Prognosis of pediatric ulcerative colitis after infliximab failure: A multicenter registry-based cohort study.

BACKGROUND AND AIM: Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC. METHODS: A prospective cohort study of pertinent cases enrolled in the Japanese Pediatric Inflammatory Bowel Disease Registry between 2012 and 2020 was conducted to determine outcomes for pediatric UC patients who received IFX but required its discontinuation during follow-up (IFX failure). RESULTS: Of the 301 pediatric UC patients in the registry, 75 were treated with IFX; in 36 of these, IFX was discontinued during follow-up. Severity of UC at onset and absence of concomitant immunomodulator therapy were significant risk factors for IFX failure (P = 0.005 and P = 0.02, respectively). The cumulative colectomy rate after IFX failure was 41.3% at 1 year and 47.5% at 2 years. Colectomy was significantly more frequent when IFX was discontinued before June 1, 2018, than when IFX was discontinued later (P = 0.013). This difference likely involves availability of additional biologic agents for treatment of UC beginning in mid-2018 (P = 0.005). CONCLUSION: In pediatric UC patients, approximately 50% underwent colectomy during a 2-year interval following IFX failure. Prognosis after IFX failure appeared to improve with availability of new biologic agents and small-molecule drugs in mid-2018.

Effects of laparoscopic sleeve gastrectomy on nonalcoholic fatty liver disease and TGF-ß signaling pathway.

Nonalcoholic fatty liver disease (NAFLD) develops as a result of unhealthy lifestyle but improves with laparoscopic sleeve gastrectomy (LSG). The transforming growth factor (TGF)-ß signaling pathway reportedly contributes to liver fibrosis, mainly in animal experiments. The aim of the present study was to evaluate changes in serum proteins before and after LSG by proteomic analysis and to investigate their association with NAFLD. This study enrolled 36 severely obese patients who underwent LSG at our hospital from January 2020 to April 2022. As a pilot study, proteomic analysis was conducted on six patients using serum collected before and at 6 months after LSG, and significantly fluctuating proteins were extracted. Subsequently, verification by enzyme-linked immunosorbent assay (ELISA) using collected serum was performed on the remaining 30 patients. The mean weight of enrolled patients was 118.5 kg. Proteomic analysis identified 1,912 proteins, many of which were related to the TGF-ß signaling pathway. Among these proteins, we focused on five TGF-ß-related proteins: asporin, EMILIN-1, platelet factor-4, serglycin, and thrombospondin-1. Verification by ELISA revealed that asporin (p = 0.006) and thrombospondin-1 (p = 0.043) levels significantly fluctuated before and after LSG. Univariate analysis with a linear regression model showed that aspartate aminotransferase (p = 0.045), asporin (p = 0.011), and thrombospondin-1 (p = 0.022) levels were significantly associated with postoperative liver fibrosis. On multivariate analysis, asporin was an independent prognostic factor for postoperative liver fibrosis (95% confidence interval: 0.114-1.291, p = 0.002). TGF-ß-related proteins dramatically fluctuated before and after LSG and were correlated with NAFLD pathogenesis. Asporin may be a useful prognostic marker of liver fibrosis in NAFLD after LSG.

Safety and efficacy of vedolizumab in pediatric patients with ulcerative colitis: multicenter study in Japan.

BACKGROUND: Vedolizumab (VDZ) is a humanized monoclonal antibody that binds to α4ß7 integrin expressed in T-lymphocytes and is gut selective. Few studies have evaluated the safety and efficacy of VDZ in pediatric ulcerative colitis (UC) patients, especially from Asia. METHODS: A longitudinal multicenter retrospective study was conducted at 10 Japanese tertiary medical institutions. Patients aged ≤18 years old who received VDZ for UC between January 2019 and July 2021 were enrolled. Information on the clinical characteristics, prior/concomitant treatment, and safety during the observation period was collected. RESULTS: The data obtained from 48 patients (males, n = 30; females, n = 18) were analyzed. The median age at VDZ induction was 14 (range 4-18) years old. VDZ was indicated in 73% of patients as switching from previous biologics due to primary failure, loss of response, and adverse events (AEs) and was the first biologic in 27%. Remission was achieved or maintained at weeks 14, 30, and 54 in 79.2%, 75.0%, and 65.8% of patients, respectively. There were no significant differences between the number of previous biologics exposures and VDZ effectiveness. The hematocrit, serum albumin concentrations, and erythrocyte sedimentation rate (ESR) at baseline differed significantly by VDZ effectiveness. Nine AEs, including infusion reaction, were noted in seven (14.3%) patients. There were no severe AEs related to VDZ administration. CONCLUSIONS: VDZ was safe and effective in children with UC. The hematocrit, albumin, and ESR at VDZ initiation might be predictors for VDZ effectiveness. VDZ may be an important option for pediatric patients and can be used as an alternative to immunomodulators.

Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

Scallop aquaculture has a potential risk of natto-induced hypersensitivity reactions in a local area of northern Japan.

BACKGROUND: Fermented soybean (natto)-induced hypersensitivity reactions (natto allergy) are rare and can result in late-onset anaphylaxis. The allergen in natto is considered to be poly-γ-glutamic acid (PGA), and marine sports are a risk factor for natto allergy due to epicutaneous sensitization to PGA from cnidarian stings. However, no research on natto allergy in fishery workers has yet been performed. METHODS: We conducted a chart review of inpatients diagnosed with anaphylaxis due to natto at Hokkaido Prefectural Haboro Hospital between April 1, 2009, and August 31, 2020. We also administered self-report questionnaires about food hypersensitivity reactions to Japanese fishery workers, including members of the Kitarumoi Fishery Cooperative Association and part-time workers in this area, from February 1 to May 31, 2021. RESULTS: We found six inpatients (29 inpatients with food-induced anaphylaxis among approximately 11,000 community-dwelling residents) with late-onset anaphylaxis due to natto; all were involved in scallop aquaculture. The questionnaires revealed that 27 participants had natto allergy. We divided the fishery workers into a scallop aquaculture (Scallop) group (n = 211) and other fishery group (n = 106). The Scallop group was significantly associated with natto allergy after adjustments for confounders (OR: 5.73, 95% CI: 1.46-22.56) by logistic regression analysis. In the Scallop group, older age, experience in repairing nets, and a longer length of work experience were significantly related to participants with natto allergy (n = 23), but not participants without natto allergy (n = 181). CONCLUSIONS: Our results indicated an association between scallop aquaculture and natto allergy.

Qing-Dai for pediatric ulcerative colitis multicenter survey and systematic review.

BACKGROUND: Pediatric ulcerative colitis (UC) is more challenging to treat than adult UC. Qing-Dai therapy is effective in adults but reports of its efficacy in children are unavailable. We conducted a questionnaire survey on Qing-Dai use among pediatric patients with UC in Japan to determine its efficacy and safety. METHODS: Questionnaires were sent to 31 high-volume centers treating pediatric patients with inflammatory bowel disease. The number of patients using Qing-Dai, short-term and long-term effects, and adverse events were assessed. A systematic review of studies on the efficacy and safety of Qing-Dai usage for UC was also performed. RESULTS: Overall, 29/31 facilities (93.5%) responded, Qing-Dai was used in 107 patients with UC, and 84/107 patients (78.5%) initiated treatment. Within 6 months, 81/101 (80.2%) patients had clinical remission, while 59/92 (64.1%) patients had no relapse and 29/92 (31.5%) experienced only one to two relapses yearly. Eighty-seven percent of the patients underwent regular follow ups for adverse events, among whom one patient was diagnosed with pulmonary arterial hypertension (PAH), five with enteritis, and one with headache. In the systematic review, the clinical remission rate was 50-80%, and PAH was observed in 14 of 1,158 patients (1.2%). CONCLUSIONS: Qing-Dai is highly effective in treating pediatric UC. However, Qing-Dai should be administered with caution as it may cause adverse events such as PAH.

A consensus statement on health-care transition for childhood-onset inflammatory bowel disease patients.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the intestine. The incidence of IBD is increasing worldwide, including Japan, and in approximately 25% of all affected patients it is diagnosed before 18 years of age. For the health maintenance of such patients, planned transition to adult care systems is essential. Previous Japanese surveys have revealed gaps between adult and pediatric gastroenterologists with regard to their knowledge and perception of health-care transition for patients with childhood-onset IBD. In 2021-2022, several Web workshops to discuss issues related to the transitional care of IBD patients were held by the Ministry of Health, Labour and Welfare of Japan as part of their program for research on intractable diseases. Clinicians experienced in IBD treatment for pediatric and adult patients participated. As a result, this panel of adult and pediatric gastroenterologists developed five consensus statements on the issue of "transfer from pediatric to adult care" and nine statements on the issue of "addressing transitional care (transition program)." To address current gaps in health-care transition for childhood-onset IBD patients, a programmed approach to transition, and better partnerships between pediatric and adult gastroenterologists are indicated. It is hoped that this consensus statement will provide a basis for the development of appropriate guidelines for clinical practice.

