Fatal SARS-CoV-2 Infection among Children, Japan, January-September 20221.

To determine the characteristics of pediatric patients 0-19 years of age who died after onset of SARS-CoV-2 infection in Japan during January 1-September 30, 2022, we reviewed multiple sources. We identified 62 cases, collected detailed information from medical records and death certificates, and conducted interviews, resulting in 53 patients with detailed information for our study. Among 46 patients with internal causes of death (i.e., not external causes such as trauma), 15% were <1 year of age, 59% had no underlying disease, and 88% eligible for vaccination were unvaccinated. Nonrespiratory symptoms were more common than respiratory symptoms. Out-of-hospital cardiac arrest affected 46% of patients, and time from symptom onset to death was <7 days for 77%. Main suspected causes of death were central nervous system abnormalities (35%) and cardiac abnormalities (20%). We recommend careful follow-up of pediatric patients after SARS-CoV-2 infection during the first week after symptom onset, regardless of underlying diseases.

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan.

BACKGROUND: The COVID-19 pandemic has affected the lives of people of all ages. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than do adults. This is the first nationwide study in Japan focusing on pediatric cases reported by pediatricians, including cases with no or mild symptoms. METHODS: We analyzed the epidemiological and clinical characteristics and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database which was maintained voluntarily by members of the Japan Pediatric Society. RESULTS: Almost half of the patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively). CONCLUSIONS: COVID-19 symptoms in children are less severe than those in adults. School closure appeared to have a limited effect on transmission. Controlling household transmission from adult family members is the most important measure for prevention of COVID-19 among children.

Willingness to Vaccinate Children against Influenza after the Coronavirus Disease 2019 Pandemic.

OBJECTIVES: To determine factors associated with parents who plan to vaccinate their children against influenza next year, especially those who did not vaccinate against influenza last year using a global survey. STUDY DESIGN: A survey of caregivers accompanying their children aged 1-19 years old in 17 pediatric emergency departments in 6 countries at the peak of the coronavirus disease 2019 (COVID-19) pandemic. Anonymous online survey included caregiver and child demographic information, vaccination history and future intentions, and concern about the child and caregiver having COVID-19 at the time of emergency department visit. RESULTS: Of 2422 surveys, 1314 (54.2%) caregivers stated they plan to vaccinate their child against influenza next year, an increase of 15.8% from the previous year. Of 1459 caregivers who did not vaccinate their children last year, 418 (28.6%) plan to do so next year. Factors predicting willingness to change and vaccinate included child's up-to-date vaccination status (aOR 2.03, 95% CI 1.29-3.32, P = .003); caregivers' influenza vaccine history (aOR 3.26, 95% CI 2.41-4.40, P < .010), and level of concern their child had COVID-19 (aOR 1.09, 95% CI 1.01-1.17, P = .022). CONCLUSIONS: Changes in risk perception due to COVID-19, and previous vaccination, may serve to influence decision-making among caregivers regarding influenza vaccination in the coming season. To promote influenza vaccination among children, public health programs can leverage this information.

Augmentation of antitubercular therapy with IFNγ in a patient with dominant partial IFNγ receptor 1 deficiency.

Osteomyelitis due to Mycobacterium bovis Bacille Calmette-Guerin (BCG) often develops in patients with interferon-γ receptor 1 (IFNγR1) deficiency. In these patients, susceptibility appears to be caused by impaired interleukin-12- and IFNγ-mediated immunity. Here we report the case of a one-year-old girl with dominant partial IFNγR1 deficiency who suffered from lymphadenitis and multiple sites of osteomyelitis due to BCG infection. She was allergic to isoniazid and rifampicin--the prescribed standard treatment--and required prior desensitization therapy. She was subsequently treated with these drugs, but her symptoms did not improve. IFNγ therapy was added to the antitubercular therapy, increasing the serum level of IFNγ and leading to the resolution of the lymphadenitis and osteomyelitis. In conclusion, high dose IFNγ therapy in combination with antitubercular drugs led to resolution of BCG infection in a patient with dominant partial IFNγ deficiency.

An infant with human parechovirus type 3 infection with a distinctive rash on the extremities.

