Evaluation of Deficient Nutrients in Infants and Toddlers Mainly Taking Amino Acid-Based Elemental Formulas: An Exploratory Study.

INTRODUCTION: This study evaluated nutrient deficiencies in infants and toddlers with inflammatory bowel disease (IBD) and eosinophilic gastrointestinal disorders (EGIDs), whose primary nutritional source is elemental formulas (EFs). METHODS: The nutrient status of children with IBD and EGID aged 6 months to 6 years was evaluated. RESULTS: Twenty-one children fed with EFs (EF group) and 25 controls (CL group) were enrolled. The selenium level in the EF group was lower than that in the CL group (2.2 µg/dL vs. 9.3 µg/dL; p < 0.01). Although fat-soluble vitamins were deficient in some EF group participants, no significant differences were observed in their concentration and insufficiency proportion. However, ascorbic acid deficiency was more frequent in the EF group, with significantly lower levels (8.6 µg/mL vs. 12.0 µg/mL; p < 0.01). The triene:tetraene ratio was significantly higher in the EF group (0.046 vs. 0.010; p < 0.01). Asparagine and taurine levels were significantly lower in the EF group (asparagine: p < 0.01; taurine: p < 0.01) and tyrosine and phenylalanine levels were higher in the EF group, resulting in a lower Fisher's ratio (p < 0.01). CONCLUSION: Long-term feeding with EFs can cause deficiencies in essential fatty acids, selenium, and ascorbic acid and also carries a risk of amino acid imbalance in infants and toddlers.

Ustekinumab Offers Long-Term Clinical Remission With Safety in Very Early-Onset Inflammatory Bowel Disease.

We observed efficacy and safety of ustekinumab in very early-onset inflammatory bowel disease, which has not been previously reported. Clinical remission at 52% was 75%, often persisting beyond 2 years. Further studies including larger numbers of cases are needed to confirm this observation.

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.

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites.

OBJECTIVE: To examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis. METHODS: Patients with 3ß-hydroxy-ΔSuchy et al. (2021)5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)4-steroid 5ß-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run). RESULTS: In healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3ß,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3ß-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5ß-cholestanoic acid for PBD1A (78%); and tauro 3ß,7ß-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen. CONCLUSIONS: Early postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

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.

Serum leucine-rich alpha-2 glycoprotein and calprotectin in children with inflammatory bowel disease: A multicenter study in Japan.

BACKGROUND AND AIM: Serum leucine-rich alpha-2 glycoprotein (LRG) and calprotectin have been studied as disease activity markers in adults with inflammatory bowel disease (IBD). We evaluated them in pediatric IBD patients. METHODS: Subjects under 17 years old undergoing care at 11 Japanese pediatric centers were retrospectively assigned to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illness. Serum LRG and calprotectin were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: We enrolled 173 subjects, including 74 with CD, 77 with UC, and 22 NC. Serum LRG concentrations in active CD (median, 200 µg/mL) were significantly greater than in remission (81 µg/mL; P < 0.001) or NC (69 µg/mL; P < 0.001). Serum calprotectin concentrations in active CD (2941 ng/mL) also were significantly greater than in remission (962 ng/mL; P < 0.05) or NC (872 ng/mL; P < 0.05). Serum LRG concentrations in active UC (134 µg/mL) were significantly greater than in remission (65 µg/mL; P < 0.01) but not significantly greater than in NC (69 µg/mL); serum calprotectin concentrations in active UC (1058 ng/mL) were not significantly different from those in remission (671 ng/mL) or NC (872 ng/mL). In receiver operating characteristic analyses of LRG, calprotectin, C-reactive protein, and erythrocyte sedimentation rate for ability to distinguish active IBD from remission, CD and UC showed areas under receiver operating characteristic curves for LRG (0.77 and 0.70, respectively), exceeding those for calprotectin, C-reactive protein, or erythrocyte sedimentation rate. CONCLUSIONS: In pediatric IBD, serum LRG may better reflect disease activity than serum calprotectin, particularly in CD.

