Hospital burden and characteristics of pediatric COVID-19 based on a multicenter collaborative retrospective study in Japan.

Objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant emergence preceded a wave of pediatric coronavirus disease 2019 (COVID-19) cases, putting considerable strain on hospitals across Japan. Our study evaluated the pediatric disease burden of COVID-19 in pediatric hospitals. Methods: This retrospective study evaluated all pediatric patients (defined as aged < 21 years) hospitalized with SARS-CoV-2 infection, or as close contacts, at four children's hospitals, between January 1 and May 31, 2022. Clinical characteristics, reasons for admission, and outcome data were analyzed. Results: In total, 492 patients (median age 3.0 years; male 58.7%) were included over the study period. Of these, 232 (47.2%) patients had at least one underlying disease. Asymptomatic and mild diseases were common during the study period (n = 451, 91.7%). Social reasons for hospitalization (including a lack of family support at home) accounted for 36.8% (n = 181) of inpatients. The median length of stay was 4.0 days. Fever was the most common symptom (n = 273, 55.5%), followed by upper respiratory (n = 77, 15.7%) and neurological (n = 60, 12.2%) symptoms. Overall, 34 (6.9%) children required invasive mechanical ventilation, 51 (10.4%) were admitted to the pediatric intensive care unit, and two (0.4%) died. COVID-19 vaccination rate was low (n =14/200, 7.0%). Conclusions: The disease burden during the Omicron-predominant period was attributable to asymptomatic and mild infections, and some patients were hospitalized for social reasons. To maintain a medical care system for critically ill patients, each medical facility must play a role according to its function.

Infectious Aneurysms Caused by Streptococcus Pyogenes in Children.

We describe the detailed clinical course of rapidly enlarging infective aneurysms during the treatment of endocarditis and purulent pericarditis caused by Streptococcus pyogenes . We show that S. pyogenes aneurysms can enlarge rapidly within 1-2 days. Moreover, we highlight the benefit of transporting patients to a facility offering multidisciplinary treatment, even if vital signs stabilize to the point.

Retropharyngeal Abscess Caused by Community-Acquired MRSA USA300 Clone in a 1-Year-Old Japanese Girl.

We describe a domestic case of retropharyngeal abscess (RPA) in a child caused by a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate that was genetically proven to be the USA300 clone (sequence type [ST]8-SCCmec IVa-Panton-Valentine leukocidin [PVL]). USA300 generally has a PVL gene, an epidemiologic association with severe and recurrent skin and soft tissue infection, and is the leading cause of RPA in the United States. A 1-year-old previously healthy girl visited the emergency department with fever, sore throat, and a difficulty in moving her neck. The patient had no recent medical exposure or history of travel abroad. Enhanced computed tomography revealed a bulky low-density area with ring enhancement in the retropharyngeal and right parapharyngeal spaces. MRSA was isolated from pus obtained from surgical drainage, and antibiotics were continued for a total of 21 days. MRSA was analyzed by whole genome sequencing and compared with representative USA300 isolates. The strain was typed as ST8-t9829-SCCmec IVa with PVL and arginine catabolic mobile element, and its sequence was 99.8% identical to USA300 isolates. The present case supports the possibility that USA300 is potentially spreading in the Japanese community and raises the possibility of USA300 invasive infections without a clear route of infection.

Invasive Haemophilus influenzae type b infection in a patient with transient hypogammaglobulinemia of infancy.

We describe a patient with invasive Haemophilus influenzae type b (Hib) infection despite being completely immunized by a conjugate Hib vaccine. Although Hib vaccination has contributed to significant reduction in invasive Hib infection, there are some case reports of invasive Hib infections despite immunization. Immunoglobulin (Ig) deficiency is the main cause of primary vaccine failure, and IgG2 subclass deficiency is known to be the leading cause. A previously healthy 13-month-old boy visited the outpatient clinic with a 5-day history of fever (40.0 °C), cough, and vomiting, and was diagnosed with bacterial meningitis, purulent pericarditis, and arthritis. Hib was recovered from blood, cerebrospinal fluid, and pericardial fluid. Immunological examination revealed subnormal IgG and IgA titers at 13 and 17 months of age. Serum IgG2 titer was recovered at 17 months of age despite being low at 13 months. Comprehensive gene analysis for primary immunodeficiency syndromes (primary antibody deficiency, common variable immunodeficiency, and toll-like receptor abnormalities) were negative. The antibody titer against Hib [anti-polyribosylribitol phosphate (PRP) antibody] was lower than the long-term protective titer (1.0 µg/ml) at 13 months of age, but was reactively increased to 2.38 µg/mL two months after booster immunization. Transient hypogammaglobulinemia of infancy (THI) is described as an accentuation and prolongation of the physiologic Ig nadir that is normally observed during infancy and defined as low IgG and IgA levels in the first three years of life. We speculate that he developed an invasive Hib infection as a result of primary Hib vaccine failure caused by THI.

