小澤 慶

We encountered a previously healthy 3-year-old girl with interstitial pneumonitis that initially developed due to human adenovirus type 2 infection and exacerbated by primary human herpesvirus 7 infection. A comprehensive serum biomarker analysis showed patterns that differed by viral infection, suggesting that respiratory and lymphotropic viral infections might have different pathophysiology in interstitial pneumonitis.

Multisystem inflammatory syndrome in children (MIS-C) was reported as a severe complication of coronavirus disease 2019; an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and was suggested to be associated with Kawasaki disease (KD) in terms of severe systemic inflammation and mucocutaneous symptoms. Because severe gastrointestinal symptoms and systemic shock are more frequently observed with MIS-C, patients with mild MIS-C might have been diagnosed with KD. In this study, titers of IgG antibodies against the SARS-CoV-2 S (S-IgG) and N proteins (N-IgG) were measured in 99 serum samples collected from patients with KD treated between January 2020 and December 2021 to evaluate the relationship between KD and SARS-CoV-2 infection. S-IgG were detected in only one patient out of 99 patients. This patient had coronavirus disease 2019 (COVID-19) 10 months before KD onset, and was unlikely MIS-C. According to characters of S-IgG and N-IgG, the patients was unlikely infected with SARS-CoV-2 just before the onset of KD. In addition to this study, the 26th Nationwide Survey and previous studies showed an association between KD and SARS-CoV-2 to be unlikely. In conclusion, SARS-CoV-2 infection was not observed in patients with KD until Delta predominance in Japan by the method of detecting SARS-CoV-2 IgG.

OBJECTIVES: Intestinal rotavirus (RV) vaccine replication and host immune response are suggested to be affected by several factors, including maternal antibodies, breastfeeding history, and gut microbiome, which are thought to be similar in pairs of twins. The aim of this study was to determine whether viral shedding from the fecal RV vaccine strain Rotarix® (RV1) and IgG and IgA responses to RV show similarity in pairs of twins. METHODS: Quantitative reverse transcription polymerase chain reaction specific to RV vaccine strain RV1 was used to monitor fecal RV1 viral shedding. RV IgG and IgA titers were measured using an in-house enzyme-linked immunosorbent assay. Fecal RV1 viral shedding and immune responses were compared between twins and singletons with mixed effects and fixed effects models. RESULTS: A total of 347 stool and 54 blood samples were collected from four pairs of twins and twelve singletons during the observation period. Although the kinetics of fecal RV1 viral shedding and immune responses differed among vaccinated individuals, they appeared to be similar within twin pairs. RV shedding after the first dose (P=0.049) and RV IgG titers during the entire observation period (P=0.015) had a significantly better fit in the fixed effect model that assumed that twins have the same response versus the model that assumed that twins have a different response. CONCLUSIONS: The similarity of RV vaccine viral replication in intestine and host immune responses in twin pairs was demonstrated using statistical analysis.

Abstract Nonpharmaceutical interventions (NPIs) to control COVID‐19 have decreased the incidence of many pediatric infectious diseases. The epidemiology of β‐ and γ‐herpesvirus infections might have been affected by NPIs. The aim of this study was to elucidate changes in trends in β‐ and γ‐herpesvirus infections and complex febrile seizures (cFS) of viral etiology before and during the COVID‐19 pandemic. Between April 2017 and March 2021, febrile children aged ≤5 years were enrolled. Detection of EBV, CMV, HHV‐6B, and HHV‐7 DNA in serum was performed using real‐time PCR. The epidemiology of viral infections and cFS were compared between the prepandemic and pandemic periods. During the observation period, 1432 serum samples were collected. The mean number of febrile children decreased during the pandemic period, but the number of patients with HHV‐6B infection increased from 35 (9.3% of all febrile children) per year before the pandemic to 43 (15.5%) during the pandemic. The change in the proportion of patients with primary HHV‐6B infection was 6.50% (95% confidence interval [CI], 2.05%–11.3%; p = 0.0047). The mean number of patients with cFS decreased during the pandemic period, but the number of patients with HHV‐6B–associated cFS was stable throughout the observation period. Therefore, the change in proportion of patients with cFS caused by primary HHV‐6B infection was 49.5% (95% CI, 12.2%–60.5%; p = 0.0048). The disease burden of primary HHV‐6B infection among patients in the emergency room remained unchanged, with a significant increase in the relative proportion after the COVID‐19 pandemic began.

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.

In the era of universal varicella vaccination, diagnosis of varicella is challenging, especially for breakthrough cases. We sought to clarify the reliability of direct varicella-zoster virus (VZV) loop-mediated isothermal amplification (LAMP) and DermaQuick® VZV using the immunochromatography technique as rapid diagnostic tests for varicella. In addition, the usefulness of saliva as a sample type for direct LAMP was investigated. Among the 46 enrolled patients with suspected VZV infection, 31 patients (67.3%) were positive for the nucleic acid test based on real-time PCR from skin swab samples. Direct LAMP of skin swabs was positive in 29 (63.0%) of 46 patients. DermaQuick® VZV was positive in 25 (54.3%) of 46 patients. VZV DNA was detected in only 48.4% of oral swabs with the direct LAMP method. With real-time polymerase chain reaction (PCR) as the standard for diagnosing varicella, the sensitivity and specificity of DermaQuick® VZV were 80.7% and 100%, respectively. The sensitivity and specificity of direct LAMP from skin swabs were 93.6% and 100%, respectively. The sensitivity and specificity of real-time PCR for DNA extracted from oral swabs were 74.2% and 93.3%, respectively. Thus, oral swab samples are not suitable for breakthrough varicella diagnosis. Although DermaQuick® VZV is considered the most convenient point-of-care test for varicella, its sensitivity and specificity were lower than those of direct VZV LAMP.

Eczema herpeticum (EH) is a disseminated cutaneous infection with herpes simplex virus (HSV) that develops in patients with atopic dermatitis. The kinetics and clinical significance of HSV viremia in EH are poorly understood. Herein, we report HSV DNAemia in a child with EH 12 months after the completion of chemotherapy for Hodgkin lymphoma.

We analyzed serially collected serum samples from healthy adults who underwent BNT162b2 vaccination to elucidate the association between spike (S)-IgG antibody titers determined by ELISA using the WHO international standard (NIBSC code 20/136) and neutralizing antibody titers against three live SARS-CoV-2 variants. This study included 53 health care workers who received two doses of the BNT162b2 vaccine. S-IgG and nucleocapsid (N)-IgG antibody titers were measured by ELISA. Neutralizing (NT) antibody responses against three variants (Wuhan D614 G: KUH003, Alpha, and Delta) were evaluated before and after the first and second vaccination. N-IgG were not detected in any serum samples. S-IgG antibody titers remarkably increased after two BNT162b2 vaccine doses in all participants. S-IgG antibody titers were strongly correlated with NT titers against three variants of live viruses: KUH003 (r = 0.86), Alpha (r = 0.72), and Delta (r = 0.84). Serum samples from participants after one dose of BNT162b2 neutralized Alpha efficiently (median titer, 113.0), but median NT titers against KUH003 and Delta variants were lower, 57.0 and 28.0, respectively (p < .01). Two doses of the BNT162b2 vaccine elicited a strong immune response in this study. The second dose was required for induction of a strong booster effect. Serum collected from BNT162b2 vaccine recipients contained significantly lower neutralizing activity against Delta than that of against KUH003 (p < .0001) and Alpha (p < .0001). If a new variant emerges, live virus-based NT titers should be examined in serum obtained from vaccine recipients to evaluate vaccine efficacy for protection against infection.

Rotavirus (RV) is a leading cause of gastroenteritis in children. In Japan, Rotarix (RV1; GlaxoSmithKline), which is a monovalent vaccine derived from human RV (G1P[8]), has been introduced since November 2011, and RotaTeq (RV5; MSD) which is an pentavalent, human-bovine mono-reassortant vaccine (G1, G2, G3, G4, and P1A[8]), has been introduced since July 2012. Long-term follow-up on vaccine efficacy and RV genotypical change should be carried out in order to control RV infection. The RV gastroenteritis (RVGE) outbreak occurred during the 2018/2019 season in Aichi prefecture, Japan. Therefore, the molecular epidemiology of RV among three different groups of RVGE, which were outpatients who received RV1, those who received RV5, and those without vaccination, was explored. Clinical features of RVGE patients were compared among the three patient groups. Children less than 15 years of age with gastroenteritis who visited any of seven pediatric practices between January and June 2019 were enrolled in the study. G, P, and E genotypes were determined by direct sequencing of reverse transcription-polymerase chain reaction products amplified from stool samples. Among 110 patients, there were 27, 28, and 55 in the RV1-vaccinated, RV5-vaccinated, and unvaccinated groups, respectively. The most frequent genotype was G8P[8] (92/110 patients, 83.6%). Genotype distributions did not significantly differ among the three patient groups (P = .125). Mean Vesikari score was significantly lower among RV1-vaccinated (7.1) and RV5-vaccinated patients (6.4) than among unvaccinated patients (10.2) (P < .001). Even in RVGE patients treated in an outpatient clinic, RV vaccine reduced the severity of the disease in this cohort.

Here, we present a previously healthy adolescent with aseptic meningitis without skin rash caused by varicella vaccine derived from the Oka/Biken strain; the patient received a single dose of varicella vaccine at 1 year of age. Pediatricians should be aware of the potential for reactivation of varicella vaccine derived from the Oka/Biken strain, which can cause aseptic meningitis in vaccinated children even in the absence of a skin rash.

HHV-6 and HHV-7 can reactivate in the salivary gland in response to various host stresses. Lactococcus lactis strain Plasma (LC-Plasma) can activate plasmacytoid dendritic cells (pDCs) and decrease viral infection. We investigated whether LC-Plasma intake could decrease HHV-6 and HHV-7 reactivation in the salivary gland. A total of 54 healthy volunteers were enrolled in this study. Participants took LC-Plasma granules daily for 6 weeks. Saliva samples were collected from subjects weekly for 4 weeks before (first), during (second), and after (third period) LC-Plasma intake. There was a 2-week interval between the first and second periods and a 3-week interval between the second and third periods. Mean salivary HHV-6 and HHV-7 DNA loads were compared among the three observation periods. In the first period (baseline data of viral DNA shedding), HHV-6 DNA shedding was significantly higher in subjects under 40 years old, and HHV-7 DNA shedding was significantly higher in males. HHV-6 and HHV-7 DNA loads did not significantly differ between periods. Meanwhile, in a subgroup analysis of the subjects under 40 years old, HHV-6 DNA load was significantly lower in the second period than in the first period. LC-Plasma decreases HHV-6 reactivation in the salivary glands in younger adults.

<title>Abstract</title> <sec> <title>Background</title> Human herpesvirus 6 (HHV-6) can be genetically transmitted from parent to child as inherited chromosomally integrated HHV-6 (iciHHV-6). HHV-6 reactivation occurs in pregnant women with iciHHV-6. We found no sex differences in the frequency of index cases with iciHHV-6 but inheritance from the father was more common. We evaluated the association between iciHHV-6 status and spontaneous abortion. </sec> <sec> <title>Methods</title> iciHHV-6 was confirmed by high viral DNA copy numbers in whole blood and somatic cells. The origin of integrated viral genome, paternal or maternal, was examined using the same method. The pregnancy history of 23 mothers in families with iciHHV-6 and 285 mothers in families without iciHHV-6 was abstracted. </sec> <sec> <title>Results</title> Of 23 iciHHV-6 index cases, 8 mothers and 15 fathers had iciHHV-6. Spontaneous abortion rates in mothers with and mothers without/fathers with iciHHV-6 and mothers in families without iciHHV-6 were 27.6%, 10.3%, and 14.8%, respectively (P = .012). Mothers with iciHHV-6 (odds ratio [OR], 6.41; 95% confidence interval [CI], 1.10–37.4) and maternal age at the most recent pregnancy ≥40 years (OR, 3.91; 95% CI, 1.30–11.8) were associated with 2 or more spontaneous abortions. </sec> <sec> <title>Conclusions</title> Mothers with iciHHV-6 is a risk factor for spontaneous abortion. </sec>

OBJECTIVE: The aim of this study was to elucidate vaccine effectiveness (VE) during varicella outbreaks in schools and nurseries in Japan. METHODS: An outbreak was defined as emergence of three or more cases of varicella within 21 days at the same institute. Clinical information such as varicella vaccination status, and history of varicella was collected. If a child had varicella during the outbreak, information about absences, fever, and disease severity was collected. RESULTS: From September 2018 to January 2020, four outbreaks were reported around our institute from three elementary schools and one nursery. A total of 676 children were analyzed in this study. Seventy-six children (11.2%) were unvaccinated, 309 (45.7%) had received one dose of vaccine, and 291 (43.0%) had received two doses. Most children in Pre-K2 (1-2 years old) to Pre-K6 (5-6 years old), who were the targets of the national immunization schedule, received two doses. Meanwhile, most children older than third grade received single dose. Seventy-five children (11.1%) had varicella. Varicella prevalence from Pre-K5 to the third grade was greater than 10%. The adjusted VEs of single- and two-dose of varicella vaccine were 57.8% and 89.0%. The number of days absent was significantly longer in unvaccinated children than single-dose recipients (P = 0.0145). Unvaccinated children had significantly more severe skin eruptions than single-dose recipients (P = 0.0046) and two-dose recipients (P = 0.0258). CONCLUSIONS: Although VEs of single-dose varicella vaccination during outbreaks was not high, the VE of two-dose vaccination was similar to that in a previously reported case-control study.

Pediatric cases of the coronavirus disease 2019 (COVID-19) are generally mild or asymptomatic, and are usually detected by virological examination following close contact with COVID-19 patients, often the children's parents. The detailed clinical features and virological data of pediatric patients with COVID-19, particularly young infants, remain unclear. Here, the clinical and virological characteristics of four children with COVID-19 including two young infants were investigated. One- and 4-month-old boys with COVID-19 were both asymptomatic, and seroconversion was demonstrated. These findings suggest that even young infants can mount an immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite having weaker immune defenses than adolescents and adults. Three-year-old boy, who was SARS-CoV-2-negative, was admitted to the same room as his SARS-CoV-2-positive father due to the lack of caregivers. Although he was asymptomatic, he had seroconverted to SARS-CoV-2. Eleven-year-old boy, who was sibling of the 3-year-old boy, was also SARS-CoV-2-negative. He was isolated in his own room and did not seroconvert. If young children are SARS-CoV-2 negative, they should be isolated from their SARS-CoV-2-positive parents. This may be difficult in practice, if parents with COVID-19 are the only available caregivers. In such situations, the most appropriate measures should be taken for each patient.

BACKGROUND: Entire genome of human herpesvirus 6 (HHV-6) that integrates into human chromosomes is called chromosomally integrated HHV-6 (ciHHV-6). Several viral infections have been suggested to be involved in autoimmune connective tissue diseases (CTDs). Reactivated HHV-6 from the integrated viral genome can induce immune responses against the virus. Thus, it is plausible that ciHHV-6 is associated with autoimmune CTDs. OBJECTIVES: We sought to determine whether the prevalence of ciHHV-6 was significantly higher in patients with autoimmune CTDs than in a healthy population. STUDY DESIGN: A total of 846 peripheral blood samples collected from autoimmune CTD patients were analyzed. Since there was a large number of samples, they were pooled into 24 samples per group. Copy numbers of HHV-6 DNA were measured by real-time PCR. The threshold level for distinguishing between ciHHV-6 and active viral infection and the reliability of pooled DNA analysis were examined as initial validation experiments. RESULTS: The threshold level was 1.6 × 10^6 copy/mL in whole blood. The reliability of pooled DNA analysis to identify one ciHHV-6 sample among 23 HHV-6 DNA-negative samples was high. No HHV-6 DNA was detected in any of the pooled DNA samples collected from the patients. The probability of the present study including the 846 autoimmune CTD patient's samples was statistically not different with a healthy Japanese population which was 0.2 % or 0.6 %. CONCLUSIONS: There was no significant difference in the prevalence of ciHHV-6 between a healthy population and patients with autoimmune CTDs.

OBJECTIVE: To elucidate the trend and clinical spectrum of virologically diagnosed varicella patients after implementation of universal vaccination as a national immunization program in Japan. PATIENTS AND METHODS: Study subjects were patients suspected of varicella, less than 15 years of age, who visited 14 pediatric clinics in the Nagoya VZV Study Group from September 2015 to August 2019. Practitioners collected patient samples and information such as backgrounds, clinical symptoms, and previous immunization status. All patients were confirmed as having varicella based on molecular diagnostic assays. RESULTS: Varicella zoster virus (VZV) DNA was detected in swab samples from 506 (83.1%) of the 609 suspected patients. The 455 varicella patients for whom vaccination status was available were divided into two groups: 180 universal vaccination targets and 275 non-targets. Numbers of monthly varicella patients decreased gradually during the observation period. In the 2016/17 season, the seasonal epidemic of varicella became undetectable in the universal vaccination target group, and starting in the 2017/18 season, it was obscured even in the non-target group. The median age of patients was significantly lower in the universal vaccination target group (3 years) than the non-target group (7 years) (P < 0.001). Vaccination status differed significantly between the two groups (P < 0.001). Most varicella patients were in the non-target group, especially those who had been vaccinated once (60.4%). Frequency of fever (P < 0.001) and number of skin rashes at the time of the first hospital visit (P = 0.001) were significantly higher in the non-target group. CONCLUSIONS: Although the number of childhood varicella patients declined after implementation of national immunization with two doses of varicella vaccination, sporadic outbreaks still occurred, mainly in the non-universal vaccination target group. Insufficient vaccination of members of this group is likely to be a major reason for small local outbreaks.

Varicella-zoster virus (VZV) reactivation from the enteric nervous system can cause ileus (Ogilvie's syndrome) in adult patients. Since no pediatric cases have been described, we sought to retrospectively analyze VZV reactivation in pediatric hematology-oncology patients to determine whether VZV infection including subclinical VZV reactivation can induce gastrointestinal complications such as Ogilvie's syndrome. Thirty-five patients who received chemotherapy at our institution between September 2013 and June 2018 were included. Serum samples were collected weekly during hospitalization and every 3 months during outpatient maintenance chemotherapy. A real-time polymerase chain reaction assay was used to measure VZV DNA load in serum. The clinical features of patients with VZV infection were retrospectively analyzed. Of 1165 serum samples, 7 (0.6%) were positive for VZV DNA. VZV DNA was detected in 3 of 35 patients. In patient A, VZV DNA was detected during two episodes. The first episode involved varicella-like eruptions caused by the Oka VZV vaccine strain. The second episode involved herpes zoster (HZ) caused by the same strain. Patients B and C had a clinical course that was typical for HZ caused by wild-type VZV. No gastrointestinal symptoms were observed at the time of VZV infection in these three patients. VZV DNA was not detected in any other samples. No pediatric cases with Ogilvie's syndrome caused by VZV reactivation were demonstrated in this cohort. Additionally, no subclinical VZV reactivation was found in this cohort. Further study is needed to elucidate the precise incidence of pediatric Ogilvie's syndrome caused by VZV reactivation.

Immunocompetent sisters with chromosomally integrated human herpesvirus 6A (HHV-6A) transiently excreted HHV-6B genome in their saliva. They did not have past histories of exanthema subitum but had antibodies against HHV-6A and HHV-6B. This suggests that endogenous HHV-6A may modify the clinical features of HHV-6B coinfection.