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Background: As best practices for treating children with severe-onset ulcerative colitis remain controversial in the era of biologic agents, we prospectively investigated treatments and outcomes in a multicenter cohort., Methods: Using a Web-based data registry maintained in Japan between October 2012 and March 2020, we compared management and treatment outcomes in an S1 group defined by a Pediatric Ulcerative Colitis Activity Index of 65 or more points at diagnosis with those in an S0 group defined by an index value below 65., Results: Three hundred one children with ulcerative colitis treated at 21 institutions were included, with follow-up for 3.6 ± 1.9 years. Among them, 75 (25.0%) were in S1; their age at diagnosis was 12.3 ± 2.9 years, and 93% had pancolitis. Colectomy free rates in S1 were 89% after 1 year, 79% after 2, and 74% after 5, significantly lower than for S0 (P = 0.0003). Calcineurin inhibitors and biologic agents, respectively, were given to 53% and 56% of S1 patients, significantly more than for S0 patients (P < 0.0001). Among S1 patients treated with calcineurin inhibitors when steroids failed, 23% required neither biologic agents nor colectomy, similarly to the S0 group (P = 0.46)., Conclusions: Children with severe ulcerative colitis are likely to require powerful agents such as calcineurin inhibitors and biologic agents; sometimes colectomy ultimately proves necessary. Need for biologic agents in steroid-resistant patients might be reduced to an extent by interposing a therapeutic trial of CI rather than turning to biologic agents or colectomy immediately., (© 2023. Japanese Society of Gastroenterology.)

Background: The aim of this study was to evaluate the standard values for gender- and age-stratified serum pepsinogen (sPG) in Helicobacter pylori (H. pylori) non-infected children and to determine the optimal cut-off values of sPG for predicting H. pylori-infected gastritis in children., Methods: A prospective study for determination of sPG levels was performed in children with epigastric pain who underwent esophagogastroduodenoscopy over the past 16 years. After excluding subjects diagnosed with inflammatory bowel diseases, eosinophilic gastrointestinal disorders, or immunoglobulin A vasculitis, the diagnosis of H. pylori infection was defined by positive tissue culture or concordant-positive results for histology and the rapid urease test., Results: A total of 405 subjects were diagnosed as being H. pylori-infected (79) or non-infected (326). In the H. pylori non-infected group, there were no significant differences in sPG levels among age groups; males had higher sPG I and sPG II levels than females. In the H. pylori-infected group, sPG I and sPG II levels were significantly higher and the sPG I/II ratio was lower than those in the non-infected group. In receiver operating characteristics analyses in diagnosing H. pylori infection, the areas under the curves for sPG I, sPG II and sPG I/II ratio were 0.896, 0.980, and 0.946, respectively. The optimal cut-off value of sPG II of ≥9.0 ng/mL was considered positive for H. pylori infection (sensitivity: 92.4%, specificity: 93.9%)., Conclusions: The optimal cut-off value of sPG II of ≥9.0 ng/mL may be a good predictor of H. pylori-infected gastritis in children., (© 2022 Japan Pediatric Society.)

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease., Methods: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel., Results: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon., Conclusions: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions., (© 2021 Japan Pediatric Society.)

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment., Objective: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT., Methods: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed., Results: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT., Conclusions: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate the short-term effectiveness of adalimumab therapy in patients with ulcerative colitis (UC), especially its rapid response.This retrospective, multicenter, cohort study involved 7 institutes in Japan, compiling data from patients with UC who had received at least 1 induction dose of 160 mg of adalimumab between June 2013 and May 2017. Patients should have a Lichtiger clinical activity index score of ≥5 at the initial adalimumab administration. Remission was defined as clinical activity index score of ≤4, whereas response was defined as a reduction of ≥50% from the baseline value. Rapid responders are defined as patients who achieved response at 2 weeks.A total of 91 patients were included in this study: 37.4% and 45.1% achieved clinical response at 2 and 8 weeks, respectively, whereas clinical remission rates 12 weeks were 45.1%. Among the rapid responders, 82.4% achieved clinical remission at 12 weeks. Multivariate logistic regression analysis identified a higher platelet count as an independent prognostic factor for a higher rate of rapid response. Receiver operating characteristic curve showed that a platelet counts cutoff value of ≥312 × 10/L was associated with a rapid response.Approximately 40% of patients with UC showed a rapid response to adalimumab therapy after 2 weeks. Up to 80% of the rapid responders also achieved remission at 12 weeks. A higher platelet count was identified as an independent prognostic factor for a higher rapid response rate.

Background: The infection route of Helicobacter pylori has been recognized to be mainly intrafamilial, preferentially mother-to-child, especially in developed countries. To determine the transmission route, we examined whether multilocus sequence typing (MLST) was useful for analysis of intrafamilial infection. The possibility of intraspousal infection was also evaluated., Materials and Methods: Clonal relationships between strains derived from 35 index Japanese pediatric patients, and their family members were analyzed by two genetic typing procedures, MLST and random amplified polymorphic DNA (RAPD) fingerprinting., Results: Mostly coincident results were obtained by MLST and RAPD. By MLST, the allele of loci in the isolates mostly matched between the index child and both the father and mother for 9 (25.7%) of the 35 patients, between the index child and the mother for 25 (60.0%) of the 35 patients., Conclusions: MLST is useful for analyzing the infection route of H. pylori as a highly reproducible method. Intrafamilial, especially mother-to-children and sibling, infection is the dominant transmission route. Intraspousal infection is also thought to occur in about a quarter in the Japanese families., (© 2015 John Wiley & Sons Ltd.)

Objective: We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency., Patients and Methods: Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed., Results: Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm(3) and 1248/mm(3), approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential., Conclusions: Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.

Background: Long-term effectiveness of enteral nutrition for maintaining remission in pediatric Crohn's disease (CD) is poorly documented. The aim of this study was therefore to examine the long-term effectiveness of enteral nutrition with aminosalicylates as maintenance therapy for those in whom remission was primarily induced by total parenteral nutrition or exclusive enteral nutrition with aminosalicylates., Methods: We retrospectively analyzed data for 58 pediatric patients with newly diagnosed CD during a median follow-up period of 50 months (range, 12-216 months). Data for remission-induced patients in whom enteral nutrition with aminosalicylates was used as maintenance therapy were analyzed with particular reference to time to first relapse and time to first intestinal surgery., Results: Twenty-five (43.1%) of the patients relapsed with a median duration of remission of 32.4 months (range, 6-73.2 months). The cumulative rates of continuous remission were 0.88 (95%CI: 0.79-0.96) at 1 year, 0.73 (95%CI: 0.61-0.85) at 2 years, and 0.52 (95%CI: 0.35-0.68) at 5 years. None of the patients received corticosteroids, immunomodulators or anti-tumor necrosis factor agents until relapse. Disease location had no impact on timing of relapse, but with regard to disease behavior there was a trend towards earlier relapse in patients with penetrating type. Only six of the 58 patients (10.3%) needed intestinal surgery. There was a trend towards need for surgery in patients with ileal disease and with stricturing type., Conclusions: Enteral nutrition therapy with aminosalicylates is effective for maintaining remission and decreasing the rate of intestinal surgery in pediatric CD., (© 2014 Japan Pediatric Society.)

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for >7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication., (© 2015 Japan Pediatric Society.)

Numerous studies have suggested a link between iron-deficiency anemia(IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-iron-dependent rapid proliferation than those of strains derived from patients without IDA. Recently we examined the nucleotide sequences of nap A, fur, and feo B of H. pylori strains from 24 IDA patients and those from 25 non-IDA patients. Frequency of neutrophil-activating protein A(Nap A), which encoded by nap A, with threonine at amino acid residue No. 70 (Thr70-type Nap A) was significantly higher in IDA strains than non-IDA strains. Strains with Thr70-type Nap A showed significantly higher levels of Fe3+ and Fe2+ uptake than strains with other type, Ser70-type Nap A, which is found in standard strains.

Background: Numerous studies have suggested a link between iron-deficiency anemia (IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-ion-dependent rapid proliferation than those of strains derived from patients without IDA., Materials and Methods: Twenty-four H. pylori strains from IDA patients (IDA strains) and 25 strains from patients who had H. pylori gastritis without anemia (non-IDA strains) were examined. Their nucleotide sequences of napA, fur, and feoB, which contribute to Fe ion uptake, were determined., Results: Numerous polymorphisms of the three genes were found in both strains. Frequency of neutrophil-activating protein A (NapA), which encoded by napA, with threonine at amino acid residue No. 70 (Thr70-type NapA) was significantly higher in IDA strains than in non-IDA strains. Strains with Thr70-type NapA showed significantly higher levels of Fe(3+) and Fe(2+) uptake than did strains with other types, Ser70-type of NapA, which is found in standard strains. Other significantly different occurrences of polymorphisms between IDA and non-IDA groups were not observed in these genes., Conclusion: The results suggest that H. pylori strains with Thr70-type NapA have enhanced Fe ion uptake ability and are associated with the pathogenesis of IDA., (© 2012 Blackwell Publishing Ltd.)

Background. The number of Helicobacter pylori clones infecting a single host has been discussed in numerous reports. The number has been suggested to vary depending on the regions in the world. Aim. The purpose of this study was to examine the number of clones infecting a single host in a Japanese urban population. Materials and Methods. Thirty-one Japanese patients undergoing upper gastrointestinal endoscopy were enrolled in this study. H. pylori isolates (total 104 strains) were obtained from biopsy specimens (antrum, corpus, and duodenum) and gastric juice. Clonal diversity was examined by the random amplified polymorphic DNA (RAPD) fingerprinting method. Results. The RAPD fingerprinting patterns of isolates from each patient were identical or very similar. And the isolates obtained from several patients with 5- to 9-year intervals showed identical or very similar RAPD patterns. Conclusion. Each Japanese individual of an urban population is predominantly infected with a single H. pylori clone.

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology. It is quite difficult to diagnose CD without typical localized signs or symptoms. We present a 5-year-old boy with unicentric plasma cell CD in the mesentery, which was too small to be detected by any conventional imaging. (18)F-fluorodeoxyglucose positron emission tomography image and a serum cytokine profile prompted us to perform a curative surgical excision, confirming his diagnosis. Our case also supported an important role of interleukin-6 in the pathophysiology of plasma cell CD.

A 14-year-old Japanese girl with a progressing combined immunodeficiency had developed non-Hodgkin's diffuse large B cell lymphoma. Her molecular analysis showed a compound heterozygote of novel mutations in the LIG4 gene, M249V substitution and a five nucleotides deletion from nucleotide position 1,270-1,274. She had also a set of characteristic clinical features of LIG4 syndrome. Mutations in the LIG4 gene, which plays a critical role in the repair of DNA double-strand breaks, imply a correlation with malignancies and several cases with leukemia or lymphoma have already been reported. We report here on a case of LIG4 syndrome complicated with distinct EBV-associated B-cell lymphoma.

Objective: Juvenile Sjögren's syndrome (SS) is an early-onset type of SS. Autoantibody against the N-terminal 120 kDa form of a-fodrin is a specific and sensitive disease marker for both juvenile and adult SS. We investigated the initial and major determinants of a-fodrin in SS., Methods: Sera were obtained from patients with juvenile SS, 10 with primary SS and 10 with secondary SS. Epitope specificities of IgG antibodies were examined by dot-blot analyses using overlapping fusion proteins of the N-terminal part (561 amino acid residues) of a-fodrin as antigens., Results: All sera from patients with primary SS reacted with amino acid residues 1 to 98 and 36 to 150, but not with 91 to 199. Epitope mapping using fusion proteins with subfragments, each consisting of about 50 amino acid residues, showed reactivity with amino acid residues 27-80 and 79-132, suggesting that at least 2 epitopes are contained in the first 150 amino acid residues. All 3 cases with neurological complications had additional epitope specificities. Sera from patients with secondary SS showed more diversified specificities and strongly reacted with amino acid residues 1-98 and 334-432, whereas the reactivities to 36-150, a major epitope in primary SS, were minimal., Conclusion: Major and initial B cell epitopes specifically reside in N-terminal amino acids 36-132 and could be used as a diagnostic tool for primary SS. The epitope subsequently expands to other regions of a-fodrin in association with the development of neurological complications or disease progression. Secondary SS has distinct epitope specificities.