Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fped.2019.00183

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Streptococcus pyogenes is an uncommon pathogen of purpura fulminans, and the pathogenesis of S. pyogenes-purpura fulminans remains unclear because of paucity of cases. We reported a pediatric case of S. pyogenes-purpura fulminans with literature review of the disease. CASE PRESENTATION: A 3-year-old boy showed limping, lethargy and acral gangrene within 24 h. A diagnosis of S. pyogenes-purpura fulminans was made for bacterial isolation from throat and peripheral blood. Intensive therapy led to a survival with amputation of the left distal metatarsal bone, and normal development. The isolated M12 carried no mutation of csrS/R or rgg. Thrombophilia or immunodeficiency was excluded. DISCUSSION: Twelve-reported cases (9 pediatric and 3 elderly) of S. pyogenes-purpura fulminans started with shock and coagulopathy. Five patients age < 8 years had no underlying disease and survived. One youngest and two immunocompromised patients died. CONCLUSION: Streptococcus pyogenes-acute infectious purpura fulminans is a distinctive rare form of aggressive GAS infections.

DOI： 10.1186/s12941-018-0282-9

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Langerhans cell histiocytosis (LCH) occurs as a clonal disease with enigmatic immune responses. LCH patients occasionally present with fever, although the significance remains elusive. We investigated the predicting factors for developing intractable disease of refractory and/or reactivated LCH. In total, 40 pediatric LCH patients managed in Kyushu University from 1998 to 2014 were enrolled. The medical records were analyzed retrospectively. Sixteen patients suffered from multisystem (MS) LCH involving risk organs (ROs) (n=4) or not (n=12). In total, 24 patients had single-system LCH affecting bone (multi n=8, single n=13), skin (n=2), or lymph node lesions (n=1). Eight patients had the intractable disease of 7 MS or 1 multibone LCH. Two patients died from MS LCH with or without RO involvement. Ten patients showed persistent fever (>38°C) at onset. Intractable cases had fever, RO and skin involvement, leukocytosis, coagulopathy, microcytic anemia, higher levels of soluble interleukin-2 receptor and C-reactive protein, more frequently at diagnosis. Multivariate analysis indicated that fever and skin lesions at diagnosis were independently associated with the intractability (odds ratio: fever, 35.5; 95% confidence interval, 3.0-1229.1; skin lesions, 24.6; 95% confidence interval, 1.9-868.7). Initial fever and skin involvement might predict the development of intractable and fatal-risk LCH even without the RO involvement.

DOI： 10.1097/MPH.0000000000001080

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Histiocytic necrotizing lymphadenitis (HNL), also called Kikuchi-Fujimoto disease, is a benign, self-limiting inflammatory disease with fever and painful cervical lymphadenopathy of unknown etiology. A lymph node biopsy is required for the definitive diagnosis because of no specific symptoms or laboratory findings for HNL. To establish the rapid non-invasive diagnostic method for this disease, we investigated genes specifically expressed in the patients by analyzing whole transcriptome using microarray analysis of peripheral blood mononuclear cells (PBMC). The top five up-regulated genes (IFI44L, CXCL10, GBP1, EPSTI1 and IFI27) in HNL were interferon-induced genes (ISGs). The expression levels of the up-regulated genes by microarray were verified by quantitative PCR. High levels of serum CXCL10 concentration were confirmed at the symptomatic phase of HNL patients. The expression levels of these 5 genes positively correlated with each other (r(2) = 0.28-0.60). The genes were also highly expressed in HNL lymph nodes. The discriminant analysis using the expression levels of these five genes distinguished HNL with 84% accuracy. The combination of up-regulated ISGs in HNL seemed to be a specific response induced by viral infections or autoantigens. An analysis of the gene expression profile of PBMC may provide a rapid non-invasive diagnosis of HNL.

DOI： 10.1007/s10875-013-9897-y

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

To determine the prevalence and clinical characteristics of patients with in Japan, we conducted a nationwide survey of primary immunodeficiency disease (PID) patients for the first time in 30 years. Questionnaires were sent to 1,224 pediatric departments and 1,670 internal medicine departments of Japanese hospitals. A total of 1,240 patients were registered. The estimated number of patients with PID was 2,900 with a prevalence of 2.3 per 100,000 people and homogenous regional distribution in Japan. The male-to-female ratio was 2.3:1 with a median age of 12.8 years. Adolescents or adults constituted 42.8% of the patients. A number of 25 (2.7%) and 78 (8.5%) patients developed malignant disorders and immune-related diseases, respectively, as complications of primary immunodeficiency disease. Close monitoring and appropriate management for these complications in addition to prevention of infectious diseases is important for improving the quality of life of PID patients.

DOI： 10.1007/s10875-011-9594-7

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A 12-year-old Japanese boy suffered from severe acute hepatitis and pancytopenia. The patient underwent successful bone marrow transplantation from an HLA-identical sister. Torque teno virus (TTV) DNA of genotype 1a and IgM-class antibody against the virus were detected in sera at the onset of hepatitis. TTV/1a DNA and anti-TTV/1a IgM antibody levels were undetectable on the 16th and 46th days after the onset of illness, respectively. Anti-TTV/1a IgG antibody was positive throughout the observation period. Sequential viral load and anti-TTV/1a IgM antibody suggested a primary infection of TTV/1a. Genomic sequence of the virus coincided with that of the original strain first isolated from human. TTV DNA was quantified at 130 copies in 10(5) bone marrow mononuclear cells, which suggested that infection of hematopoietic cells might be the cause of aplasia. This is the first report of TTV hepatitis-associated aplastic anemia assessed by the anti-TTV antibodies and viral load in peripheral blood and bone marrow.

DOI： 10.1007/s00431-009-1116-8

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A 13-month-old Japanese female with Haemophilus influenzae type b meningitis presented with unusually severe septic shock and cerebral infarction in half a day of fever. The initial therapy of plasma-derived activated protein C (Anact C) led to an impressive effect on the aggressive condition. However, purpura fulminans and the consistent decline of plasma protein C activity (<20%) required prolonged activated protein C therapy and gene analysis. The patient carried a novel heterozygous mutation of PROC (exon 4; 335 GAC>TAC, Asp46Tyr). This is the first report of infectious purpura fulminans in a protein C-deficient heterozygote. The clinical onset and treatment course adequately corroborated the aggravated immune/hemostatic reactions and the cytoprotective effects of activated protein C replacement in human heterozygous protein C deficiency. The monitoring of plasma protein C activity and sufficient administration of activated protein C product could improve the outcome of severe sepsis in children.

DOI： 10.1007/s00431-008-0816-9

Language：English   Publishing type：Research paper (scientific journal)  

A 13-yr-old boy developed post-transplant liver tumor. At three yrs of age, this patient underwent a histocompatible sibling donor BMT for severe aplastic anemia, after a conditioning with antithymocyte globulin and cyclophosphamide. He became a HBV carrier after BMT. Stable mixed chimerism and mild thrombocytopenia, but no active hepatitis continued. At age 13, abdominal pain was a sign of massive tumor. Extremely high levels of alpha-fetoprotein indicated the clinical diagnosis of hepatoblastoma that might be the first report as post-BMT malignancy. The necropsy specimens revealed that the tumor was recipient cell-origin and showed the histopathological features of both hepatoblastoma and hepatocellular carcinoma. Prolonged mixed chimerism and hepatitis virus infection might induce a rare oncogenesis after non-irradiated conditioning.

Language：English   Publishing type：Research paper (scientific journal)  

An 11-year-old boy with severe chronic active Epstein-Barr virus infection (CAEBV) underwent successful cord blood transplantation (CBT) after consecutive failure of peripheral blood and bone marrow transplantation from his HLA-mismatched mother. CB cells from an unrelated donor were infused after conditioning with total body irradiation (12 Gy), melphalan (120 mg/m(2)), and etoposide (600 mg/m(2)). Complete remission without circulating EBV-DNA has continued for 15 months after a delayed hematologic recovery. This is the first successful report of CBT for CAEBV. CB may therefore be an alternate source of stem cells for the curative treatment of CAEBV, despite the absence of EBV-specific cytotoxic T lymphocytes.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Immunology  

Background: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. Methods: We retrospectively analyzed patients with IL10RA deficiency in Japan. Results: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. Conclusion: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250).

DOI： 10.1007/s10875-024-01795-6

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Language：English   Publisher：International Journal of Hematology  

When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.

DOI： 10.1007/s12185-024-03786-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Haemophilia  

Introduction: Studies of treatment preferences in haemophilia have been conducted in many countries. This study is the first to examine treatment characteristic preferences among people with haemophilia (PWH) and their caregivers, and physicians in Japan. Aim: To examine current treatment preferences of PWH and their caregivers, plus those of physicians at haemophilia treatment centres (HTCs) and non-HTCs for different treatment characteristics in Japan. Methods: Physicians listed on a survey panel were invited to participate in the survey and to refer PWH and caregivers to participate in the survey. Web-based surveys were conducted to examine physician and PWH/caregiver background, prophylaxis background, prophylaxis goals, understanding of haemophilia treatment products, important information sources, preferences while choosing prophylaxis products, understanding of the patient's condition, and potential product switching. A discrete choice experiment exercise was included in the survey. Results: A total of 107 physicians and 44 PWH/caregivers participated in the study. Key treatment goals of physicians included optimisation of haemophilia management. PWH/caregivers were focused on quality of life and reduced treatment burden. Consistent differences in haemophilia treatment strategies at HTCs and non-HTCs were observed for prescribed treatments, preferences in choosing prophylaxis products, understanding of patients’ condition, and reasons for potential product switch. Conclusion: Our study utilises real-world survey data and presents preferences for haemophilia treatment characteristics among physicians, PWH and their caregivers in Japan, which could encourage improvements in individualised treatment and disease management. Alignment between treatment approaches at HTCs and non-HTCs could facilitate improvements in the quality of care for PWH across Japan.

DOI： 10.1111/hae.15028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Immunology  

The clinical spectrum of Down syndrome (DS) ranges from congenital malformations to premature aging and early-onset senescence. Excessive immunoreactivity and oxidative stress are thought to accelerate the pace of aging in DS patients; however, the immunological profile remains elusive. We investigated whether peripheral blood monocyte-derived dendritic cells (MoDCs) in DS patients respond to lipopolysaccharide (LPS) distinctly from non-DS control MoDCs. Eighteen DS patients (age 2-47 years, 12 males) and 22 controls (age 4-40 years, 15 males) were enrolled. CD14-positive monocytes were immunopurified and cultured for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and IL-4, yielding MoDCs in vitro. After the LPS-stimulation for 48 hours from days 7 to 9, culture supernatant cytokines were measured by multiplex cytokine bead assays, and bulk-prepared RNA from the cells was used for transcriptomic analyses. MoDCs from DS patients produced cytokines/chemokines (IL-6, IL-8, TNF-α, MCP-1, and IP-10) at significantly higher levels than those from controls in response to LPS. RNA sequencing revealed that DS-derived MoDCs differentially expressed 137 genes (74 upregulated and 63 downregulated) compared with controls. A gene enrichment analysis identified 5 genes associated with Toll-like receptor signaling (KEGG: hsa04620, P = 0.00731) and oxidative phosphorylation (hsa00190, P = 0.0173) pathways. MoDCs obtained from DS patients showed higher cytokine or chemokine responses to LPS than did control MoDCs. Gene expression profiles suggest that hyperactive Toll-like receptor and mitochondrial oxidative phosphorylation pathways configure the immunoreactive signature of MoDCs in DS patients.

DOI： 10.1093/cei/uxae048

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Arthritis and Rheumatology  

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor-α agents was effective for IBD– and CAPS-associated symptoms not resolved by canakinumab monotherapy. Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. (Figure presented.).

