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.

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.

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.

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.

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.

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.

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.

Effectiveness of low-dose riboflavin as a prophylactic agent in pediatric migraine.

BACKGROUND: Riboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines. METHODS: We retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response. RESULTS: The frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3-7) vs. 4.0 (2-5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%-50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27-13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16-12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04-0.73; p = 0.013). No adverse effects of riboflavin were identified. CONCLUSIONS: Low-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types.

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.

Gastrointestinal and liver lesions in primary childhood Sjögren syndrome.

Sjögren syndrome (SS) is characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands, leading to keratoconjunctivitis sicca and xerostomia. SS is one of the most common autoimmune rheumatic diseases in adults; however, few cases of primary childhood SS with gastrointestinal and liver lesions have been reported in the literature. We report five cases of primary childhood SS with gastrointestinal and liver lesions. Multiple gastric biopsies in four cases revealed atrophic gastritis in the antrum of the stomach or chronic gastritis. Liver biopsies in two cases revealed nonalcoholic steatohepatitis. Careful clinical approach and follow-up for gastrointestinal and liver lesions are required.

Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell-Based Phenotype Dissection.

OBJECTIVE: To elucidate the genetic background of a patient with neonatal-onset multisystem inflammatory disease (NOMID) with no NLRP3 mutation. METHODS: A Japanese male child diagnosed as having NOMID was studied. The patient did not have any NLRP3 mutation, even as low-frequency mosaicism. We performed whole-exome sequencing on the patient and his parents. Induced pluripotent stem cells (iPSCs) were established from the patient's fibroblasts. The iPSCs were then differentiated into monocyte lineage to evaluate the cytokine profile. RESULTS: We established multiple iPSC clones from a patient with NOMID and incidentally found that the phenotypes of monocytes from iPSC clones were heterogeneous and could be grouped into disease and normal phenotypes. Because each iPSC clone was derived from a single somatic cell, we hypothesized that the patient had somatic mosaicism of an interleukin-1ß-related gene. Whole-exome sequencing of both representative iPSC clones and the patient's blood revealed a novel heterozygous NLRC4 mutation, p.T177A (c.529A>G), as a specific mutation in diseased iPSC clones. Knockout of the NLRC4 gene using the clustered regularly interspaced short palindromic repeat/Cas9 system in a mutant iPSC clone abrogated the pathogenic phenotype. CONCLUSION: Our findings indicate that the patient has somatic mosaicism of a novel NLRC4 mutation. To our knowledge, this is the first case showing that somatic mutation of NLRC4 causes autoinflammatory symptoms compatible with NOMID. The present study demonstrates the significance of prospective genetic screening combined with iPSC-based phenotype dissection for individualized diagnoses.

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.

Nonalcoholic steatohepatitis and insulin resistance in children.

Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a "two-hit" model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH.

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.