Twenty-Five Year Trend Change in the Etiology of Pediatric Invasive Bacterial Infections in Korea, 1996-2020.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has contributed to the change in the epidemiology of many infectious diseases. This study aimed to establish the pre-pandemic epidemiology of pediatric invasive bacterial infection (IBI). METHODS: A retrospective multicenter-based surveillance for pediatric IBIs has been maintained from 1996 to 2020 in Korea. IBIs caused by eight bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella species) in immunocompetent children > 3 months of age were collected at 29 centers. The annual trend in the proportion of IBIs by each pathogen was analyzed. RESULTS: A total of 2,195 episodes were identified during the 25-year period between 1996 and 2020. S. pneumoniae (42.4%), S. aureus (22.1%), and Salmonella species (21.0%) were common in children 3 to 59 months of age. In children ≥ 5 years of age, S. aureus (58.1%), followed by Salmonella species (14.8%) and S. pneumoniae (12.2%) were common. Excluding the year 2020, there was a trend toward a decrease in the relative proportions of S. pneumoniae (rs = -0.430, P = 0.036), H. influenzae (rs = -0.922, P < 0.001), while trend toward an increase in the relative proportion of S. aureus (rs = 0.850, P < 0.001), S. agalactiae (rs = 0.615, P = 0.001), and S. pyogenes (rs = 0.554, P = 0.005). CONCLUSION: In the proportion of IBIs over a 24-year period between 1996 and 2019, we observed a decreasing trend for S. pneumoniae and H. influenzae and an increasing trend for S. aureus, S. agalactiae, and S. pyogenes in children > 3 months of age. These findings can be used as the baseline data to navigate the trend in the epidemiology of pediatric IBI in the post COVID-19 era.

Cytomegalovirus disease in a retinoblastoma cohort: The role of preemptive screening.

BACKGROUND: Cytomegalovirus (CMV) disease is underrecognized in children with retinoblastoma. This study investigated rates of CMV infection and disease in this specific population receiving chemotherapy. METHODS: From a cohort of 164 patients with retinoblastoma diagnosed from 2011 to 2018, 107 patients were evaluated for CMV infection determined by antigenemia assay or real-time PCR. Preemptive CMV screening was implemented in 2013. CMV disease was diagnosed by tissue biopsy, culture, or ophthalmic examination. RESULTS: Thirty-seven and 70 patients before and after the screening strategy, respectively, were included. Before screening, 10/37 (27%) were diagnosed with CMV infection during chemotherapy. Among them, 5 (50%) developed CMV disease (hepatitis, pneumonia, and retinitis) and one patient died of CMV pneumonia. During screening, 18/70 (26%) were documented with 36 episodes of CMV infection and 9 patients received 25 preemptive antiviral therapies. Age at chemotherapy tended to be younger in patients with CMV infection, and fewer were seronegative prior to chemotherapy. Patients who started chemotherapy at <12 months of age received preemptive therapies significantly more often than those started at ≥12 months. Two (11%) out of 18 patients with CMV infection developed CMV retinitis and colitis, and there were no fatal cases. Preemptive therapy along with active CMV screening significantly reduced the risk of developing CMV disease, from 14% to 2.9% (P = 0.047). CONCLUSIONS: Children with retinoblastoma can experience significant morbidity and even mortality from CMV infection during chemotherapy in Korea. Preemptive screening and appropriate antiviral therapy can reduce the development of CMV disease and subsequent mortality.

Molecular epidemiology of respiratory syncytial virus for 28 consecutive seasons (1990-2018) and genetic variability of the duplication region in the G gene of genotypes ON1 and BA in South Korea.

