Incidence and disease burden of autoimmune inflammatory rheumatic diseases after non-pharmaceutical interventions in the COVID-19 era: A nationwide observational study in Korea.

BACKGROUND: Infections are considered risk factors for autoimmune inflammatory rheumatic diseases (AIRDs), the incidence of which is considered to have been impacted by the COVID-19 pandemic. The impact of non-pharmaceutical interventions (NPIs) on the incidence of AIRDs and their associated health care services and medical expenses in Korea was investigated. METHODS: We included all AIRD cases reported between January 2016 and February 2021 based on the National Health Insurance Service data. We evaluated changes in incidence trends for each AIRD before and after NPI implementation (Feb 2020 to Feb 2021) using segmented regression analysis. Changes in health care utilization and medical costs for each AIRD before and after NPI implementation were also investigated. RESULTS: After NPI implementation, monthly incidence rates declined significantly by 0.205 per 1 000 000 (95% confidence interval [CI], -0.308 to -0.101, p < .001) in patients with systemic lupus erythematosus (SLE). No significant changes in the incidence of all AIRDs other than SLE were observed before and after implementation. Further, annual outpatient department visits per patient were lower during implementation for all diseases, except juvenile idiopathic arthritis (JIA). The prescription days per outpatient visit increased significantly during implementation for all diseases, except JIA and ankylosing spondylitis. During implementation, the total annual medical costs per patient tended to decrease for all diseases, except JIA and mixed connective tissue disease. CONCLUSION: Implementation of NPIs to contain the pandemic led to a reduction in the incidence of SLE and changed patterns of medical care utilization and treatment cost for most AIRDs.

The First Case of a Korean Patient with a Mutation-Confirmed Tumor Necrosis Factor Receptor-Associated Periodic Syndrome.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS, OMIM: #142680) is a rare autoinflammatory disease (AID) with recurrent febrile episodes. To our knowledge, we report herein the first case of a patient with TRAPS in South Korea whose symptoms included fever, arthralgia, abdominal pain, rash, myalgia, cough, and lymphadenopathy. A pathogenic de novo mutation, c.175T>C (p.Cys59Arg), in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene, was confirmed by gene sequencing. The patient has been with tocilizumab (an interleukin-6 inhibitor); tocilizumab administration every other week has completely alleviated the patient's symptoms. Our report further expands the clinical spectrum of patients with TRAPS and reaffirms the use of tocilizumab as a viable alternative treatment option for those patients who are unsatisfactorily responsive to other commonly used biologics, such as canakinumab, anakinra, infliximab, and etanercept. Furthermore, our report may aid in increasing awareness about the existence of mutation-confirmed TRAPS in South Korea in addition to emphasizing the importance of actively pursuing genetic testing to correctly diagnose rare AID.

Prediction of effectiveness of universal rotavirus vaccination in Southwestern Vietnam based on a dynamic mathematical model.

Vaccinating young children against rotavirus (RV) is a promising preventive strategy against rotavirus gastroenteritis (RVGE). We evaluated the relative risk reduction of RVGE induced by universal vaccination in Vietnam through dynamic model analysis. We developed an age-stratified dynamic Vaccinated-Susceptible-Infectious-Recovered-Susceptible model to analyze RV transmission and assess vaccine effectiveness (VE). We assumed 3 different vaccine efficacies: 55%, 70%, and 85%. For model calibration, we used a database of patients under 5 years of age admitted to Ho Chi Minh No.1 Hospital with RVGE between January 2013 and December 2018. Assuming a vaccination rate of 95%, the number of RVGE hospitalizations after 5 years from universal RV vaccination decreased from 92,502 cases to 45,626 with 85% efficacy, to 54,576 cases with 70% efficacy, and to 63,209 cases with 55% efficacy. Additionally, RVGE hospitalizations after 10 years decreased from 177,950 to 89,517 with 85% efficacy and to 121,832 cases with 55% efficacy. The relative risk reductions of RVGE after 10 years were 49.7% with 85% efficacy, 40.6% with 70% efficacy, and 31.5% with 55% efficacy. The VE was 1.10 times (95% CI, 1.01-1.22) higher in the 4-months to 1-year-old age group than in the other age groups (P = 0.038), when applying 85% efficacy with 95% coverage. In conclusion, despite its relatively lower efficacy compared to high-income countries, RV vaccination remains an effective intervention in Southwestern Vietnam. In particular, implementing universal RV vaccination with higher coverage would result in a decrease in RVGE hospitalizations among Vietnamese children under 5 years of age.