Transitional Care for Patients with Inflammatory Bowel Disease: Japanese Experience.

BACKGROUND: Transition-related healthcare intervention has recently been receiving worldwide attention. Given the increasing incidence of pediatric inflammatory bowel disease (IBD) and its lifelong impact, transitional care has become an important issue. In Japan, guidelines to support the autonomy of IBD patients during transition were recently published. SUMMARY: Here, we review current issues regarding care for IBD patients during transition from the pediatric to adult period in order to identify the barriers and key elements for successful transition in the context of the Japanese system. Although no single optimal model of transitional care exists, crucial elements identified so far include a joint pediatric/adult clinic or alternating visits between pediatric and adult healthcare providers, a multidisciplinary approach, and good coordination among stakeholders. Self-reliance and independence of patients with childhood-onset IBD are also considered essential for successful transition. Various tools for assessment of transition readiness have been validated and are considered useful. Better outcomes are expected for individually tailored transition, including improvements in medication adherence, perceived health status, quality of life, and self-management. The timing of transfer from a pediatric to an adult gastroenterologist should not be fixed because the issue is not chronological age but rather the degree of individual maturity. We also propose a standardized medical summary with a checklist template for official referral of patients from a pediatric to an adult gastroenterologist. Key Messages: Transition programs require a multidisciplinary approach with a coordinator (IBD nurse) and optimal collaboration and communication. Lack of resources and funding are also pertinent issues.

Transitional care for inflammatory bowel disease: A survey of Japanese pediatric gastroenterologists.

BACKGROUND: In 2019 we reported the results of a Japanese national survey designed to explore the views of adult gastroenterologists regarding transitional care for patients with childhood-onset inflammatory bowel disease (IBD). For the present study, we conducted a similar survey of pediatric gastroenterologists to compare the views of the two sets of specialists. METHODS: The survey conducted in 2019 involved 48 representative members of the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition. They were contacted by conventional mail and their answers were not anonymized. Respondents who had already referred patients with IBD to adult gastroenterologists were asked in a questionnaire to rank the importance of specific statements on a Likert scale. RESULTS: The response rate was 79% and 29 (60%) of the respondents had experienced transitional care for patients with IBD. Transfer to adult care was considered by 90% of the respondents to be the ideal form of medical care for adolescents/young adults with IBD. However, 59% of the respondents had experienced some degree of difficulty when making referrals for such care. The majority of pediatric gastroenterologists considered that the ideal age for transfer was 18-22 years. Among the respondents, physicians at municipal hospitals considered that the presence of diseases other than IBD and a shortage of manpower were significantly more important issues than other practice settings. CONCLUSIONS: The present survey revealed that the general views regarding transitional care for IBD between pediatric and adult gastroenterologists were similar, except for the appropriate time for transfer. The results underline the importance of preparing a transition program appropriate to practice settings.

Adult gastroenterologists' views on transitional care: Results from a survey.

BACKGROUND: In 2018, Japanese guidelines for autonomy support of patients with inflammatory bowel disease (IBD) in the transitional period were published. These guidelines, however, were prepared mainly by pediatric gastroenterologists. In order to improve such supportive guidelines, it is necessary for pediatric gastroenterologists to be aware of the attitudes and expectations of adult gastroenterologists. Accordingly, the first Japanese national survey designed to explore the views of adult gastroenterologists regarding successful transitional care was conducted. METHODS: The survey involved institutions at which adult gastroenterologists in the Ministry of Health, Labor and Welfare of Japan's Inflammatory Bowel Diseases Study Group, were working. Physicians were contacted by conventional mail, and their answers were not anonymized. A total of 100 eligible adult institutions were identified. Further specific subgroup analysis was conducted. RESULTS: A response rate of 34% was achieved. Seventy-six percent of the respondents had experienced some degree of difficulty when accepting patients with childhood-onset IBD referred from pediatric gastroenterologists. With regard to the ideal form of medical care for adolescent patients with IBD, transfer to adult care was supported by 94% of the respondents. Only 27% of respondents, however, stated they would have no hesitation in accepting patients referred from pediatric care centers. Two crucial areas requiring improvement were identified: inadequate clinical summaries and lack of patient independence from their parents/caregivers. CONCLUSIONS: The present survey results reinforce the importance of a transitional program of education for childhood-onset IBD patients and the need to improve communication between adult and pediatric gastroenterologists.