We investigated the molecular epidemiology of respiratory syncytial virus (RSV) isolated from children during 28 consecutive seasons (1990-2018) and the genetic variability of the duplication region of RSV genotypes ON1 and BA in South Korea. RSV was identified using culture-based methods in Hep-2 cells and was grouped as RSV-A or RSV-B by an immunofluorescence assay. The second hypervariable region of the G gene was sequenced for genotyping. The nucleotide and deduced amino acid sequences of the duplication region of RSV ON1 and BA were analyzed. A total of 670 RSV-A and 233 RSV-B isolates were obtained. For RSV-A, the NA1 genotype predominated during the 2004/2005-2011/2012 seasons. The ON1 genotype was first detected in 2011 and has since replaced all other genotypes. For RSV-B, the GB3 genotype predominated during the 1999/2000-2005/2006 seasons, but the BA genotype also replaced all other genotypes of RSV-B after the first season in which it was isolated (2005/2006). In ON1 and BA genotype RSV strains, novel sequence types of the duplication region of the G gene were identified in 50-95% and 33-80% of the isolates, respectively, in each season. The ON1 and BA9 genotypes are responsible for the current epidemics of RSV infection in South Korea. The sequences in the duplication region of the G gene have evolved continuously and might be sufficient for the identification of specific strains of the RSV-A ON1 and RSV-B BA genotypes.

Mycobacterium bovis Osteitis Following Immunization with Bacille Calmette-Guérin (BCG) in Korea.

BACKGROUND: Mycobacterium bovis Bacille Calmette-Guérin (BCG) osteitis, a rare complication of BCG vaccination, has not been well investigated in Korea. This study aimed to evaluate the clinical characteristics of BCG osteitis during the recent 10 years in Korea. METHODS: Children diagnosed with BCG osteitis at the Seoul National University Children's Hospital from January 2007 to March 2018 were included. M. bovis BCG was confirmed by multiplex polymerase chain reaction (PCR) in the affected bone. BCG immunization status and clinical information were reviewed retrospectively. RESULTS: Twenty-one patients were diagnosed with BCG osteitis and their median symptom onset from BCG vaccination was 13.8 months (range, 6.0-32.5). Sixteen children (76.2%) received Tokyo-172 vaccine by percutaneous multiple puncture method, while four (19.0%) and one (4.8%) received intradermal Tokyo-172 and Danish strain, respectively. Common presenting symptoms were swelling (76.2%), limited movement of the affected site (63.2%), and pain (61.9%) while fever was only accompanied in 19.0%. Femur (33.3%) and the tarsal bones (23.8%) were the most frequently involved sites; and demarcated osteolytic lesions (63.1%) and cortical breakages (42.1%) were observed on plain radiographs. Surgical drainage was performed in 90.5%, and 33.3% of them required repeated surgical interventions due to persistent symptoms. Antituberculosis medications were administered for a median duration of 12 months (range, 12-31). Most patients recovered without evident sequelae. CONCLUSION: Highly suspecting BCG osteitis based on clinical manifestations is important for prompt management. A comprehensive national surveillance system is needed to understand the exact incidence of serious adverse reactions following BCG vaccination and establish safe vaccination policy in Korea.

Erratum: Addition of a Co-Author: Etiology of Invasive Bacterial Infections in Immunocompetent Children in Korea (2006-2010): a Retrospective Multicenter Study.

This corrects the article on e45 in vol. 33, PMID: 29349940.

Clonal Expansion of Macrolide-Resistant Sequence Type 3 Mycoplasma pneumoniae, South Korea.

To investigate the genetic background for the emergence of macrolide resistance, we characterized the genetic features of Mycoplasma pneumoniae using multilocus sequence typing. Of the 146 M. pneumoniae strains collected during the 5 consecutive outbreaks of M. pneumoniae pneumonia during 2000-2016 in South Korea, macrolide resistance increased from 0% in the first outbreak to 84.4% in the fifth. Among the 8 sequence types (STs) identified, ST3 (74.7%) was the most prevalent, followed by ST14 (15.1%). Macrolide-susceptible strains comprised 8 different STs, and all macrolide-resistant strains were ST3 (98.3%) except 1 with ST14. The proportion of macrolide-resistant strains in ST3 remained 2.2% (1/46) until the 2006-2007 outbreak and then markedly increased to 82.6% (19/23) during the 2010-2012 outbreak and 95.0% (38/40) during the 2014-2016 outbreak. The findings demonstrated that clonal expansion of ST3 M. pneumoniae was associated with the increase in macrolide resistance in South Korea.

Genetic structures of invasive Streptococcus pneumoniae isolates from Korean children obtained between 1995 and 2013.

