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.

A case of respiratory syncytial virus-associated encephalopathy in which the virus was detected in cerebrospinal fluid and intratracheal aspiration despite negative rapid test results.

We report a first case of respiratory syncytial virus (RSV) infection-associated encephalopathy in which RS virus was detected in the patient's intratracheal aspiration and cerebrospinal fluid despite negative rapid test results of the nasal swab. The patient's findings and clinical course coincided with those of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) with severe subsequent sequelae. Our case indicates that clinicians should consider RSV infection when patients have AESD with unknown etiology.

Ferroportin Disease Caused by a Heterozygous Variant p.Cys326Phe in the SLC40A1 Gene and the Efficacy of Therapeutic Phlebotomy in Children.

Therapeutic phlebotomy is recommended for treating hereditary hemochromatosis. However, the procedure and its efficacy for children remain unclear. We describe a young female patient with ferroportin disease, which was confirmed from excess iron deposition within hepatocytes and by identifying a heterozygous variant p.Cys326Phe in SLC40A1. She had been followed without phlebotomy. Liver histology at age 13 years revealed iron deposition progression. Phlebotomy was initiated and her iron markers and imaging findings improved without severe adverse effects. Therapeutic phlebotomy for children is effective and well-tolerated and should be considered as early as possible after a hemochromatosis diagnosis.

Marked Elevation of Excitatory Amino Acids in Cerebrospinal Fluid Obtained From Patients With Rotavirus-Associated Encephalopathy.

Rotavirus is the most common cause of severe gastroenteritis in young children; however, its pathogenesis and immunity are not completely understood. Even less well recognized is rotavirus-induced central nervous system (CNS) involvement, which has been associated with seizure, encephalopathy and death, among others. To elucidate the host response to rotavirus infection, we retrospectively examined neurotransmitter amino acids in the cerebrospinal fluid (CSF) of 19 children with CNS involvement associated with rotavirus infection. Subjects were classified into two groups: those with encephalopathy followed by prolonged seizure (encephalopathy group) and those who had experienced afebrile, brief cluster of seizures without encephalopathy (cluster group). The levels of glutamate, glycine, and taurine in the encephalopathy group were significantly higher than those in the cluster group. Increased levels of excitatory amino acids in the CSF may induce neurological disorders and be related to disorder severity. To the best of our knowledge, this is the first report regarding amino acids in the CSF obtained from patients with rotavirus-induced CNS involvement. Further study is necessary to elucidate the role of CSF amino acid levels in rotavirus-induced CNS involvement.

Young-age-onset pancreatoduodenal carcinoma in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome, which is characterized by pancreatic fatty degeneration, skeletal growth retardation, and hematological dysfunction, is a congenital disease caused by SBDS gene mutations. Although hematological disorders often accompany this syndrome, carcinomas associated with this syndrome have not been reported except in one breast cancer and one moderately differentiated pancreatic cancer case. We report on an autopsy of a 24-year-old case of pancreatoduodenal carcinoma in Shwachman-Diamond syndrome. The histology of the tumor was undifferentiated carcinoma, which seems to have originated from either the pancreatic duct or the duodenal epithelium. The tumor was intermingled with two pathological changes characteristic of Shwachman-Diamond syndrome: fatty degeneration of the pancreas and inflammation of the villous stroma of the duodenum. Considering that SBDS protein regulates mitosis and its suppression causes genomic instability, this case might provide an example of carcinogenesis based on genomic instability, together with degenerative changes and chronic inflammation, at a very young age.

Current status of pediatric human immunodeficiency virus infection in Japan.

There are currently very few English reports about Japanese pediatric human immunodeficiency virus (HIV). In this study, we introduce our experience with pediatric HIV in a single hospital, and review the present status of HIV infections in children in Japan. In Japan, the main infection routes of HIV include sexual activity, mother-to-child transmission (MTCT), blood or blood product transfusion, and drug use. Most pediatric HIV patients have been infected by MTCT in recent years. One survey showed that in Japan, 52 babies were infected by MTCT between 1984 and 2011. Only 2 cases of pediatric HIV infection have been reported since 2010. The MTCT rate has decreased to 0.5% owing to several preventive interventions. In addition, the HIV antibody test is now performed in more than 98.3% of pregnant women in Japan.

Efficacy of re-treatment by peginterferon alpha-2a and ribavirin in a child with hepatitis C.

BACKGROUND: There is currently no consensus treatment for children non-responsive to peginterferon (Peg-IFN) and ribavirin. CASE PRESENTATION: Here, we present a Japanese child with chronic hepatitis C with fibrosis, who did not respond to Peg-IFN α-2b but responded to Peg-IFN α-2a with ribavirin, accompanied with fluvastatin. To date, there has been no reported case of re-treatment in children. The early viral response occurred soon after starting treatment using Peg-IFN α-2a/ribavirin plus fluvastatin. CONCLUSION: Our result indicates that when treatment by Peg-IFN α-2b/ribavirin combination therapy is not efficient, combination therapy using Peg-IFN α-2a/ribavirin plus fluvastatin should be considered in children with advanced liver change.