Human parechovirus type 3 (HPeV3) is known to cause sepsis-like syndrome and meningoencephalitis in neonates and young infants. We herein report a neonatal case of sepsis-like syndrome due to HPeV3 infection, diagnosed using polymerase chain reaction (PCR), with a distinctive erythematous rash present mainly on the soles and palms that helped in the diagnosis of the disease. Combining the unique characteristics of rash and confirmation by PCR at the early stage of the disease led to the diagnosis of HPeV3, distinguishing it from sepsis and other critical disease conditions, and allowing for appropriate, rapid management.

Predictive biomarker of mortality in children with infectious diseases: a nationwide data analysis.

Biomarkers play a crucial role in the early identification of high-risk children with infectious diseases. Despite their importance, few studies evaluated biomarkers' capabilities in predicting mortality. The aim of this study was to evaluate the biomarkers' predictive capabilities for mortality in children with infectious diseases. From an inpatient database covering ≥200 acute-care hospitals in Japan, we included children who underwent blood culture, and received antimicrobial treatment between 2012 and 2021. Biomarkers' results from the day of the initial blood culture were used. Biomarker discriminative capabilities were assessed using the area under receiver operating characteristic curves (AUCs). Of 11,365 eligible children with presumed infection, 1,378 (12.1%) required mechanical ventilation or vasoactive agents within 2 days of blood culture, and 100 (0.9%) died during admission. Of all children, 10,348 (91.1%) had community-onset infections and 1,017 (8.9%) had hospital-onset infections. C-reactive protein and white blood cell demonstrated limited discriminatory capabilities with AUCs of 0.44 [95% confidence interval (CI): 0.38-0.51] and 0.45 (95% CI: 0.39-0.52). In contrast, pH, prothrombin time-international normalized ratio, and procalcitonin exhibited strong discriminatory capabilities with AUCs of 0.77 (95% CI: 0.65-0.90), 0.77 (95% CI: 0.70-0.84) and 0.76 (95% CI: 0.29-1.00). In conclusions, our real-world data analysis suggested that C-reactive protein and white blood cell may not be reliable indicators for predicting mortality in children with presumed infection. These findings could warrant future studies exploring promising biomarkers, including those from blood gas analyses, coagulation studies and procalcitonin.

Comparison design and evaluation power in cohort and self-controlled case series designs for post-authorization vaccine safety studies.

Background: Post-authorization safety studies (PASSs) of vaccines are important. PASSs enable the evaluation of association between vaccination and adverse events following immunization through common study designs. Clinical trials during vaccine development typically include a few thousand to 10,000 participants while a PASS might aim to detect a few adverse events per 100,000 vaccine recipients. While all available data may be utilized, prior consideration of power analyses are nonetheless crucial for interpretation in cases where statistically significant differences are not found. Methods: This research primarily examined cohort study design and self-controlled case series (SCCS) design, estimating the power of a PASS under plausible conditions. Results: Both the cohort study and SCCS designs necessitated large sample sizes or high event counts to guarantee adequate power. The SCCS design is particularly suited to evaluating rare adverse events. However, extremely rare events may not yield sufficient occurrences, thereby resulting in low power. Although the SCCS design can more efficiently control for time-invariant confounding in principle, it solely estimates relative measures. A cohort study design might be preferred if confounding can be adequately managed as it also estimates absolute measures. It may be an easy decision to use all the data at hand for either design. We found it necessary to estimate the sample size and number of events to be used in the study based on a priori information and anticipated results.

Immune thrombocytopenic purpura and Guillain-Barré syndrome after 23-valent pneumococcal polysaccharide vaccination in Japan: The vaccine effectiveness, networking, and universal safety (VENUS) study.