BACKGROUND: Understanding the population genetics of pneumococci will allow detection of changes in the prevalence of circulating genotypes and evidence for capsular switching. We aimed to analyze the genetic structure of invasive pneumococcal isolates obtained from children before and after the use of pneumococcal conjugate vaccines (PCVs) in Korea. METHODS: A total of 285 invasive pneumococcal isolates were analyzed using serotyping, multilocus sequence typing, and antimicrobial susceptibility testing. We classified the isolation year to pre-PCV7 (1995-2003; n = 70), post-PCV7 (2004-2010; n = 142), and post-PCV13 (2011-2013; n = 73) periods. RESULTS: Of the 10 clonal complexes (CCs), antibiotic-resistant international clones, CC320 (31.6%), CC81 (14.7%), and CC166 (6.7%) were the main complexes. Serotype 19A was the main serotype of CC320 throughout the periods. Serotypes of CC81 mainly comprised of 23F (53.3%) in pre-PCV7 period and replaced by non-vaccine types (NVTs; 6C [10%], 13 [30%], 15A [40%], and 15B/C [20%]) in post-PCV13 period. The main serotype responsible for CC166 also changed from 9 V (80%) in pre-PCV7 to NVT 11A (50%) in post-PCV13 periods. Non-susceptibility to penicillin (42.3%) was the highest in CC320, increasing from 0 to 76%. CONCLUSION: The genetic structures of invasive pneumococcal isolates in Korean children have changed concomitantly with serotype after the implementation of PCVs.

Etiology of Invasive Bacterial Infections in Immunocompetent Children in Korea (2006-2010): a Retrospective Multicenter Study.

BACKGROUND: Invasive bacterial infections in apparently immunocompetent children were retrospectively analyzed to figure causative bacterial organisms in Korea. METHODS: A total of 947 cases from 25 university hospitals were identified from 2006 to 2010 as a continuance of a previous 10-year period study from 1996 to 2005. RESULTS: Escherichia coli (41.3%), Streptococcus agalactiae (27.7%), and Staphylococcus aureus (27.1%) were the most common pathogens in infants < 3 months of age. S. agalactiae was the most prevalent cause of meningitis and pneumonia and E. coli was the major cause of bacteremia without localizing signs in this group. In children 3 to 59 months of age, Streptococcus pneumoniae (54.2%), S. aureus (20.5%), and Salmonella spp. (14.4%) were the most common pathogens. S. pneumoniae was the leading cause of pneumonia (86.0%), meningitis (65.0%), and bacteremia without localizing signs (49.0%) in this group. In children ≥ 5 years of age, S. aureus (62.8%) was the predominant pathogen, followed by Salmonella species (12.4%) and S. pneumoniae (11.5%). Salmonella species (43.0%) was the most common cause of bacteremia without localizing signs in this group. The relative proportion of S. aureus increased significantly over the 15-year period (1996-2010) in children ≥ 3 months of age (P < 0.001), while that of Haemophilus influenzae decreased significantly in both < 3 months of age group (P = 0.036) and ≥ 3 months of age groups (P < 0.001). CONCLUSION: S. agalactiae, E. coli, S. pneumoniae, and S. aureus are common etiologic agents of invasive bacterial infections in Korean children.

Genotype analysis of ORF 62 identifies varicella-zoster virus infections caused by a vaccine strain in children.

This study was performed to differentiate vaccine-type strains from wild-type strains and determine the genotype of varicella-zoster virus (VZV) in 51 Korean children. A sequencing analysis of ORF 62 identified two cases of herpes zoster caused by the vaccine-type virus, without a previous history of varicella, 22 months and 5 months after VZV vaccination. The wild-type strain was identified in the remaining children. A genotype analysis of ORF 22 amino acids revealed genotype J in all children except one. Genotype E was identified in an infant with varicella imported from Egypt.

Radiologic findings as a determinant and no effect of macrolide resistance on clinical course of Mycoplasma pneumoniae pneumonia.