DOI： 10.1002/art.42808

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Language：English   Publisher：(一社)日本血液学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Perinatology  

OBJECTIVE: This prospective study compared PIVKA-II and PT-INR levels in infants who received two vitamin K (VK) prophylactic regimens. METHODS: A single institution administered 119 healthy newborns 2 mg of VK syrup. Infants were assigned to a 3-time regimen (n = 56) with VK at birth, five days (5D), and 1-month-old (1 M), or a 13-time regimen (n = 63) with VK at birth, 5D, and then weekly for 11 weeks. RESULTS: The 13-time regimen significantly lowered PIVKA-II and reduced PT-INR at 1 M in both breastfed (PIVKA-II: 18-16 mAU/mL, p = 0.02; PT-INR: 1.37-1.13, p < 0.01) and formula-fed infants (PIVKA-II: 18-15 mAU/mL, p = 0.01; PT-INR: 1.54-1.24, p < 0.01), compared to baseline measurements taken at 5D. The 3-time regimen did not significantly alter PIVKA-II levels and only improved PT-INR (2.00-1.50, p < 0.01) in formula-fed infants. CONCLUSION: The 13-time VK regimen significantly enhanced coagulation profiles more effectively than the 3-time regimen.

DOI： 10.1038/s41372-024-01981-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Haematology  

MYH9-related disorder (MYH9-RD) is characterized by congenital macrothrombocytopenia and granulocyte inclusion bodies. MYH9-RD is often misdiagnosed as chronic immune thrombocytopenia. In this study, we investigated age at definitive diagnosis and indicative thrombocytopenia in 41 patients with MYH9-RD from the congenital thrombocytopenia registry in Japan. Our cohort comprises 54.8% adults over 18 years at confirmed diagnosis. We found a significant difference (p < 0.0001) between the median age at definitive diagnosis of 25.0 years and for indicative thrombocytopenia it was 9.0 years. Our findings strongly suggest diagnostic delay of MYH9-RD in Japan. Our registry system will continue to contribute to this issue.

DOI： 10.1111/bjh.19484

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：エルゼビア・ジャパン(株)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Genetics and Genomic Medicine  

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, β-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

DOI： 10.1002/mgg3.2427

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Immunotherapy Advances  

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

DOI： 10.1093/immadv/ltae001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Hematology  

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

DOI： 10.1007/s12185-024-03721-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/μL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

DOI： 10.1002/pbc.30809

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Infectious Disease Journal  

DOI： 10.1097/INF.0000000000004230

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

DOI： 10.1002/pbc.30824

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ocular Immunology and Inflammation  

PURPOSE: This study aimed to assess the clinical features of pediatric uveitis at a tertiary referral center in Western Japan. METHODS: One hundred forty eyes of 80 patients aged <20 years at the time of uveitis onset, who visited Kyushu University Hospital between January 2010 and December 2019 were included in this study. Clinical records were retrospectively reviewed. Demographics, clinical findings, treatments, and visual prognoses were compared between the disease groups. RESULTS: Of 80 patients, 32 were males and 48 were females. The average age of onset was 12.5 ± 4.8 (0-19) years. Tubulointerstitial nephritis and uveitis (TINU) and juvenile idiopathic arthritis (JIA) were the most frequent causes, accounting for 11.3% and 10% of cases, respectively, followed by sarcoidosis (5%), Behçet's disease, acute anterior uveitis, Vogt-Koyanagi-Harada disease, and juvenile chronic iridocyclitis (3.8% each). Infectious uveitis accounted for 7.6% of the cases: cytomegalovirus was the most frequent agent. Of these cases, 43.8% were unclassified. Systemic therapies were administered to 87.5% of the patients with JIA, 33.3% of those with TINU, and 28.6% of the other diagnostic groups. In the unclassified group, 80% of the patients were followed up with only topical corticosteroids. LogMAR visual acuity of 0 or less accounted for more than 80% in the final examination. CONCLUSION: TINU and JIA were the most common causes of pediatric uveitis. Although each required systemic therapy, most unclassified cases of pediatric uveitis were managed by topical corticosteroids alone with good visual prognosis. Accurate diagnosis is important for pediatric uveitis management.

DOI： 10.1080/09273948.2023.2273363

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Language：English   Publisher：Journal of Infection and Chemotherapy  

Severe combined immunodeficiency (SCID) is one of the most serious inborn errors of immunity leading to a fatal infection in early infancy. Allogeneic hematopoietic cell transplantation (HCT) or elective gene therapy prior to infection or live-attenuated vaccination is the current standard of curative treatment. Even in the era of newborn screening for SCID, pretransplant control of severe infection is challenging for SCID. Multiple pathogens are often isolated from immunocompromised patients, and limited information is available regarding antiviral strategies to facilitate curative HCT. We herein present a case of successfully controlled pretransplant pneumonia after ribavirin and interferon-α therapy in an infant with RAG1-deficiency. A four-month-old infant presented with severe interstitial pneumonia due to a co-infection of rhinovirus and Pneumocystis jirovecii. The tentative diagnosis of SCID prompted to start antibiotics and trimethoprim-sulfamethoxazole on ventilatory support. Because of the progressive respiratory failure four days after treatment, ribavirin and then pegylated interferon-α were started. He showed a drastic response to the treatment that led to a curative HCT 32 days after admission. This patient received the genetic diagnosis of RAG1-deficiency. Currently, he is an active 3-year-old boy with normal growth and development. The review of literature indicated that rhinovirus had a comparable or rather greater impact on the mortality of pediatric patients than respiratory syncytial virus. Considered the turn-around time to the genetic diagnosis of SCID, prompt ribavirin plus interferon-α therapy may help to control severe rhinovirus pneumonia and led to the early curative HCT for the affected infants.

DOI： 10.1016/j.jiac.2023.11.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Immunology  

Microglia play versatile roles in progression of and protection against neuroinflammatory diseases. Little is known, however, about the mechanisms underlying the diverse reactivity of microglia to inflammatory conditions. We investigated how human induced microglia-like (iMG) cells respond to innate immune ligands. Quantitative PCR showed that poly-I:C and lipopolysaccharide (LPS) activated the expression of IL1B and TNF. Immunoreactivity of iMG did not differ between controls (n = 11) and patients with neuroinflammatory diseases (n = 24). Flow cytometry revealed that CD14high cells expressed interleukin (IL) -1β after LPS treatment. Immunoblotting showed that poly-I:C and LPS differentially activated inflammatory pathways but commonly induced mitochondrial instability and the expression of pyruvate kinase isoform M2 (PKM2). Furthermore, a potent stimulator of PKM2 (DASA-58) alleviated IL-1β production after LPS treatment. These data indicate that heterogeneous cell populations and mitochondrial stability underlie the divergent immunoreactivity of human iMG in environments.

DOI： 10.1016/j.clim.2023.109756

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

Introduction: Primary immunodeficiency diseases (PIDs) are rare inherited diseases resulting in impaired immunity. People with PID experience lower health-related quality of life (HR-QOL) and disease-related burdens in daily activities. This ongoing, prospective observational study aims to evaluate disease activity, treatment status, treatment-related burden, daily activities, and HR-QOL in patients with PID in Japan over a 1-year period. In this interim report (database lock: July 29, 2022), we present baseline results. Methods: Participants were enrolled between November 2021 and May 2022; data were collected four times/year per participant until May 2023 using an online electronic patient-reported outcomes system. Patients with PID and healthy volunteers aged ≥12 years, residing in Japan, and with access to a smartphone were eligible. HR-QOL (primary endpoint) was assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Work productivity was assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire. Other aspects of PID and burden were assessed with a new questionnaire developed in-house. The study is registered at the University hospital Medical Information Network clinical trials registry (UMIN000045622). Results: The full interim analysis set comprised 71 patients with PID and 47 healthy volunteers. The most common International Union of Immunological Societies PID category was primary antibody deficiency (56.3% of patients). Complications were common, especially recurrent respiratory tract infections (63.4%). Most patients with PID were treated with immunoglobulin replacement therapy (73.2%); 22.4% of these patients had serum immunoglobulin levels <700 mg/dL. Among patients who did not undergo hematopoietic cell transplantation, EQ-5D-5L (n=67) and SF-36 (n=59) Physical and Mental Component Summary scores were significantly lower than in healthy volunteers (p < 0.001). WPAI absenteeism, work productivity loss, and activity impairment scores were significantly lower in 42 working patients with PID than in 37 working healthy volunteers (p < 0.05). Other results indicated that patients with PID experience substantial burdens related to medical visits, expenses, work, and daily activities. Discussion: This interim analysis confirms that patients with PID in Japan have lower HR-QOL and work productivity compared with healthy individuals and experience substantial limitations and burdens in their daily lives.

DOI： 10.3389/fimmu.2023.1244250

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小児血栓症患者における遺伝素因の報告が増えている。小児期は年齢ごとに発症リスクが異なり,遺伝素因の寄与度も様々である。20歳までに発症する血栓症のうち遺伝素因が関与するものを"早発型遺伝性血栓症(early-onset thrombophilia,EOT)"として登録し,網羅的文献検索と併せて本邦患者の遺伝的背景と臨床経過を明らかにした。患者の60&#37;以上をプロテインC(PC)欠乏症が占め,その半分以上が片アレル変異の保有者だった。年齢とともにプロテインS(PS)およびアンチトロンビン欠乏症が増加して主体となった。6～8歳の発症はなかった。日本人高頻度・低リスクバリアントのPC-TottoriとPS-Tokushimaも確認されたが,前者は重症PC欠乏症の発症に寄与していなかった。解析した32家系中de novo発症は1家系のみで,周産期の同時発症母子例が3家系あった。PC欠乏症を標的に適切なEOTスクリーニングを行って周産期血栓症から母子を守ることが期待される。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

INTRODUCTION: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. METHODS: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28 days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18 months of age. RESULTS: Ninety-seven (58 %) of 168 eligible neonates were admitted to the hospital, and 71 (42 %) were not. The median admission rate in patients with disease onset at ≤14 days after birth (80 %) was significantly higher than that in patients with disease onset at ≥15 days (42 %). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100 days. Among 25 diseases treated in intensive care unit, 17 (68 %) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n = 58, 35 %) and physical examination (n = 34, 20 %). CONCLUSION: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

DOI： 10.1016/j.earlhumdev.2023.105869

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Journal of experimental medicine  

Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.

DOI： 10.1084/jem.20212276

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：国家公務員共済組合連合会  

脾膿瘍は稀な疾患で,発熱,腹痛,左上腹部圧痛,白血球増多などを来すが,その非特異性から診断に至るのが難しい.今回,生来健康な男児の多発性脾膿瘍を経験した.症例は10歳男児.発熱,腹痛があり,虫垂炎または腸炎として抗菌薬加療を行ったが,2週間後に再度発熱,腹痛を認め,造影CT検査で脾臓腫大および脾内に多発する低吸収域を認めた.原因精査で免疫不全や真菌感染症,結核等は否定的で,細菌性多発性脾膿瘍と診断した.脾膿瘍治療開始後の病勢評価は超音波検査で行った.コンベックス型プローブでは脾臓腫大のみの所見しか得られなかったが,高周波であるリニア型プローブでは脾内に低エコー域が観察された.臨床症状や血液検査所見が改善しMRI検査で所見が消失後も,超音波検査では低エコー域の残存を確認することができ,脾膿瘍の病勢評価に超音波検査が特に重要であると考えられた.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Immunology  

DOI： 10.1007/s10875-023-01543-2

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Language：English   Publisher：AJP Reports  

Ductus arteriosus aneurysm (DAA) asymptomatically occurs in newborn infants and resolves spontaneously. High-risk DAA with compression, rupture, and thrombosis requires early surgical intervention. Newborn infants have the highest risk of thrombosis among pediatric patients, but the genetic predisposition is difficult to determine in infancy. We herein report a neonatal case of massive thromboses in DAA and pulmonary artery. Desaturation occurred in an active full-term infant 2 days after birth. Echocardiography and contrast-enhanced computed tomography indicated thrombotic occlusion of the DAA and pulmonary artery thrombus. Urgent thrombectomy and ductus resection were successfully performed. After 6 months of anticoagulant therapy, the dissociated low plasma activity levels of protein S from protein C suggested protein S deficiency. A genetic study of PROS1 identified a heterozygous variant of protein S K196E, a low-risk variant of thrombophilia in Japanese populations. There have been seven reported cases with neonatal-onset symptomatic thromboses of DAA involving the pulmonary artery. All survived without recurrence after surgical intervention in five and anticoagulant therapy alone in two. Two newborns had a heterozygous methylenetetrahydrofolate reductase (MTHFR) variant, but information on thrombophilia was not available for any other cases. A genetic predisposition may raise the risk of DAA thrombosis, leading to rapid progression.

