common cold coronavirus (ccCoV) usually causes mild respiratory illness. There are reports of coronavirus causing central nervous system (CNS) infection in experimental animal models. Some immunocompromised patients have also been reported to have fatal CNS infections with ccCoV. The aim of this study was to investigate the clinical characteristics of CNS complications related to ccCoV infection. METHODS: From January 2014 to December 2019, a retrospective analysis was performed of medical records from hospitalized patients under 19 years of age whose ccCoV was detected through polymerase chain reaction in respiratory specimens. The CNS complications were defined as clinically diagnosed seizure, meningitis, encephalopathy, and encephalitis. RESULTS: A total of 436 samples from 420 patients were detected as ccCoV. Among the 420 patients, 269 patients were immunocompetent and 151 patients were immunocompromised. The most common type of ccCoV was OC43 (52% in immunocompetent, 37% in immunocompromised). CNS complications were observed in 9.4% (41/436). The most common type of CNS complication was the fever-provoked seizure under pre-existing neurologic disease (42% in immunocompetent and 60% in immunocompromised patients). Among patients with CNS complications, two immunocompetent patients required intensive care unit admission due to encephalitis. Three patients without underlying neurological disease started anti-seizure medications for the first time at this admission. There was no death related to ccCoV infection. CONCLUSION: ccCoV infection may cause severe clinical manifestations such as CNS complications or neurologic sequelae, even in previously healthy children.

Impact of Nonpharmacological Interventions on Severe Acute Respiratory Infections in Children: From the National Surveillance Database.

BACKGROUND: Nonpharmacological interventions (NPIs) reduce the incidence of respiratory infections. After NPIs imposed during the coronavirus disease 2019 pandemic ceased, respiratory infections gradually increased worldwide. However, few studies have been conducted on severe respiratory infections requiring hospitalization in pediatric patients. This study compares epidemiological changes in severe respiratory infections during pre-NPI, NPI, and post-NPI periods in order to evaluate the effect of that NPI on severe respiratory infections in children. METHODS: We retrospectively studied data collected at 13 Korean sentinel sites from January 2018 to October 2022 that were lodged in the national Severe Acute Respiratory Infections (SARIs) surveillance database. RESULTS: A total of 9,631 pediatric patients were admitted with SARIs during the pre-NPI period, 579 during the NPI period, and 1,580 during the post-NPI period. During the NPI period, the number of pediatric patients hospitalized with severe respiratory infections decreased dramatically, thus from 72.1 per 1,000 to 6.6 per 1,000. However, after NPIs ceased, the number increased to 22.8 per 1,000. During the post-NPI period, the positive test rate increased to the level noted before the pandemic. CONCLUSION: Strict NPIs including school and daycare center closures effectively reduced severe respiratory infections requiring hospitalization of children. However, childcare was severely compromised. To prepare for future respiratory infections, there is a need to develop a social consensus on NPIs that are appropriate for children.

Childcare Exposure to Severe Acute Respiratory Syndrome Coronavirus 2 for 4-Year-Old Presymptomatic Child, South Korea.

Data on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from preschool-age children to children and adults are limited. We investigated SARS-CoV-2 exposure at a childcare center in South Korea. A 4-year-old child, probably infected by his grandmother, attended the center during the presymptomatic period (February 19-21, 2020). Fever developed on February 22, and he was given a diagnosis SARS-CoV-2 infection on February 27. At the center, 190 persons (154 children and 36 adults) were identified as contacts; 44 (23.2%) were defined as close contacts (37 children and 7 adults). All 190 persons were negative for SARS-CoV-2 on days 8-9 after the last exposure. Two close contacts (1 child and 1 adult) showed development of symptoms on the last day of quarantine. However, subsequent test results were negative. This investigation adds indirect evidence of low potential infectivity in a childcare setting with exposure to a presymptomatic child.

Influenza Vaccine Effectiveness in Children at the Emergency Department during the 2018-2019 Season: the First Season School-aged Children Were Included in the Korean Influenza National Immunization Program.