Zinc monotherapy for young children with presymptomatic Wilson disease: A multicenter study in Japan.

BACKGROUND AND AIM: Few studies of zinc monotherapy for presymptomatic Wilson disease have focused on young children. We therefore evaluated long-term efficacy and safety of zinc monotherapy for such children and established benchmarks for maintenance therapy. METHODS: We retrospectively and prospectively examined children under 10 years old with presymptomatic Wilson disease who received zinc monotherapy from time of diagnosis at 12 participating pediatric centers in Japan. RESULTS: Twenty-four patients met entry criteria. Aspartate aminotransferase and alanine aminotransferase decreased significantly beginning 1 month after initiation of treatment and usually remained under 50 U/L from 1 to 8 years of treatment. Twenty four-hour urinary copper decreased significantly at 6 months and usually remained under 75 µg/day and between 1 and 3 µg/kg/day for the remainder of the study. All patients continued to take zinc, and none became symptomatic. In patients under 6 years old who received 50 mg/day of zinc as an initial dose, aspartate aminotransferase and alanine aminotransferase significantly decreased at 1 month after initiation of treatment, as did γ-glutamyltransferase and 24-h urinary copper at 6 months. CONCLUSIONS: To our knowledge, this is the first multicenter study of zinc monotherapy for young children with presymptomatic Wilson disease. Such monotherapy proved highly effective and safe. Maintaining normal transaminase values (or values under 50 U/L when normalization is difficult) and 24-h urinary copper excretion between 1 and 3 µg/kg/day and under 75 µg/day is a reasonable goal. An initial dose of 50 mg/day is appropriate for patients under 6 years old.

Occult hepatitis B virus infection in immunized children born to carrier mothers.

BACKGROUND: The prevalence of occult hepatitis B virus (HBV) infection (OBI) in children due to mother-to-child transmission (MTCT) despite immunoprophylaxis remains controversial and is still unknown in Japan. The aim of this study was to determine the OBI prevalence in such children in Japan and identify the genomic mutations that might be associated with the pathogenesis of OBI in children. METHODS: The data on 158 children born to HBV carrier mothers and who received complete passive-active immunoprophylaxis after birth in 2002-2014 were reviewed. HBV markers were detected using commercial enzyme-linked immunosorbent assay kits. HBV-DNA was detected using real-time and nested polymerase chain reaction. Complete genomic sequences were determined. RESULTS: Among the 158 children studied, three had HBV MTCT: two had OBI, and one had resolved HBV infection (RBI). The prevalence of OBI and RBI was estimated to be 1.3% and 0.6%, respectively. The HBV genomes of the two OBI children were wild type and 100% identical to those of their mothers. Of these two children, one received repeated hepatitis B immunoglobulin (HBIG) and developed overt HBV infection. Her HBV genome had a G145R mutation in the S gene that might have been induced by HBIG treatment. The RBI child was persistently positive for antibody to HBV core antigen (10-12 signal/cut-off ratio; S/CO). CONCLUSIONS: A low prevalence of OBI was observed in children who received immunoprophylaxis for preventing MTCT in Japan. The development of overt HBV infection in infants with OBI indicates the necessity of close and long-term monitoring.

Double-balloon Enteroscopy for Pediatric Patients: Evaluation of Safety and Efficacy in 257 Cases.

OBJECTIVES: The safety and efficacy of double-balloon enteroscopy (DBE) in pediatric patients has not been well documented. We aimed to evaluate the clinical efficacy and safety of DBE in children, especially those under 10. METHODS: We retrospectively analyzed our database of DBE procedures performed between September 2000 and September 2013. Procedures performed in pediatric patients (under 18) were selected from a total of 3980, including double-balloon endoscopic retrograde cholangioscopy (DBERC). RESULTS: Two hundred fifty-seven DBE procedures were performed in 117 pediatric patients (median age 12.5 years). Antegrade (oral-route) DBE was performed in 166 procedures including 104 DBERC procedures (lowest body weight 13.5 kg, youngest age 3 years), and retrograde (anal-route) DBE in 91 (lowest body weight 12.0 kg, youngest age 2 years). The overall diagnostic yield for obscure gastrointestinal bleeding and abdominal pain was 58.8%. The purpose of DBERC was achieved in 76.9% of procedures. The overall complication rate in our series was 5.4% (1.9% with the DBERC cases removed); in patients under 10, it was 10.4% (7/67). No severe complications associated with enteroscope insertion and sedation were observed. Serum amylase levels tended to be elevated in patients who underwent oral-route DBE. CONCLUSIONS: DBE is safe and feasible for diagnostic evaluation of small bowel disorders in pediatric patients, even those younger than 10 years. Special attention for possible complications must, however, be paid during therapeutic DBE procedures, including DBERC, especially for patients under 10.