DOI： 10.1055/a-2101-7738

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Language：English   Publisher：Bone Marrow Transplantation  

DOI： 10.1038/s41409-023-01937-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.30047

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新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

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新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Haemophilia  

Introduction: Haemophilia B patients with factor IX inhibitors have particularly unmet needs for conventional therapy. Aim: Phase II/III clinical trial, multicentre, open-label, prospective, self-controlled study was conducted to assess MC710 prophylaxis in haemophilia B patients with inhibitors. Methods: We enrolled haemophilia patients who had received episodic or prophylactic treatment with bypassing agents up to that time. The participants continued their conventional therapy for 24 weeks and then MC710 was prophylactically infused intravenously every 2 or 3 days at 60 to 120 μg as FVIIa per kilogram of body weight for 24 weeks. The primary endpoint was the annual bleeding rate (ABR) requiring bypassing agents, which was compared intraindividually between the conventional therapy period and the MC710 prophylaxis period. Results: A total of 11 male haemophilia B patients were enrolled. The median ABR ratio for each participant (the prophylaxis period ABR divided by the conventional therapy period ABR) was.33 (2.1/6.5), range from.00 to 3.77. ABR ratios for 9 of the 11 patients ranged from.00 to.60, and 3 of the 9 patients had zero bleeding events during the prophylaxis period. Meanwhile, ABR ratios for the remaining two patients were 2.53 and 3.77, respectively. Although a fibrinogen decrease recovered by the dose reduction was reported for only one participant as the sole adverse drug reaction in this study, no thrombotic events or other safety concerns were reported. Conclusion: MC710 prophylaxis is considered to be decrease the bleeding rate in haemophilia B patients with inhibitors without safety concerns.

DOI： 10.1111/hae.14710

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Language：English   Publisher：Pediatrics and Neonatology  

DOI： 10.1016/j.pedneo.2022.09.012

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Language：English   Publisher：Frontiers in Pediatrics  

Muckle-Wells syndrome (MWS) is an autosomal dominant autoinflammatory disease recognized as the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS) caused by NLRP3 gene mutation. It often takes a long time before the diagnosis is made because the clinical presentation of MWS is variable. We report a pediatric case who had had persistently elevated serum C-reactive protein (CRP) level since infancy and was diagnosed with MWS by the development of sensorineural hearing loss in school age. The patient had no periodic symptoms of MWS until the development of sensorineural hearing loss. It is important to differentiate MWS in patients with persistent serum CRP elevation, even if no periodic symptoms, including fever, arthralgia, myalgia and rash, are observed. Furthermore, in this patient, lipopolysaccharide (LPS)-induced monocytic cell death occurred, but to a lesser degree than has been reported in patients with chronic infantile neurological cutaneous, and articular syndrome (CINCA). Because CINCA and MWS are phenotypic variants on the same clinical spectrum, this suggests that a further large-scale study is desired to investigate the association between degree of monocytic cell death and disease severity in CAPS patients.

DOI： 10.3389/fped.2023.1133097

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DOI： 10.1002/pbc.30250

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＜文献概要＞小児の血液疾患・悪性腫瘍は,日常診療においてありふれた症状や所見で発症し,感染症として治療を開始されることが多い.通常と異なる経過や長引く場合には,必ずこれらを鑑別に挙げて速やかに診療を進める.確定診断には専門施設での特殊検査が必要な場合もある.とくにOncologic/Hematologic emergencyの場合は,専門施設での治療開始までにかかる時間が予後を大きく左右する.非典型的な症状や経過を呈する例もあるが,他科との連携や遺伝子解析の進歩から,迅速で正確な診断を行う環境も整ってきた.近年のゲノム医療の実装を最大限に活用しながら,病態を正しく理解して,患者それぞれに最適な治療を選択していく必要がある.

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INTRODUCTION: Williamsia muralis is an environmental bacterium first detected in 1999. Infections with W. muralis isolated have been reported in two elderly patients, and were associated with the surgical intervention of artificial objects. We present a case of bacteraemia caused by W. muralis following haematopoietic cell transplantation (HCT). CASE PRESENTATION: A 10-year-old Japanese boy presented with fever and the swelling of the left cheek 8 days after HCT for the treatment of Fanconi anaemia. Gram-positive, rod-shaped bacteria were isolated from the blood cultures after 5 days incubation. 16S rRNA sequencing, but not mass spectrometry, identified a strain of W. muralis (1 414 bp, %ID 100 %). The phlegmon did not respond to antimicrobial therapy, but remitted with defervescence after a successful engraftment with teicoplanin and meropenem therapy on day 16 after HCT. The patient experienced recurrence of the bacteraemia, leading to central venous catheter (CVC) line removal. The same strain of W. muralis was isolated from the cultured tip of the CVC. To our knowledge, this is the first reported case of W. muralis bacteraemia and was complicated by CVC infection after HCT. CONCLUSION: W. muralis bacteraemia developed in an immunocompromised child. Introduction of artificial objects into the body raises a risk of rare infection with slowly growing environmental bacteria.

DOI： 10.1099/acmi.0.000679.v3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

B-cell expansion with NF-κB (nuclear factor-kappa B) and T-cell anergy (BENTA) is a rare congenital lymphoproliferative disorder caused by germline gain-of-function mutations in the CARD11 gene. We herein report a familial case of BENTA due to a G123D heterozygous missense mutation in CARD11 inherited by a male from his mother. The mother's clinical course was characterized by polyarthritis and encephalitis in young adulthood, suggesting that autoimmune-like manifestations can occur in BENTA. The B-cell lymphocytosis and splenomegaly seen in her child have been managed with prednisolone and tacrolimus. Further investigations are needed to evaluate the efficacy of calcineurin inhibitors for BENTA.

DOI： 10.1002/pbc.29941

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DOI： 10.1182/blood-2022-168565

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アメーバ赤痢はEntamoeba histolyticaによる感染症で,血便を呈する疾患の一つである.主に途上国で不衛生による水系感染をきたすが,日本では海外渡航歴のないアメーバ赤痢の小児例はまれである.今回われわれは,持続する血便を呈し,診断確定までに1年間要した海外渡航歴のないアメーバ赤痢の1歳児例を経験したので報告する.症例は1歳5ヵ月から鮮血便が持続し,便培養で有意菌は検出されなかった.下部消化管内視鏡で上行結腸から直腸に連続するリンパ濾胞様の隆起と多発するアフタ様びらんおよび潰瘍を認めた.食物蛋白誘発胃腸炎,超早期発症型炎症性腸疾患などを念頭に精査を進めたが診断に至らなかった.他に随伴症状はなく全身状態良好であったが,血便は持続し,貧血と低ガンマグロブリン血症を合併した.発症1年後に再検した下部消化管の生検病理でアメーバ赤痢と診断し,メトロニダゾール内服が奏効した.海外渡航歴や家族内感染はなく,感染経路は特定できなかった.アメーバ赤痢は日本人の乳幼児にはまれであり,診断に有用な検査は容易ではなく保険収載の問題もあり診断に難渋した.(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本小児感染症学会  

アメーバ赤痢はEntamoeba histolyticaによる感染症で,血便を呈する疾患の一つである.主に途上国で不衛生による水系感染をきたすが,日本では海外渡航歴のないアメーバ赤痢の小児例はまれである.今回われわれは,持続する血便を呈し,診断確定までに1年間要した海外渡航歴のないアメーバ赤痢の1歳児例を経験したので報告する.症例は1歳5ヵ月から鮮血便が持続し,便培養で有意菌は検出されなかった.下部消化管内視鏡で上行結腸から直腸に連続するリンパ濾胞様の隆起と多発するアフタ様びらんおよび潰瘍を認めた.食物蛋白誘発胃腸炎,超早期発症型炎症性腸疾患などを念頭に精査を進めたが診断に至らなかった.他に随伴症状はなく全身状態良好であったが,血便は持続し,貧血と低ガンマグロブリン血症を合併した.発症1年後に再検した下部消化管の生検病理でアメーバ赤痢と診断し,メトロニダゾール内服が奏効した.海外渡航歴や家族内感染はなく,感染経路は特定できなかった.アメーバ赤痢は日本人の乳幼児にはまれであり,診断に有用な検査は容易ではなく保険収載の問題もあり診断に難渋した.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Infection and Chemotherapy  

Schizophyllum commune is a widely distributed basidiomycete fungus that occasionally causes sinusitis or allergic bronchopulmonary mycosis. The invasive infection mostly occurs in immunocompromised adults. The number of reports on S. commune infection have increased in this decade due to the expansion of diagnostic techniques and awareness in clinical practice. However, S.commune infection in patients with primary immunodeficiencies has not been reported yet. Here, we described S. commune-abscesses developed in the brain and lung of a boy with chronic granulomatous disease (CGD) after allogenic hematopoietic cell transplantation (HCT). A 12-year-old CGD patient developed febrile neutropenia from day 4 after HCT, followed by chest pain on day 23. He had no obvious infection before HCT. Diagnostic imaging revealed disseminated lung and brain abscesses. He received administration of voriconazole, and his symptoms improved after engraftment. Chronic administration of voriconazole had also a favorable therapeutic response to brain lesion. A part of the fungus ball exhaled by the patient was cultured to develop a filamentous fungus. S. commune was identified by the analysis of the 28S rRNA gene. The catalase test was positive for S. commune, indicating that S. commune had virulence in this patient with CGD. The assessment of specific-IgG to S. commune suggested peri-transplant infection, although colonization was not excluded. This rare pediatric case of S. commune infection highlights that CGD patients are vulnerable to invasive infection, especially when undergoing HCT.

DOI： 10.1016/j.jiac.2022.10.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Rheumatology  

Objective To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in a subset of Japanese patients with familial Mediterranean fever (FMF). Methods We performed a double-blind, randomised, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF) (UMIN000028010). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study (UMIN000032557). Results We randomly assigned 23 patients to either TCZ (n=1) or placebo (n=12). The TCZ-placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189-2.531; p=0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240-0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups. Conclusion Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.

DOI： 10.55563/clinexprheumatol/fgx9vv

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＜ここがポイント!＞▼DICの基本的病態は、新生児・小児と成人とは相違ない。▼新生児・小児の凝固線溶機能は、生理的成熟過程においてDICの感受性が変化する。▼新生児期および小児期におけるDICの契機となる要因は成人と異なる。▼わが国では新生児DICのための診断・治療指針が策定されている。▼新生児と小児の早期かつ正確な診断には、採血方法や検査項目の選択が重要である。▼進行が速い新生児DICに適切に対応するため、治療戦略の標準化が課題である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Clinical Nutrition  

Vitamin deficiencies are an emerging concern in the management of children with autism spectrum disorder (ASD). Particular attention is required for recognizing the variable signs caused by unbalanced food intakes. We herein report two patients with multiple vitamin deficiencies who needed critical care showing different prognoses. Patient 1 with 'Shoshin' beriberi presenting with cardiac arrest had thiamine deficiency developed severe neurological sequelae despite rapid vitamin supplementation. Patient 2, who had leg pain and a limping gait, showed a rapid recovery with intravenous infusion and tube feeding after being diagnosed with scurvy. A literature search revealed several children with ASD with critically ill thiamine deficiency, but few reports documented a life-threatening condition in the form of cardiac arrest at the onset. Considering the high observation rate of food selectivity in children with ASD, early intervention is required to prevent the exacerbation of vitamin deficiencies to severe neurological disabilities.