BACKGROUND: To address the lack of an active vaccine safety surveillance system in Japan, the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study was initiated in 2021 as a pilot system using existing health insurance claims data and vaccination records. METHODS: This study evaluated the value of the VENUS study by assessing the incidence of immune thrombocytopenic purpura (ITP) and Guillain-Barré syndrome (GBS) following vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) using a self-controlled case series (SCCS) design. RESULTS: Incidence rate ratios for ITP during 28-day and 42-day risk periods were 0.89 (95% confidence interval [CI], 0.12-6.4), and 0.58 (95% CI, 0.081-4.2), respectively. Neither was statistically significant. Incidence rate ratios could not be estimated for GBS due to the limited sample size. CONCLUSION: The VENUS study can provide valuable insights to facilitate the establishment of an advanced vaccine monitoring system in Japan.

The value of radiographic findings for the progression of pandemic 2009 influenza A/H1N1 virus infection.

BACKGROUND: Most illnesses caused by pandemic influenza A (H1N1) pdm09 virus (A/H1N1) infection are acute and self-limiting among children. However, in some children, disease progression is rapid and may require hospitalization and transfer to a pediatric intensive care unit (PICU). We investigated factors associated with rapid disease progression among children admitted to hospital for A/H1N1 infection, particularly findings on initial chest radiographs. METHODS: In this retrospective study, we investigated the records of children who had received a laboratory or clinical diagnosis of A/H1N1 infection and were admitted to the largest children's hospital in Japan between May 2009 and March 2010. The medical records were reviewed for age, underlying diseases, vital signs on admission, initial chest radiographic findings, and clinical outcomes. According to chest radiographic findings, patients were classified into 4 groups, as follows: [1] normal (n = 46), [2] hilar and/or peribronchial markings alone (n = 64), [3] consolidation (n = 64), and [4] other findings (n = 29). Factors associated with clinical outcomes were analyzed using logistic regression. RESULTS: Two hundreds and three patients (median 6.8 years) were enrolled in this study. Fifteen percent (31/203) of patients were admitted to PICU. Among 31 patients, 39% (12/31) of patients required mechanical ventilation (MV). When the initial chest radiographic findings were compared between patients with consolidation (n = 64) and those without consolidation (n = 139), a higher percentage of patients with consolidation were admitted to PICU (29.7% vs.8.6%, P < 0.001) and required MV (17.2% vs. 0.7%, P < 0.001). These findings remain significant when the data were analyzed with the logistic regression (P < 0.001, P < 0.001, respectively). CONCLUSIONS: Consolidation on initial chest radiographs was the most significant factor to predict clinical course of hospitalized children with the 2009 A/H1N1 infection.

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

BACKGROUND: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. METHODS: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. RESULTS: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). CONCLUSIONS: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

[Haemophilus influenzae type b vaccine].

Haemophilus influenzae type b (Hib) vaccine has been included in the national Immunization Program in more than 120 countries around the world and its effectiveness and safety have been confirmed. In Japan, Hib vaccine was recently licensed in December 2008. Because it has included in the category of voluntary vaccine and the burden of out-of-pocket expense is a major concern for caregivers, payment coverage through the local government funded by the temporal national budget has been initiated since November 2010. It is important to make an effort to fill the "vaccine gap" between Japan and other developed countries and increase a vaccine coverage rate including Hib vaccine to decrease vaccine preventable diseases in Japanese children.

Changes in childhood vaccination during the coronavirus disease 2019 pandemic in Japan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected daily life. COVID-19 often causes asymptomatic or mild disease in children; however, delayed routine childhood immunization is a concern, as it could increase the risk of vaccine-preventable disease. No study has evaluated the status of childhood vaccinations in Japan during the COVID-19 pandemic. METHODS: This retrospective observational study evaluated the number of vaccine doses administered to children in 4 Japanese cities (2 cities in the Tokyo metropolitan area and 2 cities far from Tokyo) during the period from 2016 to 2020. Vaccine doses administered between January and September 2020 during the COVID-19 pandemic were compared, by month, with those given during 2016-2019. Age-stratified demographic data were collected to determine whether factors other than change in the child population over time affected vaccination trends. RESULTS: In all cities the decrease in vaccine doses administered was most apparent in March and April 2020, i.e., just before or coincident with the declaration of a nationwide COVID-19 emergency on April 7, 2020. The decrease started as early as February in the Tokyo metropolitan area. As child age increased, the decrease became more apparent. Before the lift of national emergency on May 25, catch-up of the vaccination was observed in all age groups in all cities. Vaccine doses persistently increased in older age groups but not in infants. The overall vaccination trends did not differ significantly among the 4 cities. CONCLUSIONS: The COVID-19 pandemic significantly affected routine childhood immunization in Japan. Thus, a nationwide electronic surveillance system and announcements for guardians to encourage timely routine immunization are warranted.