Changes in tuberculosis risk after transplantation in the setting of decreased community tuberculosis incidence: a national population-based study, 2008-2020.

BACKGROUND: Transplant recipients are immunocompromised and vulnerable to developing tuberculosis. However, active tuberculosis incidence is rapidly declining in South Korea, but the trend of tuberculosis infection among transplant recipients has not been elucidated. This study aimed to evaluate the risk of active tuberculosis after transplantation, including risk factors for tuberculosis and standardized incidence ratios, compared with that in the general population. METHODS: This retrospective study was conducted based on the South Korean health insurance review and assessment database among those who underwent transplantation (62,484 recipients) between 2008 and 2020. Tuberculosis incidence was compared in recipients treated during higher- (2010-2012) and lower-disease burden (2016-2018) periods. Standardized incidence ratios were analyzed using the Korean Tuberculosis Surveillance System. The primary outcome was the number of new tuberculosis cases after transplantation. RESULTS: Of 57,103 recipients analyzed, the overall cumulative incidence rate 1 year after transplantation was 0.8% (95% confidence interval [CI]: 0.7-0.8), significantly higher in the higher-burden period than in the lower-burden period (1.7% vs. 1.0% 3 years after transplantation, P < 0.001). Individuals who underwent allogeneic hematopoietic stem cell transplantation had the highest tuberculosis incidence, followed by those who underwent solid organ transplantation and autologous hematopoietic stem cell transplantation (P < 0.001). The overall standardized incidence ratio was 3.9 (95% CI 3.7-4.2) and was the highest in children aged 0-19 years, at 9.0 (95% CI 5.7-13.5). Male sex, older age, tuberculosis history, liver transplantation, and allogeneic hematopoietic stem cell transplantation were risk factors for tuberculosis. CONCLUSIONS: Transplant recipients are vulnerable to developing tuberculosis, possibly influenced by their immunocompromised status, solid organ transplant type, age, and community prevalence of tuberculosis. Tuberculosis prevalence by country, transplant type, and age should be considered to establish an appropriate tuberculosis prevention strategy for high-risk groups.

Aetiology and Prognosis of Encephalitis in Korean Children: A Retrospective Single-Centre Study, 2005-2020.

PURPOSE: Encephalitis is a heterogeneous syndrome that occurs in childhood and is not rare. However, epidemiological studies of encephalitis based on the International Encephalitis Consortium (ICS) and expert recommendations are lacking. We investigated the aetiology and prognosis of encephalitis in Korean children. MATERIALS AND METHODS: This retrospective study included children aged <19 years hospitalised for encephalitis at Severance Children's Hospital between 2005 and 2020. The 2013 ICS criteria were used to diagnose encephalitis, and causality was classified according to the site from which the specimen was obtained. Neurological sequelae were categorised using the modified Rankin Scale (mRS) score. RESULTS: In total, 551 children were included, with 7% classified as possible, 77% as probable, and 15% as proven cases. A cause was identified in 42% of the cases (n=222), with viruses being the most common (42%), followed by bacteria (38%) and autoimmune encephalitis (12%). In cases of proven/probable encephalitis (n=65), bacteria accounted for 52%, followed by viruses (25%) and autoimmune encephalitis (22%). In cases with a single pathogen, the anti-N-methyl-D-aspartate receptor autoantibody (n=14) was the most common, followed by Group B streptococcus (n=13), herpes simplex virus (n=11), enterovirus (n=4), and others. Approximately 37% of patients had severe sequelae (mRS score ≥3) at discharge, which decreased to 31% 6 months after discharge. CONCLUSION: This large-scale study showed that autoimmune and infectious causes accounted for a significant proportion of encephalitis in Korean children. Further studies are needed to determine whether early targeted treatment following early diagnosis leads to a favourable prognosis in these populations.