Incidence and diagnostic performance of ultrasound for perianal abscess or fistula-in-ano in pediatric patients with perianal inflammation.

OBJECTIVES: To describe the incidence and diagnostic performance of ultrasound for perianal abscess or fistula-in-ano in pediatric patients with perianal inflammation. METHODS: We included 45 patients with perianal inflammation who underwent ultrasonography. To demonstrate the diagnostic performance of ultrasound for fistula-in-ano, a definite diagnosis of perianal abscess, and fistula-in-ano was determined as that proven through magnetic resonance imaging (MRI) or computed tomography (CT). The absence or presence of perianal abscess and fistula-in-ano on ultrasonography was recorded. RESULTS: Among the 45 patients, on ultrasound, perianal abscess and fistula-in-ano were detected in 22 (48.9%) and 30 (68.2%) patients, respectively. Nine patients had MRI or CT and a definite diagnosis of perianal abscess or fistula-in-ano; accuracy, negative predictive value, and positive predictive value of ultrasound for perianal abscess were 77.8% (7/9; 95% confidence interval [CI]: 40.0%-97.1%), 66.7% (2/3; 95% CI: 9.4%-99.2%), 83.3% (5/6; 95% CI: 35.9%-99.6%), and those of fistula-in-ano were 100% (9/9; 95% CI: 66.4%-100%), 100% (8/8; 95% CI: 63.1%-100%), and 100% (1/1; 95% CI: 2.5%-100%), respectively. CONCLUSIONS: Perianal abscess and fistula-in-ano were detected by ultrasound in half of the patients with perianal inflammation. Accordingly, ultrasound has an acceptable diagnostic performance for perianal abscess and fistula-in-ano.

Clinical outcome of ulcerative colitis with severe onset in children: a multicenter prospective cohort study.

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.

Expert consensus on vaccination in patients with inflammatory bowel disease in Japan.

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients' IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Monogenic inflammatory bowel disease with STXBP2 mutations is not resolved by hematopoietic stem cell transplantation but can be alleviated via immunosuppressive drug therapy.

STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects.

Small bowel endoscopy for children: Collaboration of capsule endoscopy and device-assisted enteroscopy.

Capsule endoscopy (CE) and balloon-assisted enteroscopy (BAE) have become indispensable techniques for the diagnosis and management of small bowel disease in both adult and pediatric cases. However, relevant differences exist in the indications between these cohorts, with body weight and age having particular relevance in decisions for the latter. Both CE and BAE are designed for adult physique and they were not widely used among children. In addition, the types of small intestinal diseases differ between adults and children, and consequently, the indications also differ between them. This review focuses on the issues relevant to pediatric cases and describes the practical application of endoscopy in clinical practice. In conclusion, although there are age and weight restrictions, both CE and BAE are safe and useful devices for use in children, and their indications for use in children are likely to expand in the future.

Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function.

Germline gain-of-function (GOF) variants in the signal transducer and activator of transcription 3 (STAT3) gene is an inborn error of immunity presenting with autoimmunity and lymphoproliferation. Symptoms can vary widely, and no effective treatment has been established. This study investigated the efficacy of Janus kinase (JAK) inhibitors (JAKi) in patients with STAT3-GOF. Four patients were enrolled and their clinical symptoms before and after the initiation of treatment with JAKi were described. A cell stimulation assay was performed using Epstein-Barr virus transformed lymphoid cell lines (EBV-LCLs) that were derived from the patients with STAT3-GOF. The patients presented with various symptoms, and these symptoms mostly improved after the initiation of JAKi treatment. Upon interleukin-6 stimulation, the EBV-LCLs of patients showed enhanced STAT3 phosphorylation compared with those of the EBV-LCLs of healthy controls. In conclusion, four Japanese patients with STAT3-GOF were successfully treated with JAKi. JAKi ameliorated various symptoms and therefore, the use of JAKi could be an effective treatment option for patients with STAT3-GOF.