Comparative Analysis of Pediatric COVID-19 Infection in Southeast Asia, South Asia, Japan, and China.

There is a scarcity of data regarding coronavirus disease 2019 (COVID-19) infection in children from southeast and south Asia. This study aims to identify risk factors for severe COVID-19 disease among children in the region. This is an observational study of children with COVID-19 infection in hospitals contributing data to the Pediatric Acute and Critical Care COVID-19 Registry of Asia. Laboratory-confirmed COVID-19 cases were included in this registry. The primary outcome was severity of COVID-19 infection as defined by the World Health Organization (WHO) (mild, moderate, severe, or critical). Epidemiology, clinical and laboratory features, and outcomes of children with COVID-19 are described. Univariate and multivariable logistic regression models were used to identify risk factors for severe/critical disease. A total of 260 COVID-19 cases from eight hospitals across seven countries (China, Japan, Singapore, Malaysia, Indonesia, India, and Pakistan) were included. The common clinical manifestations were similar across countries: fever (64%), cough (39%), and coryza (23%). Approximately 40% of children were asymptomatic, and overall mortality was 2.3%, with all deaths reported from India and Pakistan. Using the multivariable model, the infant age group, presence of comorbidities, and cough on presentation were associated with severe/critical COVID-19. This epidemiological study of pediatric COVID-19 infection demonstrated similar clinical presentations of COVID-19 in children across Asia. Risk factors for severe disease in children were age younger than 12 months, presence of comorbidities, and cough at presentation. Further studies are needed to determine whether differences in mortality are the result of genetic factors, cultural practices, or environmental exposures.

Comparison of immunization systems in Japan and the United States - What can be learned?

Recently, efforts have been made to fill a so-called "vaccine gap" between Japan and other countries; however, more work remains. Concerns about adverse events following immunization (AEFI) resulted in an historically passive approach to policy making in the National Immunization Program (NIP). For example, reports of AEFI following human papillomavirus vaccine (HPVV) in 2013 led the Japanese government to withdraw its proactive recommendations, resulting in a sharp drop in HPVV coverage rate to less than 1.0%. In this report, we review key historical incidents that led to the current immunization system in Japan, compare it to that in the United States, and discuss strategies for improving the Japanese immunization system. By strengthening existing policies and programs, such as National Immunization Technical Advisory Groups and AEFI reporting, compensation laws, and immunization education, the remaining vaccine gap in Japan could be filled.

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

BACKGROUND: Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. METHODS: This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. RESULTS: We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01). CONCLUSION: The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.

Japanese physicians' attitudes and intentions regarding human papillomavirus vaccine compared with other adolescent vaccines.

INTRODUCTION: Japan has experienced extremely low human papillomavirus vaccine (HPVV) coverage following the suspension of proactive governmental recommendations in 2013. Several studies have reported that recommendations from physicians increase adolescents' vaccine acceptance. In this survey, we evaluated the attitudes and intentions of Japanese physicians related to adolescent immunizations, particularly HPVV. METHODS: We conducted a cross-sectional study using a mailed questionnaire targeting 330 Japanese physicians including 78 pediatricians, 225 internists and 27 obstetricians and gynecologists (OB/GYNs) in Kawasaki City, Japan in 2016. The survey measured physicians' reported frequency of educating adolescents about vaccines as well as their own perceptions and intentions related to adolescent immunizations. RESULTS: Valid responses were obtained from 148 (45%) physicians. Though 53% agreed that the HPVV should be recommended, only 21% reported educating about HPVV. The majority of respondents (90%) agreed that they would restart HPVV for adolescents if the government reinstated its recommendation. CONCLUSIONS: Although Japanese physicians reported support for adolescent immunizations, they were less likely to recommend or discuss HPVV compared with other adolescent vaccines. Responses indicated this was, at least in part, due to the lack of governmental support for HPVV, indicating that their recommendations would improve with government endorsement of the vaccine.