Incidence and Features of Lymphoid Proliferation and Lymphomas after Solid Organ or Hematopoietic Stem Cell Transplantation in a National Database Cohort.

PURPOSE: Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. MATERIALS AND METHODS: We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. RESULTS: During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). CONCLUSION: We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death.

Corrigendum: Genetic diagnosis of inborn errors of immunity using clinical exome sequencing.

[This corrects the article DOI: 10.3389/fimmu.2023.1178582.].

The impact of non-pharmaceutical interventions on premature births during the COVID-19 pandemic: a nationwide observational study in Korea.

Background: Non-pharmaceutical interventions (NPIs), such as social distancing and hand washing, have been associated with a decline in the preterm birth rate worldwide. We aimed to evaluate whether the preterm birth rate in Korea during the coronavirus disease 2019 lockdown has changed compared to that in previous years. Method: A birth registry from the Korea Statistical Information Service, which is a nationwide official database, was used to include all births claimed to have occurred between 2011 and 2020. Newborns with gestational age (GA) less than 22 weeks and birth weight less than 220 g were excluded. The pre-NPI period was designated as January 2011 to January 2020, and the NPI period was defined as February 2020 to December 2020. We assessed the effect of NPI on the incidence of prematurity per 100 births using an interrupted time-series quasi-experimental design and implementing an autoregressive integrated moving average (ARIMA) model. Results: From 2011 to 2020, a total of 3,931,974 live births were registered, among which 11,416 were excluded. Consequently, the final study population included 3,920,558 live births (both singleton and multiple births) among which 275,009 (7.0%) were preterm. The preterm birth rate was significantly higher during the NPI period (8.68%) compared to that in the pre-NPI period (6.92%) (P < 0.001). The ARIMA model showed that in all singleton and multiple births, except those in July (observed 9.24, expected 8.54, [95% prediction interval {PI} 8.13-8.96], percent difference 7.81%), September (observed 7.89, expected 8.35, [95% PI 7.93-8.76], percent difference -5.66%), and December (observed 9.90, expected 9.40, [95% PI 8.98-9.82], percent difference 5.2%), most observed values were within the 95% PI of the expected values and showed an increasing trend. Conclusion: In this nationwide observational study, the trend in premature birth rate did not significantly change due to NPI implementation in Korea, as it had been increasing since 2011. The trend of Korea's birth rate appears to be unaffected by the implementation of NPIs; however, further studies with a longer follow-up period are needed.

Genetic diagnosis of inborn errors of immunity using clinical exome sequencing.

Inborn errors of immunity (IEI) include a variety of heterogeneous genetic disorders in which defects in the immune system lead to an increased susceptibility to infections and other complications. Accurate, prompt diagnosis of IEI is crucial for treatment plan and prognostication. In this study, clinical utility of clinical exome sequencing (CES) for diagnosis of IEI was evaluated. For 37 Korean patients with suspected symptoms, signs, or laboratory abnormalities associated with IEI, CES that covers 4,894 genes including genes related to IEI was performed. Their clinical diagnosis, clinical characteristics, family history of infection, and laboratory results, as well as detected variants, were reviewed. With CES, genetic diagnosis of IEI was made in 15 out of 37 patients (40.5%). Seventeen pathogenic variants were detected from IEI-related genes, BTK, UNC13D, STAT3, IL2RG, IL10RA, NRAS, SH2D1A, GATA2, TET2, PRF1, and UBA1, of which four variants were previously unreported. Among them, somatic causative variants were identified from GATA2, TET2, and UBA1. In addition, we identified two patients incidentally diagnosed IEI by CES, which was performed to diagnose other diseases of patients with unrecognized IEI. Taken together, these results demonstrate the utility of CES for the diagnosis of IEI, which contributes to accurate diagnosis and proper treatments.

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.

A decrease in the incidence of encephalitis in South Korea during the COVID-19 pandemic: A nationwide study between 2010 and 2021.