BACKGROUND: For the 2018-2019 season, the national influenza immunization program expanded to cover children aged from 6 months to 12 years in Korea. This study aimed to analyze vaccine effectiveness (VE) against influenza in children visiting the pediatric emergency room at a tertiary hospital during the 2018-2019 season. METHODS: Patients tested for influenza antigens from October 1st 2018 to May 31st 2019 at the pediatric emergency room of Samsung Medical Center were included. Patients' influenza antigen test results, influenza vaccination history, and underlying medical conditions were reviewed retrospectively. VE was estimated from the test-negative design study. RESULTS: Among the 2,901 visits with influenza test results 1,692 visits of 1,417 patients were included for analysis. Among these 1,417 patients, 285 (20.1%) were positive (influenza A, n = 211, 74.0%; influenza B, n = 74, 26.0%). The VE in all patients was 36.4% (95% confidence interval [CI], 13.9 to 53.1). The VE for influenza A was 37.6% (95% CI, 12.6 to 55.5) and VE for influenza B was 24.0% (?38.5 to 58.3). The VE in the age group 6 months to 12 years was significant with a value of 35.6% (95% CI, 10.5 to 53.7); it was not statistically significant in the age group 13 to 18 years. In a multivariate logistic regression model, patients who received an influenza vaccination were less likely to get influenza infection (OR, 0.6; 95% CI, 0.4 to 0.8; P = 0.001), with significant confounding factors such as age group 13 to 18 years (OR, 0.5; 95% CI, 0.3 to 0.8; P = 0.003) and underlying hematology-oncology disease (OR, 0.3; 95% CI, 0.1 to 0.6; P = 0.002). CONCLUSION: We report moderate effectiveness of influenza vaccination in previously healthy children aged from 6 months to 12 years in the 2018-2019 season.

Stepwise School Opening and an Impact on the Epidemiology of COVID-19 in the Children.

BACKGROUND: Data on severe acute respiratory syndrome coronavirus-2 transmission from a pediatric index patient to others at the school setting are limited. Epidemiological data on pediatric coronavirus disease 2019 (COVID-19) cases after school opening are warranted. METHODS: We analyzed data of the pediatric patients with COVID-19 collected from the press release of the Korea Centers for Disease Control and Prevention. Information on the school opening delay and re-opening policies were achieved from the press release of the Korean Ministry of Education. RESULTS: The school openings were delayed three times in March 2020. Online classes started from April 9, and off-line (in-person) classes started from May 20 to June 8 at four steps in different grades of students. There was no sudden increase in pediatric cases after the school opening, and the proportion of pediatric cases among total confirmed cases in the nation around 7.0%. As of July 31, 44 children from 38 schools and kindergartens were diagnosed with COVID-19 after off-line classes started. More than 13,000 students and staffs were tested; only one additional student was found to be infected in the same classroom. The proportions of pediatric patients without information on infection sources were higher in older age groups than in younger age groups (17.4% vs. 52.4%, P = 0.014). In the younger age group, 78.3% of children were infected by family members, while only 23.8% of adolescents in the older age group were infected by family members (P < 0.001). CONCLUSION: Korea had a successful transition from school closure to online and off-line school opening, which did not cause significant school-related outbreak among the pediatric population.

Elevated fecal calprotectin levels are associated with severity of atopic dermatitis in children.