DOI： 10.1038/s41430-022-01170-x

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Publisher：Clinical and Experimental Neuroimmunology  

Background: Haploinsufficiency of cytotoxic T-lymphocyte antigen 4 (CTLA4) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and diverse autoimmune disorders. Although central nervous system lesions have been described in patients with CTLA4 insufficiency, there have been few reports in the field of neurology. Case presentation: A 23-year-old man was referred to Saga University Hospital (Saga, Japan) with dizziness and abnormal head magnetic resonance imaging showing hyperintensity in the left cerebellar hemisphere. He was diagnosed with immune thrombocytopenia and hypogammaglobulinemia at age 8 years. He had repeated mild upper respiratory infections. Neurological events had occurred four times, with a long spinal lesion extending over three vertebral segments. High-dose intravenous methylprednisolone was effective for acute attacks, and low-dose prednisolone prevented relapses for 7 years. When he reached the age of 37 years, he developed severe diarrhea and immune cytopenia, and lost 6 kg in half a year. It was suspected that the patient had primary immunodeficiency due to his history of recurrent infections, hypogammaglobulinemia and severe diarrhea. Genome sequencing showed a heterozygous CTLA4 variant in exon 2. Abatacept therapy with prednisolone and cyclosporine was effective for diarrhea and autoimmune cytopenia. Conclusions: A patient with CTLA4 variant might develop multiple central nervous system lesions including longitudinally-extended spinal cord lesions. As there is effective targeted immunotherapy, a complete immunological work-up is required for early diagnosis when a patient presents with central nervous system lesions and multi-organ symptoms.

DOI： 10.1111/cen3.12672

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatrics and Neonatology  

DOI： 10.1016/j.pedneo.2022.01.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Immunology  

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

DOI： 10.1007/s10875-021-01199-w

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新生児血栓症はまれと考えられてきたが、医療の進歩に伴い診断例は増加傾向にある。血栓症の原因として、心疾患や感染症などのほか、凝固因子・抗凝固因子に関する遺伝性疾患を基礎にもつ可能性がある。日本人に多い遺血栓性素因はプロテインC(PC)、プロテインS、アンチトロンビン(AT)欠乏症、およびADAMTS13欠乏症だが、新生児ではPC欠乏症がほとんどである。私たちは、小児血栓症の診断と治療の向上のため日本人小児の遺伝性血栓症の分子疫学と臨床像をまとめ、早期診断のための活性基準値および診断予測式を作成した。2020年より遺伝子検査が保険適応となり、より早く正確な診断が可能となった。血栓症治療においてもPC製剤、AT製剤などの補充療法に加え、2021年より新生児に対しても直接経口抗凝固薬も使用可能となった。重症PC欠乏症に対する根治療法としての肝移植も報告され、治療選択も拡大している。(著者抄録)

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新生児単純ヘルペスウイルス(HSV)感染症は、主に垂直感染によって発症する重要な周産期感染症の一つである。臨床病型は表在型(SEM;skin, eye, and mouth)、中枢神経型(CNS;central nervous system)および全身型(Disseminated)の3つに分類され、それぞれ異なる症状と臨床経過を示す。1970年代以降、抗ウイルス薬の登場、またHSV-DNAを検出するPCR法の開発により、早期診断・治療が可能となり飛躍的に治療成績は改善した。しかし新生児医療が高度化した現代においても、全身型の新生児死亡率は29&#37;、中枢神経型は65&#37;以上に神経学的後遺症を残し、依然として予後不良の疾患である。本稿では新生児HSV感染症に対する治療指針と現在の課題について提示する。また新生児ヘルペス脳炎や新生児HSV関連血球貪食性リンパ組織球症といった重症例のリスク因子や治療戦略についても概説する。(著者抄録)

Language：English   Publisher：Frontiers in Immunology  

Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.

DOI： 10.3389/fimmu.2022.786375

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RATIONALE: Hepatitis-associated aplastic anemia (HAAA) is a rare illness that results in bone marrow failure following hepatitis development. The etiological agent remains unknown in most HAAA cases. However, clinical features of the disease and immunotherapy response indicate that immune-mediated factors play a central role in the pathogenesis of HAAA. Activation of cytotoxic T cells and increase in CD8 cells could exert cytotoxic effects on the myelopoietic cells in the bone marrow. PATIENT CONCERNS: A 15-month-old boy was brought to our hospital with complaints of generalized petechiae and purpura observed a week prior to hospitalization. His liver was palpated 3 cm below the costal margin, platelet count was 0 × 104/μL, and alanine aminotransferase level was 1346 IU/L. A blood test indicated cytomegalovirus infection, and 3 bone marrow examinations revealed progressive HAAA. As the disease progressed to the 3rd, 6th, and 9th week after onset, CD4+ T cells were markedly decreased, CD8+ T cells were markedly increased, and the CD4/CD8 ratio was significantly decreased. The number of B cells and natural killer cells decreased with time, eventually reaching 0.0%. DIAGNOSIS: HAAA. INTERVENTIONS: Rabbit antithymocyte globulin and eltrombopag olamine (a thrombopoietin receptor agonist) were administered. OUTCOMES: The patient's platelet count returned to normal, and bone marrow transplantation was avoided. The peripheral blood lymphocytes (PBLs) improved as the patient's general condition recovered. LESSONS: This case demonstrates that HAAA induced by cytomegalovirus infection features decreasing CD4+ and increasing CD8+ PBLs as the bone marrow hypoplasia progresses. The PBLs return to their normal levels with the recovery from the disease. Our case findings thus support the involvement of immunological abnormality in HAAA.

DOI： 10.1097/MD.0000000000028953

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Language：English   Publisher：Pediatric Allergy and Immunology  

DOI： 10.1111/pai.13686

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DOI： 10.1016/j.jpeds.2021.08.015

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Rheumatology (United Kingdom)  

DOI： 10.1093/rheumatology/keab599

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Granulocyte transfusion (GTX) is a therapeutic option for patients with prolonged neutropenia suffering from severe infections. Efficient granulocyte collection by apheresis from donors requires clear separation of granulocytes from red blood cells (RBCs), and infusion of high-molecular-weight (MW) hydroxyethyl starch (HES) facilitates RBC sedimentation. Recent research has shown that apheresis with medium-MW HES may prevent adverse effects of high-MW HES on donors, but the rationale for collection with medium-MW HES has yet to be evaluated. To validate the use of medium-MW HES, we first performed experiments with whole blood samples to determine how efficiently high-, medium- and low-MW HES separated granulocytes from RBCs, and found that medium-MW HES was just as efficient as high-MW HES. We also reviewed clinical data of granulocyte apheresis at our institution to evaluate granulocyte yields. Retrospective analysis of granulocyte collection revealed that apheresis with medium-MW HES yielded sufficient granulocytes for GTX and that donor anemia reduced collection efficiency. These results collectively may help us to establish a safer method for apheresis targeting polymorphonuclear granulocytes as an alternative to high-MW HES.

DOI： 10.1007/s12185-021-03207-6

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OBJECTIVE: To clarify the incidence and genetic risk of neonatal-thromboembolism, we conducted a nationwide study exploring the impact of thrombophilia on neonatal-thromboembolism in Japan. STUDY DESIGN: A questionnaire survey was conducted for perinatal centers in Japan, focusing on the clinical expression, genotype, treatment, and outcome of patients who developed thromboembolism within 28 days of birth from 2014 to 2018. RESULTS: The estimated incidence of neonatal-thromboembolism was 0.39 cases per 10 000 live births. Intracranial lesions and purpura fulminans occurred in 66 and 5 of 77 patients, respectively. Fifty-eight (75.3%) infants presented within 3 days after birth. Four (5.2%) died, and 14 (18.2%) survived with disability. At the diagnosis, <20% plasma activity of protein C was noted in 16 infants, protein S (in 2), and antithrombin (in 1). Thirteen genetic tests identified 4 biallelic and 5 monoallelic protein C-variants but no protein S- or antithrombin-variants. Protein C-variants had purpura fulminans (P < .01), ocular bleeding (P < .01), positive-family history (P = .01), and death or disability (P = .03) more frequently than others. Protein C-variants were independently associated with disability (OR 5.74, 95% CI 1.16-28.4, P = .03) but not death. Four biallelic variants had serious thrombotic complications of neurologic disability, blindness, and/or amputation. Three monoallelic variants survived without complications. The only protein C-variant death was an extremely preterm heterozygote infant. CONCLUSIONS: Monoallelic protein C-variants had a higher incidence of neonatal-thromboembolism than biallelic variants. Thrombophilia genetic testing should be performed in the setting of neonatal-thromboembolism and low protein C to identify the underlying genetic defect.

DOI： 10.1016/j.jpeds.2021.07.001

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PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan. METHODS: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP). RESULTS: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01). CONCLUSION: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.

DOI： 10.1007/s10875-021-01112-5

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BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by rapidly progressive deterioration of neurocognitive functions and premature death. In addition to the difficulty in identifying the earliest signs of ALD, treatment-associated exacerbation of neurological symptoms has been an obstacle to achieve successful hematopoietic cell transplantation (HCT) for affected children. CASE REPORT: We report a 9-year-boy with ALD. He presented with impairment in social skills compatible to the diagnosis of autism spectrum disorder from 3 years of age. He showed progressive strabismus, slurred speech and dysmetria at 6 years of age. The head MRI showed symmetrical T2-hyperintense lesions in the occipital white matters with a gadolinium enhancement, which extended to the internal capsules. The Loes score was thus calculated as 13. Very-long-chain-fatty-acids were increased to 1.800 (C24:0/C22:0) and 0.077 (C26:0/C22:0) in leukocytes. Sanger sequencing confirmed the pathogenic variant in ABCD1 (NM_000033.4:p.Gly512Ser). After multidisciplinary discussions over the treatment options, we performed a cord blood HCT with a reduced intensity conditioning (fludarabine, melphalan and brain-sparing total body irradiation). He was fully recovered with >90% chimerism of donor leukocytes at 55 days after HCT. He experienced three times of generalized seizures after discharge, that has been well controlled for 2 years without other complications or neurocognitive deteriorations. CONCLUSION: For patients with ALD on a borderline indication for HCT, brain-sparing irradiation might be an alternative option in reduced intensity conditioning. Careful decision-making process and tailored conditioning are critical for the successful outcome of HCT for children with ALD.

DOI： 10.1016/j.ymgmr.2021.100778

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Subacute sclerosing panencephalitis (SSPE) is a slow virus infection associated with mutant measles virus (MeV). The long-term outcome of antiviral treatments remains to be determined. We herein present a Japanese boy who was diagnosed with SSPE at 10 years of age. Intraventricular infusions of interferon-α effectively prevented the progress of symptoms during 14 years of follow-up period. Flow-cytometric analysis demonstrated higher proportion of T helper 17 cells (Th17, 18.2%) than healthy controls (4.8-14.5%) despite the normal subpopulation of peripheral lymphocytes. These data suggest that a group of patients with SSPE may show favorable responses to intraventricular infusions of interferon-α.

DOI： 10.1016/j.jneuroim.2021.577656

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遺伝性骨髄不全症候群は,DNA損傷修復やテロメア維持,リボソームに関連する遺伝子異常によって発症する。輸血依存例に対して血液学的根治を目的に造血細胞移植を選択する場合には,抗がん剤と放射線による影響を考慮した前処置強度の減弱と移植後の長期観察が必要である。原発性免疫不全症は免疫担当細胞および蛋白の異常から易感染性と免疫異常を示す疾患群で,治療の基本は感染予防である。根治を目的に造血細胞移植が選択される小児は少なくないが,自己免疫・自己炎症に対する病態に応じた特異的免疫制御療法(標的治療)も可能となってきた。診断技術の進歩から,造血障害と免疫異常の両方を呈する単一遺伝子病も同定されるようになり,成人例の報告も増えてきた。造血細胞移植の血縁ドナー選択では保因者診断に配慮し,遺伝カウンセリングを必要とする。本稿では遺伝性骨髄不全症と原発性免疫不全症に対する治療戦略と注意点について概説する。(著者抄録)

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In the original version of this Article, in Table 1 the Year of HST for cases 3, 4, 15, and 25 was not shown. They now appear in Table 1 in the PDF and HTML versions of the Article.