Functional dyspepsia and irritable bowel syndrome in teenagers: Internet survey.

BACKGROUND: Only a handful of studies have investigated children with functional dyspepsia (FD) and irritable bowel syndrome (IBS) classified according to the Rome III criteria, and limited information is available on the lifestyle of affected patients. METHODS: We conducted an Internet questionnaire survey of 2060 parents among the general public in Japan who lived with their children aged 10-15, who were screened for FD and IBS. RESULTS: The prevalence of FD and IBS was 2.8% and 6.1%, respectively, and 1.4% of the subjects met the criteria for both FD and IBS. The lifestyles of 155 subjects who met the criteria for FD, IBS, or both were compared with those of 1745 control subjects. In comparison with the controls, a significantly higher percentage of subjects with FD, IBS, or both thought that their sleep was insufficient, ate meals irregularly, were susceptible to stress and to dizziness on standing, had difficulty in getting out of bed or felt sluggish in the morning, had a tendency to faint when standing, and had migraine/chronic headache. CONCLUSIONS: Children with FD and IBS are susceptible to stress, have impaired sleep and eating habits, and have more frequent symptoms of comorbid orthostatic dysregulation and headache.

Epidemiology of pediatric allergic diseases in the Ogasawara Islands.

BACKGROUND: The Ogasawara Islands, away from mainland Japan, belong to a subtropical area. Although the daily eating habits and food are relatively similar to that on the mainland, the living environment is quite different. The prevalence of allergic diseases in the Ogasawara Islands is unknown. This study aimed to identify the prevalence of allergic diseases in the Ogasawara Islands. METHODS: A survey was conducted among all children belonging to preschool, elementary school, and junior high school in the Ogasawara Islands. A questionnaire was prepared in accordance with the International Study of Asthma and Allergies in Childhood (ISAAC) core written questionnaire in bronchial asthma (BA) and the West Japan Study of Asthma and Allergies in Childhood core written questionnaire for atopic dermatitis (AD), allergic rhinitis (AR), and food allergy (FA). At the same time, height, weight, duration of dwelling on the island, home environment, lifestyle, and exercise habits were also asked. RESULTS: The target population comprised 352 children, of whom 284 (80.6%) completed the questionnaires. The current prevalence was 9.3% for BA, 4.3% for AD, 17.8% for AR, and 3.0% for FA. Significantly lower rates of current BA and AD were observed compared to previous reports from Japan. The percentage of children belonging to sports clubs, and exercising more than 3 times per week at the Ogasawara Islands is higher compared with the national average. CONCLUSIONS: The lower prevalence of BA and AD in the Ogasawara Islands implies the influence of differences in the living environment and exercise habits.

Utility of serum ferritin and lactate dehydrogenase as surrogate markers for steroid therapy for Mycoplasma pneumoniae pneumonia.

INTRODUCTION: Patients with severe mycoplasma pneumonia having very high serum interleukin-18 levels may require systemic corticosteroid treatment. However, we know of no laboratory markers that have been identified to assess the precise severity of Mycoplasma pneumoniae pneumonia. Thus, we investigated the usefulness of four clinical laboratory tests as severity indicators and surrogate markers for initiation of steroid therapy in these patients. PATIENTS AND METHODS: For 22 Japanese children (including 3 patients who needed systemic corticosteroid therapy) diagnosed with Mycoplasma pneumoniae pneumonia, white blood cell counts and serum concentrations of interleukin-18, C-reactive protein, lactate dehydrogenase, and ferritin were determined in the acute and recovery phases. RESULTS: In total, 8 and 14 patients were classified as moderate and mild pneumonia, respectively, according to clinical manifestations. The serum interleukin-18 level in the acute phase of the pneumonia group was significantly higher than that of age-matched controls. Furthermore, serum interleukin-18, lactate dehydrogenase and ferritin levels in the acute phase increased in parallel with the severity of the pneumonia. The serum ferritin level was also higher in the acute phase than in the recovery phase. Positive correlations between the levels of serum interleukin-18, lactate dehydrogenase and ferritin were observed in the acute phase. CONCLUSIONS: Serum lactate dehydrogenase and ferritin levels may be useful as indicators of the severity of pediatric Mycoplasma pneumoniae pneumonia for initiation of corticosteroid therapy.