BACKGROUND: With the emergence of macrolide resistance, concerns about the efficacy of macrolides for the treatment of Mycoplasma pneumoniae (MP) pneumonia in children have been raised. This study aimed to determine the effect of macrolide resistance on the outcome of children who were hospitalized with MP pneumonia. METHODS: Between 2010 and 2015, we performed culture of MP from nasopharyngeal samples obtained from children who were hospitalized with pneumonia at five hospitals in Korea. Macrolide resistance was determined by the analysis of 23S rRNA gene transition and the minimal inhibitory concentrations of four macrolides. Medical records were reviewed to analyze the clinical response to treatment with macrolides. RESULTS: MP was detected in 116 (4.8%) of the 2436 children with pneumonia. MP pneumonia was prevalent in 2011 and 2015. Of the 116 patients with MP pneumonia, 82 (70.7%) were macrolide-resistant. There were no differences in the age distribution, total duration of fever, and chest x-ray patterns between the macrolide-susceptible and macrolide-resistant groups. After macrolide initiation, mean days to defervescence were longer in the macrolide-resistant group than in macrolide-susceptible group (5.7 days vs. 4.1 days, P = 0.021). However, logistic regression analysis revealed that the presence of extrapulmonary signs (P = 0.039), homogeneous lobar consolidation (P = 0.004), or parapneumonic effusion (P < 0.001) were associated with fever duration of ≥7 days after the initiation of macrolides, regardless of macrolide resistance. CONCLUSIONS: This study demonstrated that fever duration in MP pneumonia was determined by the radiologic findings of chest x-ray, not by the presence of macrolide resistance. The results highlight the need for future studies to assess therapeutic benefit from macrolides in the treatment of children with MP pneumonia.

Changes in trends and impact of testing for influenza in infants with fever <90 days of age.

BACKGROUND: Infants aged <90 days who present with fever commonly undergo various invasive procedures due to the risk of bacterial infection in this age group. A great proportion of cases, however, are due to viral infection, including influenza. The aim of this study was therefore to assess the impact of influenza testing in infants <90 days with fever, as well as analyze the subject characteristics to identify which infants should be considered for such testing. METHODS: Clinical characteristics and trends in influenza virus testing and treatment were analyzed among febrile infants <90 days who presented to the emergency room and were diagnosed with influenza during 2005-2015. RESULTS: Among 5,347 febrile infants aged <90 days, 963 (18%) underwent influenza virus test. A total of 114 (11.8%) were diagnosed with influenza. The positivity rate reached 67% of febrile infants during epidemics. Of them, 83 had a history of family contact. While more than half presented with upper respiratory symptoms, 34% had only fever without respiratory symptoms. A decrease in antibiotic use and admission rates during the study period among infants diagnosed with influenza was seen (P for trend <0.05). CONCLUSIONS: During the influenza epidemic season, diagnostic tests for influenza based on a detailed contact history are necessary in assessing the cause of fever. Targeted testing for influenza may lead to a decrease in antibiotic use and admission rates in young infants.

Changes in the Serotype Distribution among Antibiotic Resistant Carriage Streptococcus pneumoniae Isolates in Children after the Introduction of the Extended-Valency Pneumococcal Conjugate Vaccine.

This study investigated the serotype distribution and antimicrobial resistance of 3,820 nasopharyngeal Streptococcus pneumoniae isolates from infants and children who presented with respiratory symptoms at Seoul National University Children's Hospital from July 2010 to June 2015 after the introduction of the extended-valency pneumococcal conjugate vaccines (PCVs). Serotypes and antimicrobial susceptibility were determined using the Quellung reaction and E-test, respectively. S. pneumoniae was isolated from 397 (10.4%) specimens. The most common serotypes were 19A (14.0%), 23A (12.8%), 15B/C (10.7%), 11A (10.1%), 6C (7.8%), and 6A (6.3%) among the typeable pneumococci (n = 335). The PCV serotype proportions significantly decreased (59.1% in 2010/11 to 17.0% in 2014/15, P < 0.001), whereas the non-PCV serotype proportions significantly increased (40.9% in 2010/11 to 83.0% in 2014/15, P < 0.001). The non-susceptibility rates for penicillin (oral), penicillin (parenteral, non-meningitis), cefotaxime, and erythromycin were 97.8%, 22.8%, 27.7%, and 95.5%, respectively. The proportions of PCV serotypes responsible for non-susceptibility to penicillin (parenteral, non-meningitis) and multidrug resistance significantly decreased (80.8% to 21.1%, P < 0.001 and 64.3% to 12.3%, P < 0.001, respectively), whereas the non-PCV serotype proportions significantly increased (19.2% to 78.9%, P < 0.001 and 35.7% to 87.7%, P < 0.001, respectively). Serotypes 23A and 15B/C demonstrated significant proportional increase among the antibiotics resistant strains. Thus, the PCV serotype proportions decreased and the non-PCV serotype proportions increased among nasopharyngeal carriage pneumococci after the introduction of extended-valency PCVs in Korea. Antimicrobial non-susceptibility rates for penicillin and erythromycin remain high despite the decrease in the proportion of PCV serotypes responsible for antimicrobial resistance over time.