Limited data are available on the impact of the coronavirus disease (COVID-19) pandemic on encephalitis. Therefore, we evaluated trends in encephalitis in South Korea between 2010 and 2021 using data from the National Health Insurance Service. During the pandemic (February 2020 to 2021), the monthly incidence of encephalitis declined by 0.027 per 100 000 population (95% confidence interval [CI]: -0.055 to 0.001, p = 0.062) compared to that before the pandemic. In subgroup analysis, the estimated coefficient for level change during the pandemic in the 0-4 and 5-9 years age groups were -2.050 (95% CI: -2.972 to -1.128, p < 0.001) and -0.813 (95% CI: -1.399 to -0.227, p = 0.008), respectively. The annual incidence of encephalitis during the pandemic period significantly decreased in the 0-4 and 5-9 years age groups (incidence rate ratio: 0.34 [p = 0.007] and 0.28 [p = 0.024], respectively). The intensive care unit admission rate (39.1% vs. 58.9%, p < 0.001) and cases of death (8.9% vs. 11.1%, p < 0.001) decreased significantly during the pandemic compared to the prepandemic. During the pandemic, the incidence of encephalitis decreased markedly in South Korea, particularly in children aged ≤9 years. In addition, there were changes in the clinical outcome of encephalitis during the COVID-19 pandemic.

Safety of Live Immunization in DiGeorge Syndrome: A Retrospective Single-Center Study in Korea, 2005-2021.

Live immunization is contraindicated in patients with DiGeorge syndrome (DGS). We retrospectively investigated the occurrence of adverse events after live immunization in patients with DGS in Korea. The data of patients matching the International Classification of Disease-10 code of DGS (D82.1) at Severance Hospital Seoul, Korea, were extracted; patients without genetically diagnosed DGS were excluded. Based on T cell immunity status, the included patients were categorized into group A (CD3 < 500 or CD8 < 200 cells/mm3); group B (CD3 ≥ 500 and CD8 ≥ 200 cells/mm3); or group C (unknown). Among 94 patients, 38 (~40%, group A: 8 [21%]; group B: 30 [79%]) underwent immunological testing and 73 (~80%) received at least one live immunization (measles−mumps−rubella vaccination was most common [66/94, ~70%]). Fifty adverse events (fever [n = 29], upper respiratory infection [n = 9], diarrhea [n = 4], rash [n = 3], thrombocytopenia [n = 3], injection site pus [n = 1], and febrile convulsion [n = 1]) were observed; 13 (26%) occurred in group A, with no significant difference in incidence between groups A and B. Serious adverse events, including intensive care unit hospitalization or death, or diseases due to vaccine strains were not observed. In this study, live immunization was well tolerated by patients with partial DGS.

Risk of Dental Discoloration and Enamel Dysplasia in Children Exposed to Tetracycline and Its Derivatives.

PURPOSE: To examine the risk of dental abnormalities after exposure to tetracycline and its derivatives (TCs) in Korean children. MATERIALS AND METHODS: Children aged 0-17 years with a claim for prescriptions of TCs between 2002 and 2015 were identified from the Sample Research Database 2.0 of the National Health Insurance Service. Children not exposed to TCs were selected as the control group by matching sex and age (1:4). Cumulative incidence rate and relative risk of dental abnormalities after TCs exposure were investigated. RESULTS: The 10-year cumulative incidence rate in the 0-12 years group was 3.1% [95% confidence interval (CI), 2.3-3.9]. The 10-year cumulative incidence rates were 7.0%, 1.9%, and 1.6% in the 0-7, 8-12, and 13-17 years age groups (95% CI: 4.7-9.3, 1.2-2.6, and 1.3-1.9, respectively). There was no significant difference in the risk of dental abnormalities according to TC exposure among the age groups of 0-7 years [adjusted hazard ratio (aHR)=1.0], 8-12 years (aHR=1.1), and 13-17 years (aHR=1.2). CONCLUSION: Short-term exposure to TCs does not appear to increase the risk of dental abnormalities in children aged 0-7 and 0-12 years. Restrictions on the use of TCs in children aged 8-12 years, in some countries, may warrant consideration.

Changes in Etiology of Invasive Bacterial Infections in Infants Under 3 Months of Age in Korea, 2006-2020.