BACKGROUND: Recent data suggested that imbalance in gut microbiota and gastrointestinal inflammation are associated with the childhood allergic disease. Fecal calprotectin has been used for a non-invasive marker of gut inflammation. OBJECTIVE: The aim of this study was to investigate the relationships between fecal calprotectin level and the clinical severity of atopic dermatitis (AD) in children. METHODS: We enrolled 65 subjects with AD. The concentration of calprotectin was measured in each subject's fecal sample. RESULTS: The geometric mean fecal calprotectin level of the total subjects was 33.1(10.1-108.9) µg/g. Among the 65 subjects, 44(67.7%) showed calprotectin levels lower than 50µg/g(Group 1), and 21(32.3%) were higher than 50µg/g(Group 2). The mean SCORAD index was significantly higher in Group 2 than Group 1(31.0±16.0 vs 22.2±15.3, p=0.046). The geometric mean serum total IgE levels was higher in Group 2 compared to Group 1(361.4[31.6-992.3]IU/mL vs 175.9[44.3-699.2]IU/mL, p=0.040). The mean blood eosinophils were significantly higher in Group 2 than in Group 1(497.7[239.8-1032.8]/µL vs 281.5[121.5-652.0]/µL, p=0.034). The incidence of exposure to environmental tobacco smoke was significantly higher in Group 2 compared to Group 1(76.2% vs 47.7%, p=0.036). Geometric mean fecal calprotectin level in severe AD was significantly higher than that of mild-to-moderate AD(66.7[13.5-330.3]µg/g vs 29.4[10.1-85.6]µg/g, p=0.044). The fecal calprotectin level significantly correlated with the SCORAD index(r=0.303, p=0.014). CONCLUSIONS: Higher fecal calprotectin levels were observed in subjects with severe AD. Elevated fecal calprotectin level as a gastrointestinal inflammatory marker may associate with childhood AD. Measurement of fecal calprotectin might be useful for assessment of severity of childhood AD.

Characterization of Brighton Collaboration criteria for myocarditis and pericarditis following COVID-19 vaccine in Korean adolescents.

BACKGROUND: Vaccines are vital for public health, but concerns about adverse effects, particularly myocarditis and pericarditis linked to COVID-19 vaccines-, persist. This study investigates the application of Brighton Collaboration case definition to national vaccine safety data related to post-COVID-19 vaccine myo/pericarditis, utilizing claims under the Korea National Vaccine Injury Compensation Program (NIVCP). METHODS: This study analyzed 190 medical records of individuals who claimed to have developed myo/pericarditis after receiving the COVID-19 vaccine, as reported to the NVICP between specified dates, categorizing cases based on the Brighton criteria for myocarditis or pericarditis. RESULTS: Between 2021-2022, NVICP received 190 cases meeting the Brighton criteria for myocarditis or pericarditis at levels 1, 2, or 3. Most cases fell into Level 2 (70%), followed by Level 1 (29%), and one at Level 3 (1%), with Level 1 cases showing a higher hospitalization rate (87.3%) and a notable proportion requiring admission to the Intensive Care Unit (25.5%). Chest pain and Troponin-I/T elevation were common findings in Level 1 cases, while Level 2 cases exhibited similar patterns but at a slightly lower frequency. Electrocardiogram and echocardiography findings differed between the two levels. CONCLUSION: The Brighton Collaboration case definition proved valuable for classifying and assessing AEFI data, enhancing our understanding of the potential relationship between myocarditis and the COVID-19 vaccine.

The Protective Effectiveness of 2-Dose Varicella Vaccination in Children in Korea: A Case-control Study.

BACKGROUND: A 2-dose vaccination against varicella has been adopted in many places; however, it has not been widely introduced in Korea. This study aimed to assess 1-dose and 2-+dose vaccine effectiveness (VE) against laboratory-confirmed varicella in Korea to provide a scientific basis for developing an immunization strategy. METHODS: We constructed a national cohort using national surveillance data and the national immunization registry. From the cohort, we conducted a 1:2 matched nested case-control study to estimate and compare the VE of the 1-dose and 2-dose of varicella vaccination using exact conditional logistic regression. VE was calculated as [1 - matched odds ratio (OR) × 100%]. RESULTS: From January 1, 2011 to December 31, 2020, a total of 205,173 varicella cases were reported to the notifiable diseases surveillance system. Of these, we included 4,387 laboratory-confirmed varicella cases and 8,774 controls for the analyses. The VE of 1-dose vaccination was 16.8% (95% CI: -9.0% to 36.5%), whereas the VE of 2-doses of the vaccination was 98.6% (95% CI: 96.0%-99.5%). CONCLUSION: These findings suggest that the 2-dose vaccination strategy can be an effective strategy to prevent varicella.

Microbiologic Epidemiology of Early-onset Sepsis in Neonates Born at ≥35 0/7 Weeks' Gestation in Korea During 2009-2018.