Clinical Characteristics of Severe Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease) in Children.

OBJECTIVES: To analyze the clinical characteristics of children with Kikuchi-Fujimoto disease focusing on cases with prolonged fever. STUDY DESIGN: This was a retrospective study of children diagnosed with Kikuchi-Fujimoto disease from March 2003 to February 2015 in South Korea. Electronic medical records were searched for clinical and laboratory manifestations. RESULTS: Among 86 histopathologically confirmed cases, the mean age was 13.2 (SD ± 3.1) years, and male to female ratio was 1:1.32. Cervical lymph node enlargement, found in 85 of the patients (99%), was predominantly unilateral in 64 (75%), and involved the cervical lymph node level V in 67 (81%). Fever was present in 76% of the cases, with a median duration of 9 days (IQR 0.25-17.0). Multivariate analysis revealed that a high fever peak ≥ 39.0°C (P = .010) and presentation with ≥ 2 systemic symptoms other than fever (P = .027) were factors that were significantly associated with longer fever duration. As the size of the largest lymph node's short diameter increased, the fever duration increased (P = .015). Leukopenia (P = .022) also had a significant association with a longer fever duration. Patients with sonographic findings of conglomerated enlarged lymph nodes had a longer median duration of fever compared with those with separate enlarged lymph nodes (11 vs 4.5 days, P = .019). CONCLUSIONS: Patients with high fever, more systemic symptoms, leukopenia, and larger lymph nodes with a conglomerated distribution may benefit from early recognition and selective consideration of corticosteroid therapy.

Risk Factors and Clinical Features of Cytomegalovirus Disease in Children Receiving Anticancer Chemotherapy.

This study was conducted to identify risk factors for cytomegalovirus (CMV) infection and demonstrate the spectrum of CMV disease in children receiving anticancer chemotherapy without hematopoietic stem cell transplantation (HSCT). A total of 289 children who received chemotherapy and were tested for CMV infection were included in the study. CMV antigenemia and DNAemia were determined by identifying the pp65 antigen in leukocytes and performing real-time PCR. CMV disease was diagnosed by tissue biopsy, culture, or ophthalmic examination. Of the 289 children, CMV infection was demonstrated in 46 patients (15.9%). Young age at cancer diagnosis was the risk factor for CMV infection by multivariate analysis (7 mo vs. 7 y, P<0.001). Among 46 children with CMV infection, 10 (21.7%) were diagnosed with CMV disease; hepatitis (n=4), retinitis (n=3), hepatitis and pneumonia (n=2), and hepatitis and retinitis (n=1). The age of the patients with CMV disease was significantly younger than those without (3 vs. 16 mo, P=0.023). Retinoblastoma and neuroblastoma were the 2 most common underlying malignancies. There were 2 fatal cases associated with CMV disease, including 1 who died of CMV pneumonia. The findings of this study demonstrated significant morbidity of CMV infection and disease in young children during the course of chemotherapy without HSCT.

The Immunogenicity and Safety of a Combined DTaP-IPV//Hib Vaccine Compared with Individual DTaP-IPV and Hib (PRP~T) Vaccines: a Randomized Clinical Trial in South Korean Infants.

Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (Pentaxim™) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP-IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%-99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 µg/mL, respectively, but 98.3% and 97.4% had titers ≥ 1 µg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP-IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, NCT01214889).

Early Changes in the Serotype Distribution of Invasive Pneumococcal Isolates from Children after the Introduction of Extended-valent Pneumococcal Conjugate Vaccines in Korea, 2011-2013.

