Group B Streptococcal Disease in Infants in Japan.

This review describes the epidemiology of group B Streptococcus (GBS) infection in infants in Japan and discusses unresolved issues and future perspectives. Guidelines for the prevention of vertical transmission in Japan were implemented in 2008. The incidence of early-onset disease in Japan has remained stable at approximately 0.10/1000 livebirths or less, which is lower than in Europe and North America. The incidence of late-onset disease is also low, but has increased over the last decade, with an estimated 0.29/1000 livebirths in 2020. National surveillance studies in 2011-2015 and 2016-2020 reported case fatality rates of 4.5% and 6.5% for early-onset disease and 4.4% and 3.0% for late-onset disease, respectively. Sequelae of neurodevelopmental impairments were considerably associated with infants who developed meningitis. Predominant neonatal invasive strains have remained in the following order of serotypes: III, Ia, Ib and V, for the past 30 years. Conversely, the predominant serotypes of maternal colonization strains markedly changed from serotypes VI and VIII around 2000 to serotypes Ia, Ib, III and V over the last decade. Recurrence rates among infants < 1-year-old were estimated to be 2.8%-3.7%, and preterm birth and antenatal maternal GBS colonization were risk factors for recurrence. Several unresolved issues remain. First, the exact disease burden remains unclear because Japan does not have a nationwide system to register all infants affected by invasive GBS disease, and even population-based surveys are limited to up to 10 of the 47 prefectures. Others include low adherence to prevention guidelines of vertical transmission and the development of strategies based on Japanese epidemiological evidence rather than the Center for Disease Control and Prevention guidelines. The effectiveness of introducing maternal vaccines in Japan, where the disease incidence is low, needs to be carefully verified.

Effect of delivery mode on postnatal platelet count dynamics in neonates born to mothers with immune thrombocytopenia.

We aimed to determine the effect of delivery mode on postnatal platelet count dynamics in neonates born to mothers with immune thrombocytopenia (ITP). This single-center, retrospective study included 41 mothers with ITP and their 65 infants born by vaginal delivery (VD, n = 30) and cesarean section (CS, n = 35) between January 1997 and March 2022. The median difference in platelet counts from day 0 to day 2 (ΔPlt [D 0-2]) was significantly lower in the VD group (- 39 × 109/L, interquartile range [IQR]: - 47 to - 24 × 109/L) than the CS group (15 × 109/L, IQR: - 6.5 to 33 × 109/L) (p < 0.001). The median ΔPlt (D 0-5) was significantly lower in the VD group (- 55 × 109/L, IQR: - 85 to - 31 × 109/L) than the CS group (33 × 109/L, IQR: 1-69 × 109/L) (p < 0.001). Multivariate analysis also showed a significant association of delivery mode with ΔPlt (D 0-2) and ΔPlt (D 0-5) (both p < 0.001). VD neonates with platelet counts ≥ 100 × 109/L at birth were significantly more likely than CS neonates to develop thrombocytopenia < 100 × 109/L at nadir (1/26 vs. 6/25) (p = 0.0496). Our findings indicate that mode of delivery is a useful predictor of postnatal platelet count dynamics in neonates born to mothers with ITP.

Epidemiology of group B streptococcal disease in infants younger than 1 year in Japan: a nationwide surveillance study 2016-2020.

We aimed to define the burden and clinical features of invasive group B streptococcus (GBS) disease in infants younger than 1 year in Japan, to explore transmission route of late-onset disease (LOD), and to identify risk factors associated with recurrent GBS disease. We conducted a retrospective, questionnaire-based nationwide surveillance study between 2016 and 2020. A total of 875 GBS cases were identified, including 186 early-onset disease, 628 LOD, and 61 ultra-late-onset disease. Case fatality rate in each age category was 6.5%, 3.0%, and 3.3%, respectively. Patients with meningitis had neurodevelopmental sequelae in 21.5% (64/297). Annual incidence in infants younger than 1 year and in LOD significantly increased from 0.28 to 0.45/1000 livebirths (p = 0.021) and from 0.19 to 0.29/1000 livebirths (p = 0.046), respectively. Maternal colonization status at the LOD diagnosis was available for 148 mothers, of whom 21/58 (36.2%) had positive rectovaginal swabs and 42/117 (36.2%) had GBS in breastmilk culture. These two sites are potentially infectious routes in LOD. The four leading disease-causing serotypes III, Ia, Ib, and V represented 95% of the available serotypes. Thirty-one recurrent cases were identified, accounting for 3.7% of total patients. A multivariate regression analysis showed that prematurity (p = 0.029) and antepartum maternal GBS colonization (p = 0.032) were significantly associated with risk for the recurrence. Our findings indicated that GBS disease burden still remains with considerable mortality and morbidity in Japan, and provided important information for developing better strategies for the prevention of GBS disease, including maternal vaccination.