BACKGROUND: Sepsis within the first 3 days of life remains a leading cause of neonatal mortality and morbidity. However, few studies have addressed the epidemiology of sepsis in late preterm and term neonates, particularly in Asia. We aimed to estimate the epidemiology of early-onset sepsis (EOS) in neonates born at ≥35 0/7 weeks' gestation in Korea. METHODS: A retrospective study was conducted in neonates with proven EOS born at ≥35 0/7 weeks' gestation from 2009 to 2018 at seven university hospitals. EOS was defined as identifying bacteria from a blood culture within 72 hours after birth. RESULTS: A total of 51 neonates (0.36/1,000 live births) with EOS were identified. The median duration from birth to the first positive blood culture collection was 17 hours (range, 0.2-63.9). Among the 51 neonates, 32 (63%) patients were born by vaginal delivery. The median Apgar score was 8 (range, 2-9) at 1 minute and 9 (range, 4-10) at 5 minutes. The most common pathogen was group B Streptococcus (n = 21; 41.2%), followed by coagulase-negative staphylococci (n = 7; 13.7%) and Staphylococcus aureus (n = 5, 9.8%). Forty-six (90.2%) neonates were treated with antibiotics on the first day of symptom onset, and 34 (73.9%) neonates received susceptible antibiotics. The overall 14-day case-fatality rate was 11.8%. CONCLUSION: This is the first multicenter study on the epidemiology of proven EOS in neonates born at ≥35 0/7 weeks' gestation and found that group B Streptococcus was the most common pathogen in Korea.

SARS-CoV-2 mRNA Vaccine Elicits Sustained T Cell Responses Against the Omicron Variant in Adolescents.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been acknowledged as an effective mean of preventing infection and hospitalization. However, the emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) has led to substantial increase in infections among children and adolescents. Vaccine-induced immunity and longevity have not been well defined in this population. Therefore, we aimed to analyze humoral and cellular immune responses against ancestral and SARS-CoV-2 variants after two shots of the BNT162b2 vaccine in healthy adolescents. Although vaccination induced a robust increase of spike-specific binding Abs and neutralizing Abs against the ancestral and SARS-CoV-2 variants, the neutralizing activity against the Omicron variant was significantly low. On the contrary, vaccine-induced memory CD4+ T cells exhibited substantial responses against both ancestral and Omicron spike proteins. Notably, CD4+ T cell responses against both ancestral and Omicron strains were preserved at 3 months after two shots of the BNT162b2 vaccine without waning. Polyfunctionality of vaccine-induced memory T cells was also preserved in response to Omicron spike protein. The present findings characterize the protective immunity of vaccination for adolescents in the era of continuous emergence of variants/subvariants.

Global varicella vaccination programs.

Varicella (chickenpox) is an infectious disease caused by the highly contagious varicella zoster virus with a secondary attack rate greater than 90%. From this perspective, we aimed to establish the basis for a national varicella vaccine policy by reviewing vaccination programs and policies of countries that have introduced universal varicella vaccinations. As a result of the spread of varicella, an increasing number of countries are providing 2-dose vaccinations and universally expanding their use. In practice, the efficacy and effectiveness of vaccination differ among vaccines and vaccination programs. Optimized vaccination strategies based on each country's local epidemiology and health resources are required. Accordingly, it is necessary to evaluate the effectiveness of varicella vaccines in different settings. Given the short-term and fragmented vaccine effectiveness evaluation in Korea, it is necessary to evaluate its effectiveness at the national level and determine its schedule based on the evidence generated through these studies.

Needs for Increased Awareness of Gastrointestinal Manifestations in Patients With Human Inborn Errors of Immunity.