This study was performed to measure early changes in the serotype distribution of pneumococci isolated from children with invasive disease during the 3-year period following the introduction of 10- and 13-valent pneumococcal conjugate vaccines (PCVs) in Korea. From January 2011 to December 2013 at 25 hospitals located throughout Korea, pneumococci were isolated among children who had invasive pneumococcal disease (IPD). Serotypes were determined using the Quellung reaction, and the change in serotype distribution was analyzed. Seventy-five cases of IPD were included. Eighty percent of patients were aged 3-59 months, and 32% had a comorbidity that increased the risk of pneumococcal infection. The most common serotypes were 19A (32.0%), 10A (8.0%), and 15C (6.7%). The PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F, and 6A) accounted for 14.7% of the total isolates and the PCV13 minus PCV7 types (1, 3, 5, 7F and 19A) accounted for 32.0% of the total isolates. Serotype 19A was the only serotype in the PCV13 minus PCV7 group. The proportion of serotype 19A showed decreasing tendency from 37.5% in 2011 to 22.2% in 2013 (P = 0.309), while the proportion of non-PCV13 types showed increasing tendency from 45.8% in 2011 to 72.2% in 2013 (P = 0.108). Shortly after the introduction of extended-valent PCVs in Korea, serotype 19A continued to be the most common serotype causing IPD in children. Subsequently, the proportion of 19A decreased, and non-vaccine serotypes emerged as an important cause of IPD. The impact of extended-valent vaccines must be continuously monitored.

Safety and immunogenicity of a freeze-dried, Vero cell culture-derived, inactivated Japanese encephalitis vaccine (KD-287, ENCEVAC®) versus a mouse brain-derived inactivated Japanese encephalitis vaccine in children: a phase III, multicenter, double-blinded, randomized trial.

BACKGROUND: Although mouse brain-derived, inactivated Japanese encephalitis vaccines (JE-MBs) have been successfully used for a long time, potential rare neurological complications have prompted the development of a Vero cell culture-derived inactivated vaccine (JE-VC). In a phase III clinical study, we aimed to compare the safety and immunogenicity of a JE-VC, KD-287 with a JE-MB, JEV-GCC, in children. METHODS: In this multicenter, double-blinded, randomized controlled trial, the study population consisted of 205 healthy Korean children aged 12-23 months. Each subject was subcutaneously vaccinated with either KD-287 or JEV-GCC twice at an interval of 2 weeks and then vaccinated once 12 months after the second vaccination. Neutralizing antibodies were measured by the plaque reduction neutralization test using the homologous and heterologous, as a post hoc analysis, challenge virus strains. RESULTS: The three-dose regimen of KD-287 showed a comparable safety profile with JEV-GCC except higher incidence of fever after the first dose (30.4% and 14.7%, respectively). Most of the fever was mild degree (61.3% and 66.7%, respectively). KD-287 fulfilled the non-inferiority criteria for seroconversion rate (SCR) and geometric mean titer (GMT) of the neutralizing antibody, which were the primary endpoints, at 4 weeks after the third vaccination (95% CI: -1.00, 3.10 for the SCR difference and 10.8, 17.6 for the GMT ratio). The SCRs of KD-287 were all 100% and the GMTs were higher in the KD-287 group than in the JEV-GCC group after the second vaccination and before and after the third vaccination (GMT ratio: 5.59, 20.13, and 13.79, respectively, p < 0.001 in all). GMTs were higher in the KD-287 group in the heterologous analysis also (GMT ratio: 4.05, 5.15, and 4.19, respectively, p < 0.001 in all). CONCLUSIONS: This study suggests that the KD-287, a JE-VC is as safe as and may be more effective than the licensed MB-derived vaccine. KD-287 could thus be useful as a second-generation vaccine and substitute for the current JE-MB vaccine in Korean children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01150942.

Neonatal sepsis in a rapidly growing, tertiary neonatal intensive care unit: Trends over 18 years.