DOI： 10.1038/s41409-020-01076-x

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

DOI： 10.1038/s41409-020-01056-1

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＜文献概要＞乳幼児期は身体成長と精神運動発達が目覚ましく,食事等の生活環境は大きく変化する.貧血の病因は多彩であり,年齢に応じた環境要因と遺伝学的背景を考慮する必要がある.乳幼児期は健診や予防接種,また,感染症等に繰り返し罹患するため,小児科医の診察を受ける機会が多い.病因に特徴的な所見と,日常診療で行われている臨床検査所見を理解することで,貧血の鑑別を進めることができる.出血や無形成発作による急激な貧血は致死的であり,緊急対応が必要である.さらに悪性腫瘍や血球貪食性リンパ組織球症による二次性貧血を鑑別しなければならない.鉄欠乏性貧血として非典型であれば,小児血液学を専門とする医師へ相談するとよい.

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BACKGROUND: Acute kidney injury (AKI) often occurs in pediatric patients who received allogeneic hematopoietic cell transplantation (HCT). We evaluated the risk and effect of HCT-related AKI in pediatric patients. METHODS: We retrospectively studied the survival and renal outcome of 69 children 100 days and 1-year posttransplant in our institution in 2004-2016. Stage-3 AKI developed in 34 patients (49%) until 100 days posttransplant. RESULTS: The 100-day overall survival (OS) rates of patients with stage-3 AKI were lower than those without it (76.5% vs. 94.3%, P = 0.035). The 1-year OS rates did not differ markedly between 21 post-100-day survivors with stage-3 AKI and 29 without it (80.8% vs. 87.9%, P = 0.444). The causes of 19 deaths included the relapse of underlying disease or graft failure (n = 11), treatment-related events (4), and second HCT-related events (4). Underlying disease of malignancy (crude hazard ratio (HR) 5.7; 95% confidence interval (CI), 2.20 to 14.96), > 1000 ng/mL ferritinemia (crude HR 4.29; 95% CI, 2.11 to 8.71), stem cell source of peripheral (crude HR 2.96; 95% CI, 1.22 to 7.20) or cord blood (crude HR 2.29; 95% CI, 1.03 to 5.06), and myeloablative regimen (crude HR 2.56; 95% CI, 1.24 to 5.26), were identified as risk factors for stage-3 AKI until 100 days posttransplant. Hyperferritinemia alone was significant (adjusted HR 5.52; 95% CI, 2.21 to 13.76) on multivariable analyses. CONCLUSIONS: Hyperferritinemia was associated with stage-3 AKI and early mortality posttransplant. Pretransplant iron control may protect the kidney of pediatric HCT survivors.

DOI： 10.1007/s00467-020-04619-y

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血栓性素因の分子疫学的解明が進み,成人では血栓症の治療管理も近年急速に進歩した。一方,成長期の血栓症は新生児と思春期に多く,各々特徴が異なり,診療に関するエビデンスの集積が遅れている。早発型遺伝性血栓症は,電撃性紫斑病,頭蓋内出血・梗塞など壮年例とは異なる発症様式で診断が難しく,重篤な後遺症を生涯残す。多因子病である血栓症の個別治療を行うためには,早発型の胚細胞異常を明らかにする必要がある。遺伝性血栓性素因は民族で異なり,強い素因ほど一般集団の頻度は低い。日本人の成人にはプロテインS多型(K196E)の頻度が高く,小児の血栓症患者にはプロテインC異常が多く見つかる。患者集団の遺伝子型は出生後に高リスクから低リスクへと変化する。「特発性血栓症」が指定難病となり,遺伝子検査も保険収載されたが,個別治療管理法の確立が課題である。本稿では成人までに発症する血栓症の遺伝性素因,治療と予防について概説する。(著者抄録)

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BACKGROUND: Human parvovirus B19 (B19V) causes glomerulopathy or microangiopathy, but not tubulopathy. We experienced an 11-year-old girl with spherocytosis who developed acute kidney injury on a primary infection of B19V. She presented with anuria, encephalopathy, thrombocytopenia, and coagulopathy, along with no apparent aplastic crisis. METHODS: Continuous hemodiafiltration, immunoglobulin, and intensive therapies led to a cure. RESULTS: A kidney biopsy resulted in a histopathological diagnosis of tubulointerstitial nephritis without immune deposits. The virus capsid protein was limitedly expressed in the tubular epithelial cells with infiltrating CD8-positive cells. CONCLUSIONS: Viral and histopathological analyses first demonstrated B19-infected tubulointerstitial nephritis due to the aberrant viremia with hereditary spherocytosis.

DOI： 10.1093/ofid/ofaa288

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Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.

DOI： 10.1182/bloodadvances.2020001451

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DOI： https://doi.org/10.11406/rinketsu.60.702

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Varicella zoster virus (VZV) causes a life-threatening infection in immunocompromised hosts. The immune response to VZV of healthy subjects has been rigorously assessed, but little is known about that of immunocompromised individuals. This study aimed to clarify the primary response to VZV infection in immunocompromised children. This prospective study enrolled six immunocompromised children (median age, 33 months; range, 20-62) receiving steroids or immunosuppressants, and 10 immunocompetent children (median age, 32 months; range, 15-81) with varicella. The immunocompromised children were three patients with acute lymphoblastic leukemia, two recipients with liver transplantation and one patient with juvenile idiopathic arthritis. Interferon-γ-producing CD69+T-cells produced by VZV stimulation (VZV-specific T-cells) were studied during the acute or convalescent phase. To further address the direct effect of immunosuppressants, we analyzed the number of VZV-specific T-cells after stimulating peripheral blood mononuclear cells obtained from healthy adults with live-attenuated VZV with or without prednisolone, cyclosporine-A, or tacrolimus. The circulating numbers of lymphocytes in the convalescent stage but not acute stage were lower in immunocompromised children compared with immunocompetent children. In the acute stage, immunocompromised patients showed lower VZV-specific CD8+T-cell counts than immunocompetent subjects. In contrast, in the convalescent phase, immunocompromised patients had lower VZV-specific CD4+T-cell counts than immunocompetent hosts. The in vitro culture of activated lymphocytes with prednisolone or immunosuppressants significantly decreased the proportion of VZV-specific CD4+T-cells. In conclusion, the decreased numbers of VZV-specific CD8+T-cells during the acute phase and VZV-specific CD4+T-cells during the convalescent phase of disease may account for severe varicella in immunocompromised children.

DOI： 10.1620/tjem.250.181

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: The novel agent pd-FVIIa/FX is a 1 : 10 protein weight mixture of activated factor VII (FVIIa) and factor X (FX) derived from donated blood plasma. A phase III clinical trial of pd-FVIIa/FX revealed high efficacy for bleeding episodes in haemophilia patients with inhibitors. However, up to now, only one case of this new agent being used for surgery had been reported. The objective of this study is to evaluate the perioperative haemostatic efficacy and safety of pd-FVIIa/FX in haemophilia patients with inhibitors. We retrospectively reviewed 25 operation charts from 14 haemophilia patients with high-responding inhibitors using pd-FVIIa/FX during the perioperative period. Efficacy was evaluated by attending physicians and results divided into four groups (excellent, good, fair, and poor). The operation chart was provided by nine Japanese medical institutes with expertise in haemophilia management. Out of the total of 25 surgical procedures, 44% (11/25) were classified as major surgery and the remainders were minor surgeries. In all of the surgeries but one, rFVIIa and/or APCC were administered in combination or sequential method. In all cases except one, the haemostatic efficiency rate was judged as excellent or good by treating physicians for an overall efficacy rate of 96%. No thrombotic adverse effects were reported. This study's results suggest that both combination and sequential therapy of pd-FVIIa/FX and other bypassing agents are well tolerated and effective for the control of perioperative bleeding in haemophilia patients with high-responding inhibitors.

DOI： 10.1097/MBC.0000000000000851

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3歳女児。2歳時より若年性特発性関節炎に対しインフリキシマブ、メトトレキサート投与中であった。今回、発熱を主訴に当院を受診し、血液培養でStreptococcus pneumoniaeが検出され、肺炎球菌菌血症と診断された。本症例は13価肺炎球菌結合型ワクチンを4回接種していたが、ワクチンに含有されない莢膜血清型24Fが同定され、分離株はシークエンスタイプ5496であった。この株はペニシリン感受性で、抗菌薬を計12日間投与した。治療終了後39日目に肺炎を再発し、血液培養から初回と同じシークエンスタイプ5496の肺炎球菌が検出された。抗菌薬投与にて血液培養の陰性化、症状の改善を認め、第22病日に退院し、退院2ヵ月後に23価肺炎球菌莢膜多糖体ワクチンを追加接種した。

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DOI： 10.1007/s10875-019-00626-3

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炎症性腸疾患(IBD)は成人だけでなく小児にも発症する疾患であり、成長に深くかかわるため、診断と治療を厳格におこなう必要がある。クローン病と潰瘍性大腸炎が主体であり、どちらかにも分類することがむずかしいものをindeterminate colitisという。IBDの病因・病態には免疫系のメカニズムや環境因子などが関与するといわれているが、詳しいことはわかっていない。基礎疾患として原発性免疫不全症(先天性免疫不全症)が隠れていることがある。そのなかには造血幹細胞移植による免疫再構築から腸炎が寛解する疾患があるため、見逃さないことが重要である。(著者抄録)

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新生児単純ヘルペスウィルス(HSV)感染症は主に産道感染によって新生児に発症する周産期感染症の重要な疾患の一つである。全身型、中枢神経型、表在型の3つの病型に分けられるが、特に全身型は新生児早期に発症し、一部ではHSV関連血球貪食性リンパ組織球症(HSV-HLH)に進展して、急激に致死的な経過をたどる予後不良な疾患である。救命のためには新生児HSV感染症を疑った時点で抗ウイルス薬の投与を開始することが、重症化の予防および生命予後の改善のために重要である。また新生児HSV-HLHに関しては高サイトカイン血症に基づいた重篤なDICの病態を合併していることから、適切な抗サイトカイン治療の選択も重要であると考えられる。しかしながら未だ新生児HSV-HLHの病態や治療に関する情報は乏しく、より良い診療のためには早期診断・治療の指針の確立が急務と考えられる。(著者抄録)

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DOI： 10.1002/pbc.27529

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ABSTARCT: OBJECTIVE: The diagnosis of neonatal-onset protein C (PC) deficiency is challenging. This study aimed to establish the neonatal screening of heritable PC deficiency in Japan. STUDY DESIGN: We determined the changes in plasma activity levels of PC and protein S (PS) in healthy neonates, and studied newborn patients with PROC mutation in the Japanese registry. RESULT: Physiological PC and PS levels increased with wide range. The PC/PS-activity ratios converged after birth. The PC/PS-activity ratios of 19 patients with biallelic mutations, but not, 9 with monoallelic mutation, were lower than those of 13 without mutation. The logistic regression analyses established a formula including two significant variables of PC activity (cut-off < 10%, odds ratio = 30.0) and PC/PS-activity ratio (cut-off < 0.35, odds ratio = 22.7), with 93% sensitivity and 44% specificity for determining patients with mutation(s). CONCLUSION: The PC/PS-activity ratio is an effective parameter for the genetic screening of neonatal-onset PC-deficiency in Japanese population.

DOI： 10.1038/s41372-018-0262-0

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DOI： 10.3389/fped.2019.00015.

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BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

DOI： 10.1016/j.jaci.2018.04.032

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BACKGROUND: Thrombotic microangiopathies (TMA) are microvascular occlusive disorders characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and red cell fragmentation. Post-operative TMA mostly occurs in adult patients with cardiovascular surgery, with the distinct pathophysiology from classical thrombotic thrombocytopenic purpura (TTP) although the exact pathophysiology remains unclear. CASE PRESENTATION: A one-month-old infant developed TMA after the initial surgery of double outlet right ventricle. ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity was sustained (64%) with the undetectable inhibitor. Von Willebrand factor (VWF) multimer analyses showed absent high-molecular weight multimers. Echocardiography disclosed severe mitral regurgitation. The mitral valve repair 32 days after the initial valvuloplasty led to prompt resolution of TMA. These suggested that TMA occurred in association with valvulopathy-triggered turbulent shear flow, mechanical hemolysis and endothelial damage. The consumption of large VWF multimers might account for the vascular high shear stress shown in Heyde syndrome. CONCLUSION: The youngest case of post-operative TMA underscores the critical coagulopathy after the first surgical intervention for congenital heart disease.