Severe Liver Disorder Following Liver Transplantation in STING-Associated Vasculopathy with Onset in Infancy.

PURPOSE: STING-associated vasculopathy with onset in infancy (SAVI) is a type-I interferonopathy, characterized by systemic inflammation, peripheral vascular inflammation, and pulmonary manifestations. There are three reports of SAVI patients developing liver disease, but no report of a SAVI patient requiring liver transplantation. Therefore, the relevance of liver inflammation is unclear in SAVI. We report a SAVI patient who developed severe liver disorder following liver transplantation. METHODS: SAVI was diagnosed in a 4-year-old girl based on genetic analysis by whole-exome sequencing. We demonstrated clinical features, laboratory findings, and pathological examination of her original and transplanted livers. RESULTS: At 2 months of age, she developed bronchitis showing resistance to bronchodilators and antibiotics. At 10 months of age, she developed liver dysfunction with atypical cholangitis, which required liver transplantation at 1 year of age. At 2 years of age, multiple biliary cysts developed in the transplanted liver. At 3.9 years of age, SAVI was diagnosed by whole-exome sequencing. Inflammatory cells from the liver invaded the stomach wall directly, leading to fatal gastrointestinal bleeding unexpectedly at 4.6 years of age. In pathological findings, there were no typical findings of liver abscess, vasculitis, or graft rejection, but biliary cysts and infiltration of inflammatory cells, including plasmacytes around the bile duct area, in the transplanted liver were noted, which were findings similar to those of her original liver. CONCLUSION: Although further studies to clarify the mechanisms of the various liver disorders described in SAVI patients are needed, inflammatory liver manifestations may be amplified in the context of SAVI.

High Rate of Febrile Seizures in Japanese Children With Occult Bacteremia.

OBJECTIVES: Fever of 39°C or higher and a white blood cell (WBC) count of 15,000/µL or greater are known predictors of occult bacteremia (OB). However, because of a decreasing prevalence of OB, WBC counts have become poor predictors of OB in populations of routinely immunized children. Thus, we aim to evaluate the clinical characteristics of OB in Japanese children and identify potential risk factors for OB. METHODS: We conducted an observational study of children aged 3 to 36 months old with positive blood cultures for Streptococcus pneumoniae or Haemophilus influenzae at an emergency department in a tertiary care children's hospital between April 2002 and December 2015. Patients with significant underlying diseases, a proven source of infection, or toxic appearance, were excluded. RESULTS: Positive blood cultures were recorded in 231 patients; of these, 110 were included in the study (S. pneumoniae, n = 102; H. influenzae, n = 8). Median age was 16 (3-34) months. Patients had a high median body temperature of 39.2 (interquartile range, 38.6-39.9) °C and median WBC of 21,120 (interquartile range, 16,408-24,242)/µL. A high rate of febrile seizures (58 patients, 53%) was observed, with complex febrile seizures accounting for 43% of the episodes. Frequency of febrile seizures was positively associated with age (P = 0.001). CONCLUSIONS: Our study revealed a high rate of children presenting with febrile seizures, especially complex seizures, among children with OB in Japan. A further study is necessary to evaluate the role of febrile seizures as a predictor for OB.

Fever as a predictor of positive lymphocyte transformation test.

BACKGROUND: Few studies have characterized the clinical manifestations of delayed antibiotic hypersensitivity (AH) diagnosed using objective methods. The lymphocyte transformation test (LTT) is a reproducible method to diagnose type IV hypersensitivity. The purpose of the study was to evaluate the characteristics of delayed AH diagnosed on LTT in children. METHODS: We performed a retrospective analysis of patients who were evaluated for AH using LTT at National Center for Child Health and Development, Tokyo, from 2002 to 2014. We extracted patient demographics, type and duration of antibiotics, and clinical characteristics from the medical records. Clinical manifestations were compared between LTT-positive and LTT-negative cases. RESULTS: Seventy-five cases for which 101 drugs were tested were included in this study. LTT was positive against 34 drugs in 26 cases. Median age was 5 years (IQR, 1-9 years), and 49% of patients had underlying disease. LTT was performed at a median of 18 days (IQR, 4-59 days) after the suspected episode. The median number of days from the initiation of therapy to the onset of symptoms was 4. Rash was the most common manifestation (89%). Fever (>38°C) was observed in 20 cases (27%). Onset of fever preceded the rash in nine cases (45%), appeared simultaneously in five (25%), appeared afterwards in four (20%), and was unknown in two (10%). Fever was an independent factor associated with AH when comparing LTT-positive and LTT-negative cases (OR, 3.61; 95%CI: 1.03-12.64). CONCLUSIONS: Fever was a common presenting symptom of delayed AH in children aged ≤18 years.

Febrile seizures with leukocytosis as a predictor for occult bacteremia.

BACKGROUND: Febrile children 3-36 months old, who had a body temperature >39°C and white blood cell (WBC) count >15 000/mm3 were known to be at risk for occult pneumococcal bacteremia (OPB) in the pre-pneumococcal conjugate vaccine (PCV) era. The positive predictive value of these criteria, however, decreased dramatically after the introduction of PCV, indicating a need for alternative criteria. A high rate of febrile seizures has been noted in children with OPB, suggesting that screening may still be practical in this population. We performed a retrospective analysis to evaluate factors that predict OPB in patients visiting the emergency department (ED) with febrile seizures. METHODS: Children 3-36 months old who visited the ED for febrile seizures and had blood cultures taken were included. Patients with underlying diseases were excluded from analysis. We performed statistical analyses comparing patient demographics according to the presence or absence of OPB. RESULTS: One thousand and eighty-two patients visited the ED with febrile seizure, and blood cultures were taken in 397, of whom 87% had received more than three doses of PCV. Of the nine patients with OPB, eight (89%) met the risk criteria. In contrast, only 12% (48/388) of those without OPB met the criteria. In this population, those who fulfilled the risk criteria were more likely to have OPB than those who did not (14.3% vs 0.3%; likelihood ratio, 7.17). CONCLUSIONS: High WBC count and fever may effectively predict OPB in pediatric patients with febrile seizure in the post-PCV era.

Hidden diagnosis behind viral infection: the danger of anchoring bias.

Anchoring bias is one of the most common diagnostic biases that may lead to closed-minded thinking and could result in unnecessary tests, inappropriate patient management and even misdiagnosis. A 4-year-old boy was brought to the emergency department because of shaking chills. On the basis of bilateral swollen preauricular areas, high level of serum amylase and the prevalence of mumps, he initially received a diagnosis of mumps in spite of the shaking chills. However, blood culture turned out to be positive for two different kinds of bacteria. The patient finally received a diagnosis of polymicrobial bacteraemia resulting from suppurative appendicitis. We must consider and rule out bacteraemia in the differential diagnosis for patients who present with shaking chills, even in the presence of symptoms or information consistent with a more common viral infection such as mumps. In addition, intra-abdominal infection should be ruled out in the presence of polymicrobial enterobacteriaceae bacteraemia.

Small serum protein-1 changes the susceptibility of an apoptosis-inducing metalloproteinase HV1 to a metalloproteinase inhibitor in habu snake (Trimeresurus flavoviridis).

Viperidae snakes containing various venomous proteins also have several anti-toxic proteins in their sera. However, the physiological function of serum protein has been elucidated incompletely. Small serum protein (SSP)-1 is a major component of the SSPs isolated from the serum of a Japanese viper, the habu snake (Trimeresurus flavoviridis). It exists in the blood as a binary complex with habu serum factor (HSF), a snake venom metalloproteinase inhibitor. Affinity chromatography of the venom on an SSP-1-immobilized column identified HV1, an apoptosis-inducing metalloproteinase, as the target protein of SSP-1. Biacore measurements revealed that SSP-1 was bound to HV1 with a dissociation constant of 8.2 × 10⁻8 M. However, SSP-1 did not inhibit the peptidase activity of HV1. Although HSF alone showed no inhibitory activity or binding affinity to HV1, the SSP-1-HSF binary complex bound to HV1 formed a ternary complex that non-competitively inhibited the peptidase activity of HV1 with a inhibition constant of 5.1 ± 1.3 × 10⁻9 M. The SSP-1-HSF complex also effectively suppressed the apoptosis of vascular endothelial cells and caspase 3 activation induced by HV1. Thus, SSP-1 is a unique protein that non-covalently attaches to HV1 and changes its susceptibility to HSF.