Clostridioides difficile Infection in a Japanese Tertiary Children's Hospital.

Purpose: Toxins produced by Clostridioides difficile infection (CDI) can cause enteritis and diarrhea. Although the number of pediatric CDI cases is increasing, the clinical management of pediatric CDI, including patient characteristics and prognosis, remains unclear. This study aimed to elucidate the background and clinical course of patients with CDI and evaluate the reliability of diagnostic tests in a tertiary pediatric hospital in Japan. Methods: We retrospectively analyzed the clinical data of children diagnosed with CDI between 2011 and 2021 at the Saitama Children's Medical Center in Saitama, Japan. Results: During the study period, 1,252 C. difficile antigen/toxin tests were performed, and 37 patients were diagnosed with CDI. The main underlying diseases among the patients were hematological and malignant disorders and gastrointestinal diseases, including inflammatory bowel disease (IBD) (59.4%). Two patients (5.4%) had an unremarkable medical history. Among the 37 patients, 27 (73.0%) were immunocompromised, 25 (67.6%) had a history of antibiotic use within the past two months, and 6 (16.2%) were negative on the initial test but were positive on the second test. Finally, 28 patients (75.7%) required primary antibiotic therapy only, and two patients with IBD required additional antibiotic therapy as secondary treatment. Conclusion: The number of pediatric patients with CDI is increasing. Both a comprehensive interview, including underlying diseases and history of antibiotic use, and an understanding of the features of clinical examinations should be emphasized to appropriately diagnose and treat CDI.

Dapsone for Refractory Gastrointestinal Symptoms in Children With Immunoglobulin A Vasculitis.

Immunoglobulin A vasculitis (IgAV) is a systemic small-vessel vasculitis. Although corticosteroids (CS) are the primary treatment for gastrointestinal manifestations associated with IgAV, some patients develop refractory or recurrent symptoms such as vomiting and abdominal pain despite CS treatment. Dapsone, a synthetic sulfone antimicrobial, has been used to treat cutaneous purpura in IgAV, but few authors have reported its use for refractory gastrointestinal symptoms. In this retrospective observational study, we describe results in 7 children with IgAV who were treated with dapsone for abdominal pain resistant to CS. Dapsone rapidly relieved abdominal pain in all 7 patients, who then were tapered off CS without relapse. Side effects of mild methemoglobinemia and hemolysis appeared to be manageable with planned monitoring and dose adjustment; a single patient who discontinued dapsone had fatigue and hypoxia associated with methemoglobinemia. No side effects were life-threatening. Dapsone may be considered as a therapeutic option for gastrointestinal symptoms refractory to CS in children with IgAV.

Association between the corrosion of ingested lithium button battery in the esophagus and its complications in pediatric patients.

PURPOSE: The incidence of lithium button battery ingestion has been increasing recently, which results in severe complications. We aimed to demonstrate the association between the corrosion of lithium button batteries in the esophagus on radiographs and their complications. METHODS: The nine pediatric patients included in this study were classified into two groups based on the presence of severe complications. The presence and degree of corrosion on plain radiographs were evaluated. The degree of corrosion was classified into the following three grades; none: 0%; moderate: 1-50%; severe: 51-100%. Fisher's exact test was used for statistical analyses. RESULTS: Of the nine patients, five showed complications. The number of patients who had grade none, moderate, and severe degrees of corrosion was three, four, and two, respectively. The incidence of severe complications differed significantly between the incidence of lithium button batteries' contour (without vs. with severe complications [presence/absence of corrosion] = 1/3 vs. 5/0, respectively; P = 0.0476). In cases with "none" degree of corrosion, all three cases had no complication, and in cases with a "severe" degree of corrosion, all two cases had complications. CONCLUSION: The cases with the presence of corrosion of lithium button batteries had a higher tendency to have severe complications. Therefore, physicians should anticipate the presence of severe complications in pediatric patients with corrosion more than those without corrosion.