OBJECTIVES: Invasive bacterial infection (IBI) causes a significant burden in infants. In this study, we analyzed changes in epidemiology of IBI among infants in Korea. METHODS: A retrospective multicenter-based surveillance for IBIs in infants <3 months of age was performed during 2006-2020. Cases were classified as an early-onset disease (EOD) (0-6 days) or late-onset disease (LOD) (7-89 days). The temporal trend change in proportion of pathogens was analyzed. RESULTS: Among 1545 cases, the median age was 28 days (IQR: 12, 53) and EOD accounted for 17.7%. Among pathogens, S. agalactiae (40.4%), E. coli (38.5%), and S. aureus (17.8%) were the most common and attributed for 96.7%. Among EOD (n = 274), S. agalactiae (45.6%), S. aureus (31.4%), E. coli (17.2%) and L. monocytogenes (2.9%) were most common. Among LOD (n = 1274), E. coli (43.1%), S. agalactiae (39.3%), S. aureus (14.9%) and S. pneumoniae (1.3%) were most common. In the trend analysis, the proportion of S. aureus (r s = -0.850, P < 0.01) decreased significantly, while that of S. agalactiae increased (r s = 0.781, P < 0.01). CONCLUSION: During 2006-2020, among IBI in infants <3 months of age, S. agalactiae, E. coli, and S. aureus were most common and an increasing trend of S. agalactiae was observed.

Comparison of Clinical Characteristics and Risk Factors for Recurrence of Kikuchi-Fujimoto Disease Between Children and Adult.

Purpose: Kikuchi-Fujimoto disease (KFD) is a rare, benign, and self-limited disease, characterized by cervical lymphadenopathy and fever. Herein, we analyzed the differences in its clinical manifestations and risk factors for recurrence between children and adults. Patients and Methods: We retrospectively reviewed the medical records of patients diagnosed with KFD at a tertiary referral hospital between 2005 and 2019. Patients were divided into two groups based on their age: children (<19 years) and adults (≥19 years). Results: During the 14-year study period, 127 patients were diagnosed with KFD. Among these, 34 (26.8%) were children and 93 (73.2%) were adults. The fever duration was longer and the frequency of myalgia was higher in adults than in children; however, no other significant symptomatic differences were noted between the two groups. Lymph node evaluation was mainly performed using ultrasound in children (61.8%) and computed tomography in adults (78.5%). Moreover, the frequency of antibiotic use was higher in children than in adults (76.5% vs 54.8%, P = 0.027). In adults, multivariable logistic regression analysis revealed anti-nuclear antibody (ANA) positivity (titer ≥1:80) as a risk factor for recurrence (odds ratio: 7.813; 95% confidence interval = 1.818-33.333; P = 0.006). Conclusion: The clinical features of KFD in children and adults were similar; however, the preferred imaging study and frequency of antibiotic use differed significantly between the two groups. Furthermore, in adults, ANA positivity was associated with KFD recurrence. Thus, patients with KFD who present with ANA positivity at diagnosis will benefit from a regular follow-up for monitoring KFD recurrence.

Respiratory Syncytial Virus Outbreak Without Influenza in the Second Year of the Coronavirus Disease 2019 Pandemic: A National Sentinel Surveillance in Korea, 2021-2022 Season.

BACKGROUND: This study aimed to investigate whether respiratory syncytial virus (RSV) and influenza virus (IFV) infections would occur in 2021-2022 as domestic nonpharmaceutical interventions (NPIs) are easing. METHODS: Data were collected from the Korean Influenza and Respiratory Virus Monitoring System database. The weekly positivity rates of respiratory viruses and number of hospitalizations for acute respiratory infections were evaluated (January 2016-2022). The period from February 2020 to January 2022 was considered the NPI period. The autoregressive integrated moving average model and Poisson analysis were used for data analysis. Data from 14 countries/regions that reported positivity rates of RSV and IFV were also investigated. RESULTS: Compared with the pre-NPI period, the positivity and hospitalization rates for IFV infection during 2021-2022 significantly decreased to 0.0% and 1.0%, respectively, at 0.0% and 1.2% of the predicted values, respectively. The RSV infection positivity rate in 2021-2022 was 1.8-fold higher than that in the pre-NPI period at 1.5-fold the predicted value. The hospitalization rate for RSV was 20.0% of that in the pre-NPI period at 17.6% of the predicted value. The re-emergence of RSV and IFV infections during 2020-2021 was observed in 13 and 4 countries, respectively. CONCLUSION: During 2021-2022, endemic transmission of the RSV, but not IFV, was observed in Korea.

Temporal Correlation Between Kawasaki Disease and Infectious Diseases in South Korea.

Importance: Infections are proposed to be triggering factors for Kawasaki disease (KD), although its etiological factors remain unknown. Recent reports have indicated a 4- to 6-week lag between SARS-CoV-2 infection and multisystem inflammatory syndrome in children with a similar presentation to that of KD. Objective: To investigate the temporal correlation between KD and viral infections, focusing on respiratory viruses. Design, Setting, and Participants: This cohort study was conducted among individuals aged 0 to 19 years diagnosed with KD between January 2010 and September 2020 from the Korean National Health Insurance Service. Data on infectious disease outbreaks from 2016 to 2019 were collected from the Korea Disease Control and Prevention Agency, Korean Influenza and Respiratory Virus Monitoring System, Korea Enteroviruses Surveillance System, and the Enteric Pathogens Active Surveillance Network in South Korea. Data were analyzed from December 2020 to October 2021. Main Outcomes and Measures: National databases for infectious diseases were used for a time-series analysis of the correlation between viral infections and KD. The temporal correlation between infectious disease outbreaks and KD outbreaks was evaluated using the Granger causality test (G-test), which is a useful tool to estimate correlations between 2 time series of diseases based on time lags. Results: Overall, 53 424 individuals with KD were identified, including 22 510 (42.1%) females and 30 914 (57.9%) males and 44 276 individuals (82.9%) younger than 5 years. Intravenous immunoglobulin-resistant KD was identified in 9042 individuals (16.9%), and coronary artery abnormalities were identified in 384 individuals (0.7%). Of 14 infectious diseases included in the analyses, rhinovirus infection outbreaks were identified as significantly correlated at 1 to 3 months before KD outbreaks in South Korea (r = 0.3; 1 month: P < .001; 2 months: P < .001; 3 months: P < .001). Outbreaks of respiratory syncytial virus infection were identified as significantly correlated with KD outbreaks by 2 months (r = 0.5; 2 months: P < .001). Additionally, varicella outbreaks were identified as significantly correlated at 2 and 3 months before KD outbreaks (r = 0.7; 2 months: P < .001; 3 months: P < .001). Conclusions and Relevance: In this cohort study with a time series analysis of children and youth in South Korea with KD, respiratory infections caused by rhinovirus and respiratory syncytial virus and varicella outbreaks were significantly correlated with KD at 1 to 3 months before KD outbreaks.

Delayed Influenza Treatment in Children With False-Negative Rapid Antigen Test: A Retrospective Single-Center Study in Korea 2016-2019.

BACKGROUND: We aimed to examine the delay in antiviral initiation in rapid antigen test (RAT) false-negative children with influenza virus infection and to explore the clinical outcomes. We additionally conducted a medical cost-benefit analysis. METHODS: This single-center, retrospective study included children (aged < 10 years) with influenza-like illness (ILI), hospitalized after presenting to the emergency department during three influenza seasons (2016-2019). RAT-false-negativity was defined as RAT-negative and polymerase chain reaction-positive cases. The turnaround time to antiviral treatment (TAT) was from the time when RAT was prescribed to the time when the antiviral was administered. The medical cost analysis by scenarios was also performed. RESULTS: A total of 1,430 patients were included, 7.5% were RAT-positive (n = 107) and 2.4% were RAT-false-negative (n = 20). The median TAT of RAT-false-negative patients was 52.8 hours, significantly longer than that of 4 hours in RAT-positive patients (19.2-100.1, P < 0.001). In the multivariable analysis, TAT of ≥ 24 hours was associated with a risk of severe influenza infection and the need for mechanical ventilation (odds ratio [OR], 6.8, P = 0.009 and OR, 16.2, P = 0.033, respectively). The medical cost varied from $11.7-187.3/ILI patient. CONCLUSION: Antiviral initiation was delayed in RAT-false-negative patients. Our findings support the guideline that children with influenza, suspected of having severe or progressive infection, should be treated immediately.