Favorable prognosis of vaccine-associated immune thrombocytopenia in children is correlated with young age at vaccination: Retrospective survey of a nationwide disease registry.

Childhood vaccine-associated immune thrombocytopenia (ITP) has a mostly favorable prognosis. To identify factors associated with prognosis, a retrospective survey was conducted with children with ITP who were registered in the Japanese Society of Pediatric Hematology/Oncology registry from 2008 to 2011. A total of 477 patients were categorized into four groups by event preceding ITP onset: vaccine-precedence (VP; n = 43), vaccine/infection-precedence (VIP; n = 34), infection-precedence (IP; n = 162), and no vaccine/infection-precedence (NVI; n = 238). Compared to IP and NVI, VP and VIP were significantly younger at diagnosis, with the age distribution peaking at infancy, and more frequently had favorable prognosis. Time to platelet recovery to 100 × 103/µL was significantly faster for VP and VIP than NVI. Multivariate Cox regression analysis with sex, age at diagnosis, infection-precedence, and vaccine-precedence as variables revealed age < 36 months (HR 0.992, 95% CI 0.989-0.995; p < 0.001) and male sex (HR 0.770, 95% CI 0.623-0.952; p = 0.015) as associated factors, but not infection-precedence (p = 0.149) or vaccine-precedence (p = 0.650). In subgroup analysis in patients < 36 months, age at diagnosis (p < 0.001) was the only associated factor. Favorable prognosis of childhood vaccine-associated ITP is correlated with young age at vaccination, but not with vaccination itself.

Incidence of Kawasaki disease before and during the COVID-19 pandemic: a retrospective cohort study in Japan.

Background: Epidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology. During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms. The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections. Methods: A retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan. We collected information of hospitalised KD children in Kobe. Child population was identified through the resident registry system. Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system. Monthly change of KD incidence was analysed using a difference-in-difference regression model. Results: Throughout the study period, 1027 KD children were identified. KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic. The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016-2019 (165/year). Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0-4 years in 2016-2020, respectively. The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (-15.8, 95% CI -28.0 to -3.5), compared with that in 2016-2019. Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic. There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19. Conclusion: This study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan. This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD.

Late onset group B streptococcus disease manifesting as acute suppurative parotitis.

Few patients with acute suppurative parotitis (ASP) due to group B streptococcus (GBS) have been documented. Limited data on clinical and microbiological features and infectious route are available. We present a 21-day-old boy with invasive GBS disease manifesting as ASP. The patient was admitted because of irritability, fever, and erythematous swelling over the right parotid area. No purulent material exuded from the Stensen's duct. Ultrasonography and computed tomography of the neck showed findings indicative of ASP. On the day after admission, blood culture yielded GBS. The isolate was determined as GBS serotype Ia and sequence type-23, and the patient was successfully treated with intravenous ampicillin for 10 days. A review of the literature revealed 11 GBS ASP infants including ours with age at onset between 13 days and 12 weeks. All infants had bacteremia while pus from the Stensen's duct was detected in only one case. This finding remarkably contrasts with ASP caused by pathogens other than GBS, where the infection usually spreads via a retrograde route from Stensen's duct. The present case and literature review indicate GBS ASP primarily arises from bloodstream infection, and that ASP should be included in an infectious focus as late onset GBS disease.

[EARLY CHILDHOOD-ONSET PORK-CAT SYNDROME DUE TO SENSITIZATION BY BOTH CATS AND DOGS -A CASE REPORT].

We present a case of early childhood-onset pork-cat syndrome possibly due to sensitization by both cats and dogs. A 6-year-old girl was referred to our hospital because of repetitive episodes of urticaria when she consumed pork meat. The patient lived with a dog and the ground floor of her house was a veterinary clinic run by her veterinarian parents. Blood tests demonstrated high specific IgE (≥50UA/ml) against cat dander, dog dander, pork, Sus s 1, Fel d 2, Can f 1, Can f 2, and Can f 3. The skin prick test was positive for raw pork and beef. Western blotting analysis detected hot spots on 67-kDa proteins in pork meat and cat dander extract. Cross-reactivity between these two proteins was confirmed by an inhibition test. Furthermore, crossreactivity between pork meat and dog dander extract was also noted. Taken together, the diagnosis of porkcat syndrome was made, and both cats and dogs were suggested to have led to the sensitization. The patient was advised to only eat well-cooked pork, and has been followed thereafter without additional reactions. The previously reported cases of this syndrome developed during adolescence and young adulthood because a considerable period from the sensitization to the development cross-reactivity with pork meat is required. To our best knowledge, this is the youngest reported case of pork-cat syndrome among English and Japanese literatures. The nomenclature of this syndrome as pet animal-meat syndrome improves the understanding of the underlying pathogenesis of cross-reactivity between animal albumins and meat albumins.

Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death.

We report a case of a neonate with Noonan syndrome presenting with concurrent hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia, which resulted in premature death. Cases with Noonan syndrome diagnosed during the neonatal period might not necessarily show mild clinical course, and premature death is a possible outcome to be considered.

Low Incidence of Osteonecrosis in Childhood Acute Lymphoblastic Leukemia Treated With ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group.

Purpose Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON. Patients and Methods The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively). Results In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P < .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols. Conclusion We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.

Invasive meningococcal disease due to ciprofloxacin-resistant Neisseria meningitidis sequence type 4821: The first case in Japan.

We present a 4-year-old girl who developed invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup C sequence type (ST)-4821. She was hospitalized due to fever, vomiting, rash and altered consciousness. Serogroup C N. meningitidis was isolated from blood culture taken on admission and was confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, a biochemical test, and molecular microbiological analysis. The patient was successfully treated with 50 mg/kg ceftriaxone every 12 hours for 7 days without any complications. The isolate was susceptible to a wide variety of ß-lactams and rifampin but was resistant to ciprofloxacin. The isolate harbored gyrA T91I and parC S87I mutations at the quinolone-resistance-determining regions. Multi-locus sequence typing revealed the isolates as ST-4821, which was identical to an endemic clone frequently detected in China. However, neither the patient nor her family members had traveled abroad. To our knowledge, this report is the first to describe an IMD patient caused by ciprofloxacin-resistant N. meningitidis ST-4821 in Japan, and is the first community-acquired IMD case due to this strain outside of China. The high proportion of ciprofloxacin resistance and hypervirulent features of this ST-4821 strain raise special public health concerns. We still consider ciprofloxacin is still appropriate drug for post-exposure chemoprophylaxis in Japan. However, nationwide surveillance for susceptibility of IMD isolates is necessary to establish the regional antibiogram, and thereby to avoid chemoprophylaxis failure.

Recurrence of Escherichia coli meningitis in a preterm infant and co-infection of echovirus 18.

Introduction: Bacterial meningitis may relapse after adequate antibiotic treatment. In most cases, however, the pathophysiology cannot be identified. Presentation of case: We describe a preterm infant with recurrent episodes of meningitis due to infection with an identical Escherichia coli strain both at birth and at 10 days after cessation of a 3 week course of appropriate antibiotic treatment. At the time of recurrence, the patient presented with fulminant severe cardiac failure due to acute myocarditis, coupled with a concurrent echovirus 18 infection (confirmed by stool culture and serological analysis). Conclusion: Co-infection by echovirus may underlie recurrence of Escherichia coli meningitis in this case.

Group B streptococcal disease in infants in the first year of life: a nationwide surveillance study in Japan, 2011-2015.

PURPOSE: This study aimed to describe the epidemiology of childhood group B streptococcus (GBS) disease including late late-onset disease (LLOD) and to clinically characterize recurrent cases and twin-sibling cases in Japan. METHODS: We collected information on infants (<1 year of age) with invasive GBS disease and institutional information about births and transfers through a nationwide questionnaire between 2011 and 2015. RESULTS: We identified 133 infants with early-onset disease (EOD), 274 late-onset disease (LOD), and 38 LLOD from 149 institutes. The case fatality rate (CFR) of EOD, LOD, and LLOD was 4.5, 4.4, and 0%, respectively. CFR in EOD was significantly (P < 0.001) associated with preterm birth, but not that in LOD and LLOD. Twenty-nine percent of infants with meningitis (49/169) had neurologic sequelae. We showed clinical details of 12 recurrent cases that accounted for 2.8% of the total patients, and 4 sets of both twins affected; 4 of 12 recurrent cases and 3 of 4 twin-sibling sets were also associated with preterm birth. Based on the livebirth number of 581,488, the instituted-based incidence of EOD, LOD, and LLOD was estimated as 0.09 (95% CI 0.06-0.11), 0.12 (95% CI 0.11-0.14), and 0.01 (95% CI 0.01-0.02) per 1000 livebirths, respectively. CONCLUSIONS: CFR of EOD and LOD in Japan is comparable with that in high-income European countries or the United States, and their incidence is much lower. Our findings also describe the clinical details of LLOD, recurrent infections, and infections in twin siblings. This study is the largest among Asian childhood GBS studies ever reported.