Case report: Immunological characteristics of de novo ulcerative colitis in a child post COVID-19.

The pathological mechanisms of de novo inflammatory bowel disease (IBD) following SARS-CoV-2 infection are unknown. However, cases of coexisting IBD and multisystem inflammatory syndrome in children (MIS-C), which occurs 2-6 weeks after SARS-CoV-2 infection, have been reported, suggesting a shared underlying dysfunction of immune responses. Herein, we conducted the immunological analyses of a Japanese patient with de novo ulcerative colitis following SARS-CoV-2 infection based on the pathological hypothesis of MIS-C. Her serum level of lipopolysaccharide-binding protein, a microbial translocation marker, was elevated with T cell activation and skewed T cell receptor repertoire. The dynamics of activated CD8+ T cells, including T cells expressing the gut-homing marker α4ß7, and serum anti-SARS-CoV-2 spike IgG antibody titer reflected her clinical symptoms. These findings suggest that SARS-CoV-2 infection may trigger the de novo occurrence of ulcerative colitis by impairing intestinal barrier function, T cell activation with a skewed T cell receptor repertoire, and increasing levels of anti-SARS-CoV-2 spike IgG antibodies. Further research is needed to clarify the association between the functional role of the SARS-CoV-2 spike protein as a superantigen and ulcerative colitis.

Gastrointestinal bleeding/ulcer among paediatric cancer patients after proton beam therapy.

BACKGROUND: The details of gastrointestinal bleeding/ulcer in paediatric cancer patients treated with proton beam therapy have not been reported previously. METHODS: Patients aged 15 years or younger at the time of proton beam therapy and whose gastrointestinal tract was included in the irradiated field participated. RESULTS: A total of 124 patients participated in the study; their median age at irradiation was 5.4 years. Concurrent chemotherapies were vincristine-cyclophosphamide (16 patients), irinotecan-based treatment (16 patients), vincristine-cyclophosphamide-ifosfamide-etoposide (14 patients), other chemotherapy (27 patients) and no chemotherapy (51 patients). Gastrointestinal bleeding/ulcer occurred in four patients (3.2%), with no death due to the bleeding/ulcer. The sites of the gastrointestinal bleeding/ulcer were the stomach (two patients) and the duodenum (two patients). The ages of the four patients at PBT were 5.3, 13.8, 14.2 and 14.8 years, which were significantly older than those of patients without GI bleeding/ulcer (p = 0.017). The maximum irradiated doses to the GI tract in the four patients were 43.2, 45, 50.4 and 50.4 gray equivalent, respectively. The concomitant chemotherapy was vincristine-cyclophosphamide-ifosfamide-etoposide 3 and vincristine-cyclophosphamide 1. Weeks from proton beam therapy to bleeding/ulcer were 15, 20, 22 and 264. DISCUSSION AND CONCLUSIONS: Patients who developed gastrointestinal bleeding/ulcer were treated concurrently with vincristine-cyclophosphamide-ifosfamide-etoposide or vincristine-cyclophosphamide, and their ages were older than those of patients without gastrointestinal bleeding/ulcer. Bleeding occurred in the upper gastrointestinal tract in all the cases, and most cases occurred early and during chemotherapy. Upper gastrointestinal irradiation in older children undergoing intensive chemotherapy may increase the risk of developing gastrointestinal complications.

Successful Treatment With Everolimus for Multifocal Lymphangioendotheliomatosis With Thrombocytopenia in an Infant.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a rare disease characterized by the presence of multiple cutaneous lesions and bleeding from the gastrointestinal tract with thrombocytopenia. Because of the varied phenotypes and rarity of MLT, a treatment strategy has not been standardized thus far. We describe a case of infantile MLT that did not respond to treatment with propranolol, prednisolone, or vincristine. We successfully treated the patient with everolimus, an inhibitor of the mammalian target of rapamycin. Our case provides the first evidence of the effectiveness of everolimus for the treatment of MLT.

Immunological characteristics of severe acute hepatitis of unknown origin in a child post SARS-CoV-2 infection.

Recent studies have reported that pediatric acute liver failure of unknown origin is immune-mediated, with CD8+ T cells playing a key role. Moreover, investigation of superantigen-mediated T-cell activation by the SARS-CoV-2 spike protein in pediatric severe acute hepatitis is needed in the context of the proposed mechanism of multisystem inflammatory syndrome in children (MIS-C). We investigated the immunological characteristics of a Japanese pediatric patient with severe acute hepatitis post SARS-CoV-2 infection. The patient demonstrated autoimmune hepatitis-like liver histology with CD8+ lymphocyte-predominant infiltration. There was Th1-type immune skewing, including remarkable peripheral CD8+ T-cell activation and a skewed T cell receptor repertoire. We also found elevated plasma levels of the anti-SARS-CoV-2 spike-specific IgG antibody, and the titer peaked after treatment, as seen with MIS-C. These findings support that immunological activation involving SARS-CoV-2 spike protein plays a crucial role in a pediatric patient with acute severe hepatitis post SARS-CoV-2 infection.

A novel BMPR1A mutation affects mRNA splicing in juvenile polyposis syndrome.

BACKGROUND: Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor ß signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS. METHODS: Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. RESULTS: A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5G>C) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41. CONCLUSION: We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS.

A novel case of congenital hepatic arterio-veno-portal shunts with umbilical vein aneurysm.

A term male infant presented with congenital hepatic arterio-veno-portal shunts. A mass-like lesion in the left lobe of the liver received blood supply from not only the umbilical vein, but also the hepatic and inferior intrahepatic arteries, communicating with the hepatic and portal veins in a complicated manner, with an umbilical vein aneurysm. The blood flow of the arterio-veno-portal shunts spontaneously and gradually declined from the neonatal period to six years of age. Although mild high-output cardiac failure had developed, no life-threatening events or health problems originating from portosystemic shunts, such as pulmonary artery hypertension and hepatopulmonary syndrome, were observed. However, this report shows that scrupulous follow-up to identify pulmonary artery hypertension and hepatopulmonary syndrome should be continued because complete resolution of the arterio-veno-portal shunts was not obtained in this case.

Kawasaki disease with dilatation of the common bile duct: A case report and review of literature.

BACKGROUND: Kawasaki disease (KD) is a syndrome that results in acute systemic vasculitis and is a major cause of acquired heart disease in developed countries. KD is diagnosed based on certain characteristic symptoms and echocardiogram results. It has been reported that abdominal ultrasound is of value in supporting the diagnosis of KD. Nevertheless, abdominal ultrasound is not a routine procedure in KD. Moreover, dilatation of the common bile duct (CBD) has been rarely reported in previous cases. CASE PRESENTATION: A 4-year-old boy presented with fever and markedly high transaminase level (aspartate aminotransferase, 5323 U/L; alanine aminotransferase, 1554 U/L). The patient was diagnosed as having KD based on characteristic symptoms and echocardiogram findings. Ultrasound revealed dilatation of the CBD as well as cervical lymphadenopathy resembling a cluster of grapes, thickening of the gallbladder wall, and increased periportal echogenicity throughout the liver parenchyma. The patient received initial treatment with intravenous immunoglobulin at day 4 of fever and second-line treatment with intravenous immunoglobulin and prednisolone because of recurrent fever on day 6. Dilatation of the CBD was improved from 6.6 mm on day 4 to 3.1 mm on day 8. Although re-dilatation was observed, it gradually diminished and normalized (4.3 mm on day 28, 4.0 mm on day 63, 3.3 mm on day 105, and 2.8 mm on day 182). CONCLUSION: This case highlights the usefulness of abdominal ultrasound and the importance of considering dilatation of the CBD as one of the complications of KD.