An intersection network based on combining SNP coassociation and RNA coexpression networks for feed utilization traits in Japanese Black cattle.

Genome-wide association studies (GWAS) of quantitative traits have detected numerous genetic associations, but they encounter difficulties in pinpointing prominent candidate genes and inferring gene networks. The present study used a systems genetics approach integrating GWAS results with external RNA-expression data to detect candidate gene networks in feed utilization and growth traits of Japanese Black cattle, which are matters of concern. A SNP coassociation network was derived from significant correlations between SNPs with effects estimated by GWAS across 7 phenotypic traits. The resulting network genes contained significant numbers of annotations related to the traits. Using bovine transcriptome data from a public database, an RNA coexpression network was inferred based on the similarity of expression patterns across different tissues. An intersection network was then generated by superimposing the SNP and RNA networks and extracting shared interactions. This intersection network contained 4 tissue-specific modules: nervous system, reproductive system, muscular system, and glands. To characterize the structure (topographical properties) of the 3 networks, their scale-free properties were evaluated, which revealed that the intersection network was the most scale-free. In the subnetwork containing the most connected transcription factors (URI1, ROCK2, and ETV6), most genes were widely expressed across tissues, and genes previously shown to be involved in the traits were found. Results indicated that the current approach might be used to construct a gene network that better reflects biological information, providing encouragement for the genetic dissection of economically important quantitative traits.

Treatment With Quadrivalent Human Papillomavirus Vaccine for Juvenile-Onset Recurrent Respiratory Papillomatosis: Case Report and Review of the Literature.

Although juvenile-onset recurrent respiratory papillomatosis (JoRRP) generally involves a benign tumor on the larynx and other respiratory tract areas, almost all patients with this disease require repeated surgical intervention (to prevent airway obstruction during the course of illness) and various adjuvant therapies such as interferon, cidofovir, acyclovir, ribavirin, indole-3-carbinol, HspE7, mumps vaccine, photodynamic therapy, propranolol, cimetidine, and bevacizumab. Some case reports recently described the effectiveness of the quadrivalent human papillomavirus vaccine (HPV4) as an adjuvant therapy. On the basis of these reports, we administered HPV4 to a 2-year-old boy with JoRRP. However, no therapeutic effect was found. A review of the available literature revealed that current evidence for the effectiveness of therapeutic HPV4 and other adjuvant therapies for JoRRP is inconsistent. Therefore, the prophylactic use of currently available HPV vaccine for adolescents is the most effective strategy for preventing not only anogenital cancers but also genital warts, which might be a risk factor for JoRRP among their children in the future.

[Local reactions after diphtheria-tetanus-acellular pertussis vaccines in mice; changes in histopathology at the injection site].

Diphtheria-tetanus-acellular pertussis vaccine (DTaP) developed in Japan is now widely used worldwide. DTaP is safer than the diphtheria-tetanus-whole-cell pertussis vaccine (DTwP) and has fewer severe side effects, but local reactions such as redness, swelling, and induration are still reported. The pathophysiological mechanism of these reactions is controversial. To clarify the cause of local reactions, we conducted studies using the mouse model. After administering either one or two abdominal subcutaneous DTaP inoculations, we observed changes in histopathology at the injection site at 24h, 48h, and 7 days. The control group, inoculated with physiologic saline, showed no significant changes either pathologically or with the naked eye. All mice after DTaP vaccination showed indurations at the injection site. Pathologically, we watched leukocyte invasion into or around the site, especially neutrophils and eosinophils. After the first vaccination, the extent of the invasion was strong 24h and 7 days later. At 24h following the second vaccination, a dramatic leukocyte invasion seen persisted at 7days. At 7 days after the first vaccination, peripheral fibrosis had begun, and when a second vaccination was administered, it began even earlier at the second site. These histopathological changes show that local reactions are caused by both inflammatory and allergic responses. Because this mouse study resulted in the same pattern of reactions observed in humans, this method will be useful for studies focusing on local reactions.