BACKGROUND: We investigated changes in the admission patterns of neonatal intensive care units and the epidemiology of neonatal sepsis following the rapid expansion and improvements in neonatal intensive care. METHODS: Data on the admission of neonates with culture-proven sepsis between 1996 and 2013 (period I, 1996-2005; period II, 2006-2013) were collected retrospectively. RESULTS: The admission of extremely low-birthweight (ELBW) infants increased between periods I and II (11.1 vs 28.7 infants per 1000 live births, P < 0.001). The survival rate of the ELBW infants improved (57.5 vs 80.1%, P < 0.001), and duration of hospital stay increased (median, 64 vs 80 days, P = 0.001). The incidence of sepsis among all infants and ELBW infants increased (all infants, 5.9 vs 12.7 cases per 1000 live births; ELBW infants, 189.5 vs 290.1 cases per 1000 live births). In ELBW infants, the incidence of sepsis caused by coagulase-negative Staphylococcus (CONS), significantly increased during period II (8.8 vs 25.4%, P = 0.039). On multivariate analysis, central vascular catheters and prolonged hospitalization were independently associated with increased sepsis rate, particularly CONS in ELBW infants. CONCLUSIONS: The inborn admission rate for ELBW infants has increased significantly and is accompanied by improved survival and longer hospital stay. The incidence of neonatal sepsis, particularly in ELBW infants, has also increased, and CONS has emerged as a major pathogen. Central vascular catheters and prolonged hospitalization could be independent risk factors for the increased sepsis rate, particularly sepsis due to CONS.

The Clinical Significance of Voriconazole Therapeutic Drug Monitoring in Children With Invasive Fungal Infections.

Voriconazole is an antifungal drug used to treat fungal infections. This was a retrospective study of 61 children with hemato-oncologic diseases or solid organ transplantation who were administered voriconazole for invasive fungal infections. Of the 61 patients, 31 (50.8%) were in the therapeutic drug monitoring (TDM) group, and 30 (49.2%) were in the non-TDM group. At 12 weeks, treatment failure rate in the non-TDM group was higher than the TDM group (78.6% versus 40.0%, p = 0.038). Drug discontinuation due to adverse events was less frequent in the TDM group than the non-TDM group (26.0% versus 92.3%, p = 0.001). Children required higher dosages to maintain drug levels within the targeted therapeutic range: an average of 8.3 mg/kg/dose in patients <12 years old and 6.9 mg/kg/dose for those ≥12 years old. Treatment failure rates were higher in patients whose voriconazole levels remained below 1.0 mg/L for more than 50% of their treatment duration than those above 1.0 mg/L (71.4% vs. 9.1% after 12 weeks, p = 0.013). Serial monitoring of voriconazole levels in children is important for improving treatment response and preventing unnecessary drug discontinuation. Higher dosages are needed in children to reach therapeutic range.

Capsular polysaccharide gene diversity of pneumococcal serotypes 6A, 6B, 6C, and 6D.

This study was performed to better understand the genetic diversity and evolutionary relatedness of pneumococcal serotypes 6A, 6B, 6C, and 6D. Multi-locus sequence typing (MLST) was performed for 160 serogroup 6 isolates from clinical specimens collected from children between 1991 and 2010. We identified 38 sequence types (STs) comprising five clonal complexes with 12 singletons. Although most STs were confined to a single serotype, some STs were shared by two serotypes, and one ST was shared by three serotypes. Many STs of serotype 6A showed genetic relatedness with those of serotype 6C or 6D in eBURST analysis. Five capsular polysaccharide (cps) genes - wchA, wciO, wciP, wzy, and wzx - were analysed in 74 isolates from our clinical samples and in 36 isolates from GenBank. There were several profiles and clades in each serotype on the analysis of the concatenated sequences of the five cps genes. Small genetic distances between serotypes 6A and 6B and between serotypes 6C and 6D were observed while serotype 6B with an indel sequence formed a distinct clade. When comparing the individual cps genes between the serotypes, there was also a high level of similarity in the wchA and wciO gene sequences between serotype 6C and serotype 6D. On the other hand, serotypes 6A and 6D had the most highly similar wzy and wzx gene sequences. The wzy sequences of serotype 6C were nearly identical (99.6%) to those of serotype 6A clade II strains. In conclusion, we revealed the diversity of the genetic background and cps sequences in each pneumococcal serotype of serogroup 6. Pneumococcal serotype diversity might be attributable to complex serial mutation and recombination events.