Endoscopic retrograde cholangiopancreatography and endoscopic ultrasound in children.

Gastrointestinal endoscopy is fundamental to diagnostic and therapeutic procedures in pediatric gastroenterology. In the decades since endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) for hepatobiliary and pancreatic disease were introduced into clinical practice, there has been increasing interest in these procedures, and practice guidelines and position papers that clearly define the role of ERCP and EUS in children have been published. Based on the distinction of endoscopy between children and adults, this review focuses on the current state of ERCP and EUS procedures in children, including the types of endoscopes used in children, general anesthesia and radiation exposure, biliary and pancreatic indications, considerations of education and training for ERCP and EUS procedures in children, and expectations for development of endoscopes for children.

Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response.

BACKGROUND & AIMS: Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS: We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS: HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRß1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPß1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION: HLA-DRß1 position 26 and HLA-DPß1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.

Pediatric Patient and Parental Anxiety and Impressions Related to Initial Gastrointestinal Endoscopy: A Japanese Multicenter Questionnaire Study.

Objective. To assess anxiety among pediatric patients and their parents related to initial gastrointestinal endoscopy. Methods. Patients aged <19 years undergoing initial gastrointestinal (GI) endoscopy and their parents were invited to complete a self-administered questionnaire related to endoscopy in 13 institutions in Japan. Results. The subjects were 128 children, aged 1 month to 17 years. Forty-eight patients (37.5%) underwent esophagogastroduodenoscopy (EGD), 32 (25%) underwent colonoscopy (CS), 39 (30.5%) underwent both EGD and CS, 3 (2.3%) underwent balloon enteroscopy (BE), 3 (2.3%) underwent capsule endoscopy (CE), and 3 (2.3%) underwent CE and other endoscopic procedures. In the preendoscopy questionnaire, the most common concerns of the patients and parents before undergoing the procedure were "Pain" (45% of the patients underwent EGD or BE via the oral approach, and 52% of the patients underwent CS or BE via the anal approach) and "Procedural accidents related to the endoscopy" (63% of parents). In the postendoscopy questionnaire, the most common difficulty that patients and parents actually experienced before and after undergoing the procedure was "Hunger." Conclusion. A preparatory intervention including an explanation regarding specific concerns before initial GI endoscopy, which this study revealed, could reduce anxiety experienced by both pediatric patients and parents.

Imatinib-induced Severe Hepatitis in a 9-Year-old Girl With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

Imatinib mesylate has dramatically improved the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph* ALL) and is now included as first-line therapy. Uncommon adverse effects of this drug for pediatric use, however, are largely unknown. We report the first case of a 9-year-old child who developed severe acute hepatitis with grade 4 transaminases and bilirubin elevation during imatinib treatment for Ph* ALL. Liver biopsy showed extensive lobular and pericentral necrosis of hepatocytes. Liver function recovered after discontinuing imatinib with a 4-week prednisolone. Extensive hepatic necrosis should be considered not only in adults but also in children under imatinib administration.

Current role of liver transplantation for methylmalonic acidemia: a review of the literature.

To evaluate the current role of liver transplantation (LT) for methylmalonic acidemia (MMA), we reviewed the literature on outcomes of this treatment, and describe three of our own cases of living-donor liver transplantation (LDLT). The total number of LT cases identified was 18. Transplantation mode was deceased donor LT in 12, including five combined liver-kidney transplantations (CLKT) from deceased donors, and LDLT in six. Three hospital mortalities were noted, because of metabolic decompensation, sepsis and aspergillosis. Although mean postoperative serum MMA level decreased to 13.8% +/- 9.2% (range 1.25-26.1%) of preoperative levels, four patients (22.2%) had renal insufficiency after isolated LT and three (16.7%) had postoperative neurological disability. Continuing metabolic damage to the kidney and brain may occur even after successful LT. Further evaluation is required to determine the long-term suitability of this treatment modality.