The gastrointestinal (GI) tract is frequently affected by inborn errors of immunity (IEI), and GI manifestations can be present in IEI patients before a diagnosis is confirmed. We aimed to investigate clinical features, endoscopic and histopathologic findings in IEI patients. This was a retrospective cohort study conducted from 1995 to 2020. Eligible patients were diagnosed with IEI and had GI manifestations that were enough to require endoscopies. IEI was classified according to the International Union of Immunological Societies classification. Of 165 patients with IEI, 55 (33.3%) had GI manifestations, and 19 (11.5%) underwent endoscopy. Among those 19 patients, nine (47.4%) initially presented with GI manifestations. Thirteen patients (68.4%) were male, and the mean age of patients 11.5 ± 7.9 years (range, 0.6 - 26.6) when they were consulted and evaluated with endoscopy. The most common type of IEI with severe GI symptoms was "Disease of immune dysregulation" (31.6%) followed by "Phagocyte defects" (26.3%), according to the International Union of Immunological Societies classification criteria. Patients had variable GI symptoms such as chronic diarrhea (68.4%), hematochezia (36.8%), abdominal pain (31.6%), perianal disease (10.5%), and recurrent oral ulcers (10.5%). During the follow-up period, three patients developed GI tract neoplasms (early gastric carcinoma, mucosa associated lymphoid tissue lymphoma of colon, and colonic tubular adenoma, 15.8%), and 12 patients (63.2%) were diagnosed with inflammatory bowel disease (IBD)-like colitis. Investigating immunodeficiency in patients with atypical GI symptoms can provide an opportunity for correct diagnosis and appropriate disease-specific therapy. Gastroenterologists and immunologists should consider endoscopy when atypical GI manifestations appear in IEI patients to determine if IBD-like colitis or neoplasms including premalignant and malignant lesions have developed. Also, if physicians in various fields are better educated about IEI-specific complications, early diagnosis and disease-specific treatment for IEI will be made possible.

A case report of intrahepatic bile duct confluence anomalies in VACTERL syndrome.

RATIONALE: The clinical manifestations of VACTERL association include vertebral anomalies, anal atresia, congenital heart diseases, tracheoesophageal fistula, renal dysplasia, and limb abnormalities. The association of intrahepatic anomalies and VACTERL syndrome is a rare coincidence. VACTER syndrome and intrahepatic bile drainage anomalies might be genetically related. PATIENT CONCERNS: A 12-year-old girl presented with episodic colicky abdominal pain, nausea, and vomiting for several years. The individual episodes resolved spontaneously within a few days. She had a history of VACTERL syndrome, including a butterfly shape of the L3 vertebra, anal atresia, and an atrial septal defect. DIAGNOSES: On laboratory findings, abnormal liver function tests included elevated total bilirubin, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase. There was no significant abnormal finding in hepatobiliary system sonography except mild gallbladder wall thickening. We performed magnetic resonance cholangiopancreatography and demonstrated an abnormal intrahepatic bile duct confluence, which showed 3 bile ducts draining directly into the neck of the gallbladder. INTERVENTION: Her symptoms related to bile reflux during gallbladder contraction. Cholecystectomy with choledochojejunostomy was undertaken because segments of the bile drainage were intertwined. OUTCOMES: After surgery, her symptoms decreased, but abdominal discomfort remained due to uncorrected left intrahepatic anomalies. LESSONS: Although hepatobiliary anomalies are not included in VACTERL association diagnostic criteria, detailed hepatobiliary work up is needed when gastrointestinal symptoms are present in VACTERL association patients.

Breast abscess caused by Staphylococcus aureus in 2 adolescent girls with atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease in children. Patients with AD experience a high rate of colonization of the skin surface by Staphylococcus aureus. Because of a skin barrier defect, there is a potential risk of staphylococcal invasive infection in patients with AD. Here, we present 2 cases of breast abscess caused by S. aureus in 2 adolescent girls with severe AD. Methicillin-sensitive S. aureus was identified from the breast abscess material. They were treated with appropriate antibiotics, however surgical drainage of the abscess was needed in case 1. Identical strains were found from the breast abscess material as well as the lesional and the nonlesional skin of the patients through matrixassisted laser desorption/ionization time-of-flight analysis. We characterized the differential abundance of Firmicutes phylum in patients' skin in microbiota analysis. In particular, S. aureus, a member of Firmicutes, differed significantly between the lesional and the normal-appearing skin. Our cases demonstrate the potential severity of bacterial deep tissue infection in AD and the dysbiosis of skin microbiota may be involved in inflammation in AD.