DOI： 10.1016/j.pedneo.2018.02.002

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INTRODUCTION: Upshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation. MATERIALS AND METHODS: Here, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls. RESULTS: Pathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p < 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p < 0.05), while C5b-9 staining did not differ significantly among groups. CONCLUSIONS: These findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.

DOI： 10.1016/j.thromres.2018.08.020

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DOI： 10.1038/s41409-018-0180-y

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Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia arising from ribosomal protein (RP) defects. Affected patients present with neonatal anemia, occasional dysmorphism, and cancer predisposition. An anemic newborn was diagnosed with DBA due to RPL5 mutation (c.473_474del, p.K158SfsX26). Refractory anemia required regular transfusions and iron chelation therapy. Pancytopenia occurred at age 16 years. Bone-marrow studies showed myelodysplasia, erythroblastosis, and clonal evolution of del(20)(q11.2q13.3). Severe anemia required transfusions. Del(20q), including the L3MBTL1 gene, is reported to be relevant to the hematological phenotype of Shwachman-Diamond syndrome. A combined defect of RPL5 and L3MBTL1 may contribute to the aberrant erythropoiesis in the present case.

DOI： 10.1007/s12185-018-2424-4

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DOI： 10.1016/j.pedneo.2017.11.002

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DOI： 10.1002/pbc.27017

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DOI： 0.1016/j.pedneo.2018.02.002

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BACKGROUND: Severe protein C (PC) deficiency is a rare heritable thrombophilia leading to thromboembolic events during the neonatal period. It remains unclear how individuals with complete PC gene (PROC) defects develop or escape neonatal stroke or purpura fulminans (PF). PROCEDURE: We studied the onset of disease and the genotype of 22 PC-deficient patients with double mutations in PROC based on our cohort (n = 12) and the previous reports (n = 10) in Japan. RESULTS: Twenty-two patients in 20 unrelated families had 4 homozygous and 18 compound heterozygous mutations. Sixteen newborns presented with PF (n = 11, 69%), intracranial thromboembolism and hemorrhage (n = 13, 81%), or both (n = 8, 50%), with most showing a plasma PC activity of <10%. Six others first developed overt thromboembolism when they were over 15 years of age, showing a median PC activity of 31% (range: 19-52%). Fifteen of the 22 patients (68%) had the five major mutations (G423VfsX82, V339M, R211W, M406I, and F181V) or two others (E68K and K193del) that have been reported in Japan. Three of the six late-onset cases, but none of the 16 neonatal cases, had the K193del mutation, which has been reported to be the most common variant of Chinese thrombophilia. A novel mutation of A309V was determined in a family of two patients with late onset. CONCLUSIONS: The genotype of double-PROC mutants might show less diversity than heterozygous mutants in terms of the timing of the onset of thrombophilia (newborn onset or late onset).

DOI： 10.1002/pbc.26404

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原発性免疫不全症と炎症性腸疾患(IBD)との関連について述べた。IBDの病因・病態には免疫学的な要因と環境因子が関与すると言われているが、明らかなメカニズムは不明である。免疫学的な機序として、腸管上皮細胞のtight junctionの減少がTumor Necrosis Factor(TNF)などのproinflammatory cytokineの放出を促すことや、腸管上皮のbarrierの変化は病原体の侵入を増やし、抗原提示細胞により多く取り込まれ免疫系を刺激することが知られている。このように、IBDと腸管の免疫機構に大きな関わりがあるのは間違いないが、IBD発症の詳細なメカニズムの原因特定にまでは至っていない。IBDを診療する時には基礎疾患を考慮するべきであり、特に早期発症のIBDでは基礎疾患を鑑別に挙げることが重要である。

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本邦の小児遺伝性血栓症の約70&#37;は、プロテインC、プロテインSとアンチトロンビンの3大抗凝固因子欠乏である。新生児期は最も血栓症の頻度が高く、電撃性紫斑病や頭蓋内出血、梗塞で発症するプロテインC欠乏症が多い。新生児期の凝固、抗凝固能は生理的範囲が広く、母体や付属物の影響を受けるため、基準範囲や遺伝子検査の適応基準は定まっていない。私たちの研究では、正期産児のプロテインC活性はプロテインS活性に比べて低く、生後2週までは活性値30&#37;未満の児も認めた。また、新生児期発症の遺伝性プロテインC欠乏症を本邦の報告例を基に解析すると、両アレル変異を有する16名のうち15名は日齢7未満に電撃性紫斑病や頭蓋内病変で発症し、プロテインC活性は10&#37;以下であった。遺伝性プロテインC欠乏症を早期診断し、適切な治療と予防を行うためには、活性値や臨床症状に基づいた遺伝子検査の適応基準の確立が求められる。(著者抄録)

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PURPOSE: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. METHODS: Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. RESULTS: The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). CONCLUSIONS: The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.

DOI： 10.1007/s10875-016-0357-3

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Neonatal thromboembolism occurs with various predispositions and triggers. Early diagnosis of the thrombosis is challenging and essential for the therapeutic interventions. We herein report two newborns who presented with transient hemi-lower limb ischemia due to (1) arterial thrombosis or (2) a persistent sciatic artery (PSA). The patient with arterial thrombosis showed elevations of fibrin degradation product and D-dimer and received antithrombin and heparin intravenously. The patient with PSA was immediately assessed by a contrast-enhanced computed tomography because of a transient ischemic episode with no evidence of hypercoagulability. Newborns suspected of having arterial thrombosis may need urgent surgical intervention along with thrombolytic and anticoagulant therapy to prevent organ ischemia and amputation of extremities. Conversely, some PSA cases have reportedly been treated conservatively. This vascular anomaly was previously reported as a cause of lower limb ischemia only in a newborn. PSA is a critical differential diagnosis of neonatal arterial thrombosis that needs urgent therapeutic intervention.

DOI： 10.1055/s-0037-1598044

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症例は13歳,男。幼少時より気道感染症を繰り返し10回以上の入院歴があった。12歳より腹痛,下痢を認め,血便を伴うようになり,下部消化管内視鏡で大腸全層性に多発するリンパ濾胞様隆起性病変を指摘された。粘膜生検でMALTリンパ腫が疑われ当院を紹介受診した。当院の病理検査所見ではclonalityのないT細胞優位のリンパ増殖でありT細胞性リンパ増殖症(T-cell LPD)と診断した。Tリンパ球減少(492/μl)と特異抗体産生不全を伴う高IgG血症から複合型免疫不全症と診断した。T-cell LPDを合併しており,活性化PI3Kδ症候群(APDS)を疑いPIK3CD遺伝子を解析し,c.1573 G to A p.Glu525Lysの既知ヘテロ変異を認め確定診断した。APDSは細胞内増殖シグナルであるPI3K-Akt-mTOR経路の活性化を背景としてリンパ球の異常増殖,細胞の早期老化,細胞死に伴う易感染性を呈する新しく見出された原発性免疫不全症であり,悪性B細胞性リンパ腫を合併しやすい。本児ではPSL,CyAの投与でT-cell LPDを制御し得たが,根治のため造血細胞移植を予定している。(著者抄録)

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OBJECTIVES: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan. METHODS: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan. RESULTS: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041; and 14.0 vs 6.0 days, p = 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53). CONCLUSIONS: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease.

DOI： 10.1016/j.jinf.2016.07.018

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We found that human cord blood nucleated red blood cells (NRBCs) have a regulatory function in the innate immune reaction. These cells suppressed the production of inflammatory cytokines including TNF-α and IL-1β from monocytes in response to lipopolysaccharide (LPS). The NRBCs exerted their regulatory function even without cell-to-cell contact with the monocytes. However, IL-10 production from the monocytes by LPS stimulation in the presence of NRBCs was higher than that from LPS-stimulated monocytes cultured in the absence of NRBCs. Addition of an anti-IL-10 receptor blocking antibody restored the inflammatory cytokine production from the monocytes, suggesting that the functional change of the monocytes caused by the interaction with NRBCs was mediated by the increased IL-10 production. A whole-genome microarray analysis revealed that the monocytes expressed increased amounts of IL-10 superfamily genes after interacting with NRBCs. IL-19, which is a member of the IL-10 superfamily, enhanced IL-10 production from the monocytes, which suggested a cooperative role of the IL-10 superfamily in the suppression of inflammatory cytokine production from monocytes. Arginase, which was reported to play an important role in the suppressive function of NRBCs in mice monocytes, was found to have no significant role in human monocytes. The NRBCs seem to have a regulatory role through the induction of IL-10/IL-19 production by monocytes to suppress a vigorous innate immune reaction, which can be harmful to fetuses.

DOI： 10.1016/j.imbio.2016.04.004

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X-linked agammaglobulinemia (XLA) is one of the most common humoral immunodeficiencies, which is caused by mutations in Bruton's tyrosine kinase (BTK) gene. To examine the possibility of using gene therapy for XLA, we constructed a helper-dependent adenovirus/adeno-associated virus BTK targeting vector (HD-Ad.AAV BTK vector) composed of a genomic sequence containing BTK exons 6-19 and a green fluorescence protein-hygromycin cassette driven by a cytomegalovirus promoter. We first used NALM-6, a human male pre-B acute lymphoblastic leukemia cell line, as a recipient to measure the efficiency of gene targeting by homologous recombination. We identified 10 clones with the homologous recombination of the BTK gene among 107 hygromycin-resistant stable clones isolated from two independent experiments. We next used cord blood CD34+ cells as the recipient cells for the gene targeting. We isolated colonies grown in medium containing cytokines and hygromycin. We found that the targeting of the BTK gene occurred in four of the 755 hygromycin-resistant colonies. Importantly, the gene targeting was also observed in CD19+ lymphoid progenitor cells that were differentiated from the homologous recombinant CD34+ cells during growth in selection media. Our study shows the potential for the BTK gene therapy using the HD-Ad.AAV BTK vector via homologous recombination in hematopoietic stem cells.

DOI： 10.1038/gt.2015.91

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Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28 weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course.

DOI： 10.1016/j.braindev.2015.07.004

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BACKGROUND: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation. METHODS: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis. RESULTS: Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0-2 y, 45%), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75%), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism. CONCLUSION: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

DOI： 10.1038/pr.2015.180

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BACKGROUND: Although deleterious mutations in interleukin-10 and its receptor molecules cause severe infantile-onset inflammatory bowel disease, there are no reports of mutations affecting this signaling pathway in Japanese patients. Here we report a novel exonic mutation in the IL10RA gene that caused unique splicing aberrations in a Japanese patient with infantile-onset of inflammatory bowel disease in association with immune thrombocytopenic purpura and a transient clinical syndrome mimicking juvenile myelomonocytic leukemia. CASE PRESENTATION: A Japanese boy, who was the first child of non-consanguineous healthy parents, developed bloody diarrhea, perianal fistula, and folliculitis in early infancy and was diagnosed with inflammatory bowel disease. He also developed immune thrombocytopenic purpura and transient features mimicking juvenile myelomonocytic leukemia. The patient failed to respond to various treatments, including elemental diet, salazosulfapyridine, metronidazole, corticosteroid, infliximab, and adalimumab. We identified a novel mutation (c.537G > A, p.T179T) in exon 4 of the IL10RA gene causing unique splicing aberrations and resulting in lack of signaling through the interleukin-10 receptor. At 21 months of age, the patient underwent allogeneic hematopoietic stem cell transplantation and achieved clinical remission. CONCLUSIONS: We describe a novel exonic mutation in the IL10RA gene resulting in infantile-onset inflammatory bowel disease. This mutation might also be involved in his early-onset hematologic disorders. Physicians should be familiar with the clinical phenotype of IL-10 signaling defects in order to enable prompt diagnosis at an early age and referral for allogeneic hematopoietic stem cell transplantation.