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.

Marked elevation of interferon-γ in acute focal bacterial nephritis.

Acute focal bacterial nephritis (AFBN) is a localized, interstitial bacterial infection of the renal parenchyma. In this study, we measured the serum levels of several cytokines in patients with AFBN. A total of 11 children were enrolled in the study and classified into two groups of patients: an AFBN group and a control group. There was no significant difference in the serum levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, granulocyte-colony stimulating factor, or tumor necrosis factor-α among the patients in the two groups. However, the serum levels of interferon-γ among the patients in the AFBN group were significantly higher than those among the patients in the control group. The current results suggest that the bacterial kidney infection in the AFBN group is localized and that interferon-γ may be produced locally in response to the infection.

Transaminase in rotavirus gastroenteritis.

BACKGROUND: Children infected with rotavirus often show increased levels of transaminase, and symptoms are characterized by white stool, similar to biliary atresia. Rotavirus infections are also sporadically accompanied with convulsions, encephalopathy and Reye syndrome. The aim of the present study was therefore to investigate transaminase and interleukin (IL)-6 levels in rotavirus infection, in order to better understand their clinical significance. METHODS: Results of liver function tests, mainly the elevation of transaminase and IL-6 in rotavirus gastroenteritis with or without convulsions, were evaluated. RESULTS: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were high in 23 of 26 samples (88.5%), and in three of 26 samples (11.5%), respectively. No significant differences in liver function tests could be found between the groups with or without convulsions. Three patients whose direct bilirubin levels were above the upper normal limit were all classified into the group without convulsions. Spearman's correlation coefficient was 0.89 between increasing AST levels and IL-6 levels. CONCLUSION: Rotavirus infection is occasionally accompanied with hepatitis, but only in a mild form, and does not correlate with neurological complications. High levels of transaminase might reflect high IL-6.

[Rotavirus infection].

Rotavirus is one of the universal viruses that causes diarrhea(acute gastroenteritis) in the worldwide, and the infections are sporadically accompanied with critical illness. Ten percent of affected individuals are admitted to hospitals. The complications are commonly serious dehydration, several diseases of central nervous system, sepsis and postrenal insufficiency accompanied with renal stone. Two safety and effective vaccinations were implemented to prevent infections. According to the overseas guideline management for estimations for the severity and treatment by oral rehydration solution are recommended.

A 17-year-old boy with lymphocytic infundibuloneurohypophysitis who developed non-alcoholic steatohepatitis effectively treated with growth hormone.

Summary: We encountered a case of childhood-onset lymphocytic infundibuloneurohypophysitis, based on the MRI and endocrinological findings, with decreased function of the anterior and posterior lobes of the pituitary. Three years after the diagnosis, the patient developed non-alcoholic steatohepatitis (NASH), which was effectively treated by growth hormone (GH) supplementation. The present case demonstrated that NASH can be effectively treated by short-term GH supplementation, even in late childhood. Learning points: In recent years, the efficacy of growth hormone replacement therapy in normalizing the liver function of adult-onset growth hormone deficiency patients with non-alcoholic steatohepatitis (NASH) has been reported. Lymphocytic infundibuloneurohypophysitis is a very rare disease, particularly in childhood. We here presented a rare case of a child with lymphocytic infundibuloneurohypophysitis who developed NASH and showed substantial improvement in liver function after growth hormone treatment.

Efficacy of prolonged valganciclovir therapy for congenital cytomegalovirus infection.

We report prolonged valganciclovir (VGCV) treatment of a symptomatic cytomegalovirus infection case. Automated auditory brainstem evoked response performed at 5 days of age revealed severe hearing impairment. Cranial magnetic resonance (MR) imaging at 11 days of age showed abnormal findings. At 5 weeks of age, VGCV was started. The viral load in blood cells, plasma, and urine decreased during the 6-week treatment. Because of improvement of hearing level and no adverse effects, VGCV was restarted for an additional 6 weeks. Neither the patient's hearing impairment nor results of cranial MR imaging have become worse in 6 months. It is crucial to gather information from as many cases as possible treated with VGCV to establish a standard protocol for VGCV treatment.

Myopathy and neurogenic muscular atrophy in unexpected cardiopulmonary arrest.

BACKGROUND: Neuromuscular disorders can be the cause of sudden death of infants because of their weakness and gastroesophageal reflux (GER). METHODS: Muscle biopsy and genetic studies were performed by usual method. RESULTS: In this report four cases of infants with neuromuscular disorders (two cases of congenital myopathy and two cases of spinal muscular atrophy) who had unexpected cardiopulmonary arrest on arrival (CPAOA) are presented. Two of the cases did not show any symptoms, such as muscle weakness prior to CPAOA. The diagnosis was based on the results of the muscle biopsy and genetic examination. CONCLUSION: These results suggest that sudden infant death caused by neuromuscular disorders should be considered.

Hepcidin Levels and Pathological Characteristics in Children with Fatty Liver Disease.

PURPOSE: Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. METHODS: This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. RESULTS: Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. CONCLUSION: There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.

Increased Platelet-Derived Growth Factor and Cytokine Levels in the Cerebrospinal Fluid of Patients of Sudden Unexpected Death with or without Viral Infection.

OBJECTIVE: To clarify the pathogenesis of sudden unexpected natural death (SUD) as well as biomarkers to differentiate the underlying diseases, by performing cytokine analysis in the acute phase of pediatric patients in whom viral infection led to SUD. METHODS: An acute phase cytokine analysis of pediatric patients in whom viral infection led to SUD was performed, and the data obtained were compared with those from SUD patients not associated with viral infections. Subjects included 4 boys aged 1-16 mo who died of cardiopulmonary arrest associated with viral infections. The causative viruses were identified as enterovirus, parainfluenza virus, respiratory syncytial virus, and rotavirus. The 4 other infants/children (aged 2-12 mo) died of non-infectious episodes, i.e., 1, 2, and 1 died of drowning, falling, and a traffic accident, respectively. Cerebrospinal fluid samples (CSF) of the subjects were collected during cardiopulmonary resuscitation or within 24 h of the events. RESULTS: The infection-induced sudden death group showed elevated CSF levels of inflammatory cytokines and chemokines. No increase was observed in interleukin-10 levels. Furthermore, in the infection-induced sudden death group, platelet-derived growth factor levels correlated with inflammatory cytokine levels. CONCLUSIONS: Infection-associated SUD may be differentiated from noninfectious SUD by measuring the levels of acute phase-inflammatory cytokines and chemokines at the onset of SUD.

A Case of Primary Ciliary Dyskinesia Caused by a Mutation in OFD1, Which Was Diagnosed Owing to Clostridium difficile Infection.

We report a Japanese 5-year-old boy with primary ciliary dyskinesia (PCD) which was diagnosed owing to Clostridium difficile (CD) infection caused by prolonged antibiotic exposure. He had intractable otitis media with effusion (OME) and had abdominal pain and diarrhea for 4 months after starting antibiotics administration. His stool contained CD toxin. After vancomycin treatment, his symptoms improved and his stools did not contain CD toxin. His past medical history included frequent pneumonia. We, therefore, performed electron microscopy of the biopsy specimen from his nasal mucosa and genetic testing, and he was diagnosed with PCD. PCD is a rare inherited genetic disease causing ciliary dysfunction, which is very difficult to diagnose because some children without PCD also develop the same symptoms. Therefore, children who have intractable OME, rhinosinusitis, frequent pneumonia, or bronchitis and are taking antibiotics for long periods of time should be checked for underlying diseases, such as PCD.

Cardiac Complications Caused by Respiratory Syncytial Virus Infection: Questionnaire Survey and a Literature Review.

We investigated 22 cases of patients with myocarditis during respiratory syncytial virus (RSV) infection by a questionnaire survey, and performed a literature search to clarify their characteristics. The age distribution was divided into 2 groups, that is, 1 group comprised of patients younger than 4-years old and the other comprised patients older than 15 years. ECG demonstrated disturbance of the conduction system (AV block) in 7 out of 18 patients (38.8%), myocardial damage (ST-T change) in 9 out of 18 patients (50.0%), and tachycardia in 3 out of 18 patients (16.6%). Echocardiography displayed a robust decrease in left-heart function in 12 out of 14 patients. The outcome was 2 deaths, 1 pacemaker placement, 4 patients with mild sequel. Our data suggest that RSV myocarditis caused by RSV infection can be divided into 3 different pathophysiologies, characterized by disturbance of the conduction system, myocardial damage, and increase of autonomy.

Serum 25-Hydroxy Vitamin D Levels in Japanese Infants with Respiratory Syncytial Virus Infection Younger than 3 Months of Age.

Low blood levels of vitamin D have been reported in children who have frequent respiratory tract infections. We measured serum concentrations of 25-hydroxy (OH) vitamin D in Japanese infants under 3 months of age who had respiratory syncytial virus (RSV) infection. Serum levels of 25-OH vitamin D in the 10 infants, excluding those with underlying diseases, were between < 4 and 29.8 ng/mL. In 8 out of 10 subjects (80.0%), serum 25-OH vitamin D levels were lower than 20 ng/mL. There was no statistically significant association between the levels of 25-OH vitamin D and age, duration of admission, respiratory severity score, white blood cell count, blood gas levels, and N-terminal pro-natriuretic peptide levels. Levels of serum 25-OH vitamin D in children who required hospitalization owing to RSV infection were low, indicating deficiency. These results suggest that vitamin D deficiency affects the susceptibility to RSV infection, but not the severity of the infection.