DOI： 10.1186/s12876-016-0424-5

Language：English   Publishing type：Research paper (scientific journal)  

Interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency (OMIM #607676) is a rare primary immunodeficiency of innate immune defect. We identified 10 patients from 6 families with IRAK4 deficiency in Japan, and analyzed the clinical characteristics of this disease. Nine patients had homozygous c.123_124insA mutation, and 1 patient had c.123_124insA and another nonsense mutation (547C>T). Umbilical cord separation occurred on the 14th day after birth or thereafter. Two patients had no severe infections owing to the prophylactic antibiotic treatment. Severe invasive bacterial infections occurred before the age of 3 in the other 8 patients. Among them, 7 patients had pneumococcal meningitis. Five patients died of invasive bacterial infection during infancy, although intravenous antibiotic treatment was started within 24 hours after onset in 4 patients among them. Analysis of cerebrospinal fluid of the patients who had fatal meningitis revealed very low glucose levels with only mild pleocytosis. The clinical courses of invasive bacterial infections were often rapidly progressive despite the early, appropriate antibiotic treatment in IRAK4 deficiency patients. The early diagnosis and appropriate prophylaxis of invasive bacterial infections are necessary for the patients.

DOI： 10.1097/MD.0000000000002437

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DOI： 10.1007/s00431-015-2638-x

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000370059

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Chronic inflammation plays a key role in the development of atherosclerosis. Early progression of atherosclerosis has been reported in patients with RA. Cryopyrin-associated periodic syndromes (CAPS) are autosomal dominant autoinflammatory disorders caused by heterozygous NLRP3 gene mutations. Chronic infantile neurological cutaneous and articular (CINCA) syndrome is the most severe form of CAPS and patients display early onset of rash, fever, uveitis and joint manifestations. However, there has been no previous report on atherosclerosis in patients with CAPS. The objective of this study is to assess the development of atherosclerosis in patients with CINCA syndrome. METHODS: Intima-media thickness (IMT) of the carotid arteries, stiffness parameter β, ankle brachial index (ABI) and pressure wave velocity (PWV) were evaluated by ultrasonography in 3 patients with CINCA syndrome [mean age 9.0 years (S.D. 5.3)] and 19 age-matched healthy controls [9.3 years (S.D. 4.3)]. RESULTS: The levels of carotid IMT, stiffness parameter β and PWV in CINCA syndrome patients were significantly higher than those in healthy controls [0.51 mm (S.D. 0.05) vs 0.44 (0.04), P = 0.0021; 6.1 (S.D. 1.7) vs 3.9 (1.0), P = 0.0018; 1203 cm/s (S.D. 328) vs 855 (114), P = 0.017, respectively]. CONCLUSION: Patients with CINCA syndrome showed signs of atherosclerosis from their early childhood. The results of this study emphasize the importance of chronic inflammation in the development of atherosclerosis. Further analysis on atherosclerosis in young patients with CINCA syndrome may provide more insights into the pathogenesis of cardiovascular disease.

DOI： 10.1093/rheumatology/keu180

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

UNLABELLED: Control of refractory bleeding in idiopathic pulmonary hemosiderosis (IPH) is challenging. Based on the effect of liposteroid (dexamethasone palmitate) for acute bleeding in two reported cases, the long-term utility was assessed in all nine IPH children (including the first two cases) treated in a tertiary center for 20 years. The median at disease onset was 2.3 years (range, 1.2 to 8.6). All had life-threatening and/or repetitive bleeding on prednisolone (PSL) therapy. Liposteroid was intravenously infused at 0.8 mg/kg/day for three consecutive days at the time of acute bleeding. Single infusion was followed by a longer interval from weekly to monthly accompanied by low-dose PSL (less than 0.3 mg/kg/day). Monthly infusion as maintenance therapy was continued for prophylaxis of bleeding. Treatment outcomes were retrospectively analyzed. During the observation period of a median of 11.0 years (range 2.4-16.9 years), no one died. Five patients were weaned and the other one was being weaned from liposteroid for the cure or long remission (median, 5.5 years). Three others were on liposteroid therapy because of active disease. Neither patient had respiratory symptoms, although three showed subnormal %vital capacity. Serum levels of KL-6 and ferritin were normal in all and all but one patient(s), respectively. Four patients (three on liposteroid therapy) showed low bone mineral density. There were no obese patients. Height SD score did not significantly decrease except for one patient. CONCLUSION: The liposteroid therapy might improve the survival of IPH patients with reducing the adverse effects of steroids, although prospective control studies are needed.

DOI： 10.1007/s00431-013-2065-9

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DOI： 10.1186/1546-0096-11-41

Language：English   Publishing type：Research paper (scientific journal)  

C1q deficiency is a rare disease that is associated with a high probability of developing systemic lupus erythematosus. We report a 4-year-old Japanese girl who presented with fever, facial erythema, joint pain, and oral ulceration. Complement deficiencies were suspected because of her persistent hypocomplementemia and normal levels of the complement proteins C3 and C4. We identified a novel homozygous splicing mutation in the C1qB gene, c.187 + 1G > T, which is the first mutation to be confirmed in a Japanese individual. Because treatment with steroids and immunosuppressive drugs was not effective, we commenced use of fresh frozen plasma to provide C1q supplements. Currently, the patient remains almost asymptomatic, and we are attempting to control the drug dosage and administration intervals of fresh frozen plasma.

DOI： 10.1186/1546-0096-11-41

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DOI： 10.1002/pbc.24553

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DOI： 10.1111/hae.12097

Language：Japanese  

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BACKGROUND: In spite of the accumulating evidence on the interaction between the immune and endocrine systems based on the recent progress in molecular genetics, there have been few epidemiological studies focused on the endocrine complications associated with primary immunodeficiency diseases (PID). OBJECTIVE: To investigate the prevalence and clinical features of endocrine complications in patients with PID in a large-scale study. DESIGN AND PARTICIPANTS: This survey was conducted on patients with PID who were alive on 1 December 2008 and those who were newly diagnosed and died between 1 December 2007 and 30 November 2008 in Japan. We investigated the prevalence and the clinical data of the endocrine complications in 923 patients with PID registered in the secondary survey. RESULTS: Among 923 PID patients, 49 (5·3%) had endocrine disorders. The prevalence of the endocrine diseases was much higher in patients with PID than in the general population in the young age group, even after excluding patients with immune dysregulation. CONCLUSIONS: Endocrine disorders are important complications of PID. Analysis of the endocrine manifestations in patients with PID in a large-scale study may provide further insights into the relationship between the immune and endocrine systems.

DOI： 10.1111/j.1365-2265.2012.04390.x

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BACKGROUND: Ring chromosome 18 [r18] is a rare constitutional chromosomal aberration syndrome, characterized by dysmorphic face, hypoactivity, short stature, and delayed development. Autoimmune thyroiditis and immunoglobulin (Ig) A deficiency are occasionally associated with chromosome-18 deletion syndromes. SUMMARY: Here, we report a 2-year-old male child with r(18) syndrome and a selective IgA deficiency (<1.6 mg/dL, reference range [rr]: 20-149), who developed hypothyroidism and liver dysfunction. Thyroid function tests (thyroid-stimulating hormone [TSH]: 1031 μIU/mL, rr 0.43-4.0; free triiodothyronine: 0.52 pg/mL, rr 2.37-4.65; free thyroxine: 0.11 ng/dL, rr 1.03-2.00) and positive thyroid antibodies (anti-TSH receptor 1.7 IU/L, cut-off index [coi]: <1.0, antithyroid peroxidase 171 IU/mL, coi <0.3, and antithyroglobulin 2.8 IU/mL, coi <0.3) indicated autoimmune hypothyroidism. Elevated levels of aspartate aminotransferase (AST, 240 IU/L, rr 17-39) and alanine aminotransferase (ALT, 315 IU/L, rr 4-23), but negative antibodies against LKM and mitochondrial M2, suggested no autoimmune hepatitis. Transaminase levels became normalized after he was given levothyroxine therapy to achieve the euthyroid state, but they repeatedly became elevated when levothyroxine was inadvertently discontinued (peak AST=409 IU/L; peak ALT=390 IU/L). A maintenance dose of levothyroxine has effectively maintained the euthyroid state and normalized liver function tests despite no immunosuppressive therapy. CONCLUSIONS: The r18 patient with autoimmune hypothyroidism and IgA deficiency suffered from idiopathic hepatitis. The liver dysfunction was associated with hypothyroidism that resolved with thyroid hormone treatment. While the former combination has been described, the latter has not. The reason for the development of hepatitis in association with hypothyroidism is unexplained. However, we postulate that it might be related, in ways that are not clear, to the deleted genes of r18.

DOI： 10.1089/thy.2011.0521

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TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations of TNFRSF1A gene and characterized by recurrent febrile episodes of prolonged duration and initial good response to steroids. Etanercept, a TNF blocker, has been used as a putative molecular-targeted agent for TRAPS, with some patients showing limited efficacy. Here, we report a patient with TRAPS who recovered from steroid dependency by etanercept and kept remission with a reduced dose of etanercept. The pathophysiology of TRAPS still remains to be elucidated and several hypotheses have been proposed. In the most recent hypothesis, the concerted action of wild-type and mutant TNF receptors plays an important role in provoking enhanced inflammation in TRAPS. The excellent response to etanercept in our patient suggested that there is heterogeneity in TRAPS patients in terms of the contribution of normal TNF signaling to autoinflammation.

DOI： 10.1111/j.1442-200X.2011.03525.x

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BACKGROUND: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) leads to an aggressive and often fatal course without appropriate treatment. Etoposide therapy is crucial for the better prognosis, although it remains unknown what patients need cytotoxic agents. Since we have complied with step-up strategy in a tertiary center, treatment outcomes were studied to search predictors for disease course. METHODS: The study enrolled 22 EBV-HLH patients treated between 1999 and 2010 in Kyushu University. Immunotherapy, chemotherapy and stem cell transplantation (SCT) proceeded in stages unless patients attained a consecutive >21 days-afebrile remission. Clinical and laboratory data and outcomes were retrospectively analyzed. RESULTS: Median age of 9 males and 13 females was 5 years (range: 9 months-41 years). Sixteen patients (73%) presented at age <15 years. Two patients remitted spontaneously, 12 attained remissions after immunotherapy, 5 after chemotherapy, and 1 after successful SCT. The remaining two patients died after chemotherapy and SCT, respectively. Median EBV load was 1 × 10(5) copies/ml of peripheral blood (range: 200-5 × 10(7)). T-cells were exclusively targeted (94%; 15/16 examined) often with EBV/T-cell receptor clonality. EBV status indicated 19 primary infections and 3 reactivations. Either death occurred in EBV-reactivated patients who underwent chemotherapy ± SCT. Age at primary infection in pediatric patients increased in the last 5 years. Patients having prolonged fever (P = 0.017) or high soluble CD25 levels (P = 0.017) at diagnosis were at higher risk for requiring chemotherapy assessed by multivariate analyses. CONCLUSIONS: No cytotoxic agents were needed for >60% of EBV-HLH patients. Early immunotherapy may modulate T-cell activation and reduce the chance of unnecessary chemotherapy.

DOI： 10.1002/pbc.24039

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BACKGROUND: In Japan, chronic active Epstein-Barr virus infection (CAEBV) may manifest with infection of T-cells or NK-cells, clonal lymphoid proliferations, and overt lymphoid malignancy. These EBV-positive lymphoproliferative disorders (EBV(+)LPD) of childhood are related to, but distinct from the infectious mononucleosis-like CAEBV seen in Western populations. The clonal nature of viral infection within lymphoid subsets of patients with EBV(+)LPD of childhood is not well described. OBJECTIVES: Viral distribution and clonotype were assessed within T-cell subsets, NK-cells, and CD34(+)stem cells following high purity cell sorting. STUDY DESIGN: Six Japanese patients with EBV(+)LPD of childhood (3 T-cell LPD and 3 NK-cell LPD) were recruited. Prior to immunochemotherapy, viral loads and clonal analyses of T-cell subsets, NK-cells, and CD34(+)stem cells were studied by high-accuracy cell sorting (>99.5%), Southern blotting and real-time polymerase chain reaction. RESULTS: Patient 1 had a monoclonal proliferation of EBV-infected γδT-cells and carried a lower copy number of EBV in αβT-cells. Patients 2 and 3 had clonal expansions of EBV-infected CD4(+)T-cells, and lower EBV load in NK-cells. Patients 4, 5 and 6 had EBV(+)NK-cell expansions with higher EBV load than T-cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in the major subsets of four patients. EBV was not, however, detected in the bone marrow-derived CD34(+)stem cells of patients. CONCLUSIONS: A single EBV clonotype may infect multiple NK-cell and T-cell subsets of patients with EBV(+)LPD of childhood. CD34(+)stem cells are spared, suggesting infection of more differentiated elements.

DOI： 10.1016/j.jcv.2011.01.014

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DOI： 10.1111/j.1399-0004.2010.01432.x.

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Urolithiasis is quite rare in pediatric inflammatory bowel disease (IBD) compared with the incidence at 9-18% in adult cases. The diagnosis and treatment of pediatric IBD is challenging. Indeterminate colitis (IC), originally proposed as a subgroup of fulminant IBD, has also been used for patients when the diagnosis of either UC or CD cannot be made with certainty. Such patients should be diagnosed as having "IBD unclassified" based on evidence including mucosal biopsy samples. We report herewith a 9-year-old boy with isolated colitis that reached a diagnosis of IBD unclassified. Infliximab therapy led to a successful remission after the refractory course. However, urolithiases were impacted in the urethral valves and vesico-ureteral junction. Microhematuria was noticed from the onset of colitis. Renal calculi were detected on the X-ray films during the first line treatment. Transurethrally crushed stones consisted of calcium oxalate. Renal calculi are more closely associated with CD than ulcerative colitis in adult patients for the ileal involvement. The oxalate stones and treatment response indicated a CD-like pathophysiology. Nephrolithiasis might be a rare but noticeable extra-intestinal presentation of pediatric IBD. Infliximab therapy could be an option in pediatric refractory colitis to change the critical steroid dependency.

DOI： 10.1016/j.crohns.2010.05.012

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DOI： 10.1111/j.1442-200X.2010.03059.x

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A boy developed ipsilateral axillary lymphadenitis after Bacillus Calmette-Guérin (BCG) inoculation at the age of 5 months. Subsequently, he was diagnosed with X-linked chronic granulomatous disease (CGD) by the nitroblue tetrazolium assay when he was 4 years old. Body computerized tomography (CT) performed at the age of 25 years showed enlarged lymph nodes in the left periclavicular and axillary regions, and was confirmed by gallium scintigraphy. Mycobacterial culture, smear, and polymerase chain reaction (PCR) of the sputum and gastric fluid were negative. Whole-blood IFN-gamma assay was negative as well. Mycobacterium bovis BCG was isolated from the lymph node biopsy by PCR amplification and culture. No mutation of the IFN-gamma receptor 1 could be identified. In conclusion, CGD can be the underlying condition for BCG-itis; whole-blood IFN-gamma assay might be useful in differentiating BCG infection and tuberculosis in CGD patients; BCG vaccination is contraindicated in X-linked CGD.

DOI： 10.1007/s00431-008-0824-9

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This study aimed to assess the outcome of cardiovascular diseases for patients with chronic active Epstein-Barr virus infection (CAEBV). The study enrolled 15 patients (7 boys and 8 girls) who fulfilled the diagnostic criteria for CAEBV, including 10 patients with T-cell type and 3 patients with natural killer (NK)-cell type. The median age at the CAEBV onset was 6.3 years (range, 1.2-17.8 years). Regular cardiologic studies were performed during the median follow-up period of 8 years (range, 2-20 years). Nine patients (60%) had cardiac diseases including coronary artery lesion (CAL) (n = 4, 44%), decreased left ventricular ejection fraction and pericardial effusion in (n = 3, 33%), complete atrioventricular block (n = 1), and sudden arrest (n = 1). The frequency of fever (78%, p = 0.04) or cytopenias (100%, p = 0.01), as the major symptom among patients with cardiac complications, was higher than among those without complications. The median time from disease onset to detection of CAL was 3.4 years (range, 1.8-8.6 years). The mean z-score increased to 3.98. Seven patients (78%) with cardiac complications died of disease progression, hematopoietic stem cell transplantation-related events, or both. In two patients, CAL regressed after allogeneic cord blood transplantation. Among CAEBV patients, CAL was the most common cardiac complication and could not be controlled without the eradication of EBV-infected T- and NK-cells.

DOI： 10.1007/s00246-008-9343-8

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Chronic active Epstein-Barr virus (EBV) infection is a rare chronic mononucleosis syndrome involving clonally proliferating EBV-infected T-/NK-cells. EBV DNA was quantified in nonpleocytotic cerebrospinal fluid (CSF) of 9 patients. Three patients with neurologic and/or neuroimaging abnormalities showed high CSF copy numbers. In 1 patient, CSF copy number exceeded the peripheral blood value. CSF EBV-load may predict the central nervous system involvement of EBVT-/NK-cells.

DOI： 10.1097/INF.0b013e318178d21e

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DOI： 10.1159/000151601

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In this report, we describe a boy who showed mild symptoms of neonatal-onset multisystem inflammatory disease. Although his symptoms and laboratory findings were similar to those of systemic juvenile idiopathic arthritis, further examinations revealed papilledema, meningitis, and a NLRP3 mutation. His peripheral blood monocytes died within 24 hours after lipopolysaccharide stimulation, a test that may be useful for diagnosis even in mild cases.

DOI： 10.1016/j.jpeds.2008.01.038

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Serial changes in the circulating and cerebrospinal fluid (CSF) cytokine levels were assessed in a patient with Sjogren's syndrome (SS)-associated meningoencephalomyelitis. A 16-yr-old girl diagnosed as having primary SS at 8 yr of age presented headache and vomiting. CSF studies revealed lymphocyte-dominant pleocytosis and high IgM index, but no evidence of infection. Disturbed consciousness and diffuse slow waves on electroencephalogram led to the diagnosis of SS-meningoencephalitis. The clinical condition subsided after a cycle of dexamethasone therapy, however, 2 months later urinary retention and paresthesia of the lower body developed. Craniospinal magnetic resonance imaging (MRI) showed extensive intraparenchymal lesions with high T2-weighted signal intensity adjacent to the posterior left horn of lateral ventricle of the brain and the longitudinal lesion from C5 to T10 of the spinal cord. High-dose methyl-prednisolone and subsequent tacrolimus therapy has effectively controlled the activity of SS-meningoencephalomyelitis. Monitoring of systemic and CSF cytokine levels during the course of illness revealed that CSF interleukin-6, but not interferon-gamma or tumor necrosis factor-alpha levels were the sensitive indicator of disease activity. The unique cytokine profile, differing from those of infectious meningitis may be useful for predicting the central nervous system involvement in autoimmune disease.

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A 10-year-old female was diagnosed as having early-onset sarcoidosis (EOS) after a prolonged skin disease. A granuloma emerged on the face at age 2 and massive lesions extended to the rest of the body. Repeated biopsies indicated histiocytic proliferation. At age 7, fever, disseminated macular eruptions, and multinucleated giant cells in the bone marrow prompted vinblastine and prednisolone therapy. Five months after stopping therapy, hypercalcemic crisis occurred along with fever, cytopenias, and interferon-gamma-nemia indicating a macrophage activation syndrome. A biopsy of nodules confirmed the diagnosis of sarcoidosis. The atypical EOS should be differentiated from histiocytosis.

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Suppressors of cytokine signalling (SOCS) proteins play important roles in the negative regulation of cytokine signal. We first searched for polymorphisms in SOCS-1, SOCS-3 and SOCS-5 genes, and examined the association of the polymorphisms with type 1 diabetes (T1D). As a result, we did not find any significant associations between SOCS genes and T1D.

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：東京   Country：Japan  

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Venue：Seoul   Country：Korea, Republic of  

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Venue：福岡   Country：Japan  

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Venue：下関   Country：Japan  

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Venue：下関   Country：Japan  

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Venue：名古屋   Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

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血栓塞栓症は遺伝性素因、基礎疾患を背景に脱水や感染、外傷を契機に発症し、重篤な後遺症を残す予後不良な疾患である。遺伝性素因として凝固因子異常(FV Leiden/FII G20210A)や凝固調節因子(プロテインC:PC、プロテインS:PSおよびアンチトロンビン:AT)欠損が知られている。わが国で小児遺伝性血栓症と診断された患者の約70&#37;は凝固調節因子欠損症(PC45&#37;、PS15&#37;、AT10&#37;)である。その多くは生後2週間までに発症した新生児PC欠損症である。遺伝性血栓症を疑う契機は、若年発症あるいは繰り返す深部静脈血栓症、電撃性紫斑病(とくに新生児期)および血栓症の家族歴を有する場合である。小児は凝固因子と凝固調節因子の活性が生理的に低く、新生児期はとくにばらつきが大きいため、遺伝性血栓症を単独の活性値測定のみで予測することは難しい。確定診断のためには遺伝子検査を必要とするが、ビタミンK依存性因子で半減期の短いPC/PS/血液凝固第VII因子FVIIを同時に測定し、年齢基準値と比べ低下している場合や、因子活性が相対的に乖離している場合は遺伝子解析を積極的に進める。治療については低分子ヘパリンやワルファリン、不足する凝固調節因子目的に新鮮凍結血漿輸血を行う。補充療法として活性化PC製剤やAT製剤も使用可能である。電撃性紫斑病を繰り返す重症例には長期的な補充療法の検討が必要であり、肝移植による根治療法も行われることがある。(著者抄録)

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DOI： 10.1007/s12185-018-2493-4

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＜Key Points＞(1)限られたウイルスに対し易感染性を示す原発性免疫不全症が存在する。(2)ウイルス特異的のみならず、臓器特異性を認める原発性免疫不全症が見出されている。(3)易感染性の原因として造血系免疫担当細胞のみならず、非造血系細胞の機能障害によることもあることが明らかとなってきた。(4)病態解析のためにiPS細胞が用いられるようになり、患者由来iPS細胞を分化誘導することでin vitroでの解析が可能となっている。(著者抄録)

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C1qB遺伝子の新規スプライシング異常を認めたC1q欠損症の一家系

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原発性免疫不全症に対する遺伝子治療は、造血幹細胞移植(hematopoietic stem cell transplantaion:HSCT)にかわる根治療法として盛んに研究がおこなわれており、1990年代から実際に遺伝子治療がおこなわれている。しかし、当初より用いられていたレトロウイルスベクターによる遺伝子導入法では、宿主のゲノムへの遺伝子挿入による発がんが問題となった。そのため、より安全で生理的な変異遺伝子そのものを修復する方法が求められている。現在、相同組換えにより変異遺伝子を修復する遺伝子ターゲティングの研究が進み、新たなウイルスベクターやzinc finger nuclease(ZFN)が登場しており、これらについて概説する。(著者抄録)

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第VIII因子抑制因子陽性血友病児に対する活性化プロトロンビン複合体製剤(APCC)による予防的止血管理

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Haemophilus influenzae type bによる髄膜炎からショック・DICとなり頭部CTで多発梗塞・出血を認め両下腿の紫斑および足趾壊疽の進行を認めた1例

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Pathophysiology and treatment of Diamond-Blackfan anemia

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タクロリムスが奏効したSjoegren症候群関連髄膜脳脊髄炎の1例 髄液サイトカインの変化

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細菌性髄膜炎に伴う電撃性紫斑病にProtein C(PC)製剤が著効し診断に至ったヘテロ接合体PC欠乏症

Language：Japanese  

Sjoegren症候群の経過中に無菌性髄膜炎、急激な感覚障害と膀胱直腸障害を来した1例

Language：Japanese  

Purpura fulminans in meningitis as the first manifestation of heterozygous protein C deficiency

Language：Japanese  

A new type of severe combined immunodeficiency with microcephaly, bird-like appearance, developmental delay and hematopoietic failure

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：21

Number of peer-reviewed articles in Japanese journals：3

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：9

Number of peer-reviewed articles in Japanese journals：2

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：13

Number of peer-reviewed articles in Japanese journals：1

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3

Number of peer-reviewed articles in Japanese journals：2

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：1

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc.