Natural history and clinical features of hepatitis C virus infection during childhood: A nationwide, observational survey in Japan.

AIM: Few data on spontaneous clearance rates of cases of mother-to-child transmission of hepatitis C viral (HCV) infection are available in Japan. Furthermore, the treatment courses of interferon-based and direct-acting antiviral agent (DAA) therapies for children are also unclear. Our aim was thus to clarify the long-term natural progression of HCV infection and the treatment outcomes of children in Japan. METHODS: We conducted a combined multicenter, observational survey involving 65 pediatric institutions in Japan. Pediatric HCV infection cases with patients born between 1973 and 2021 were collected over the 11-year period from 2012 to 2022. A total of 563 patients were enrolled, with 190 excluded for having insufficient laboratory data or treatment information, resulting in 373 eligible cases. RESULTS: Of 328 cases of mother-to-child infection, 34 (10.4%) had spontaneous clearance, with a median time to spontaneous clearance of 3.1 years (range 0.9-7.2 years). Of the total 373 eligible cases, 190 received antiviral therapy (interferon-based therapy, 158; DAA therapy, 32). Sustained virologic response rates after first-line treatment were 75.3% (119/158) and 100% (32/32) for interferon-based therapy and DAA therapy, respectively, with the DAA group showing a shorter time from therapy initiation to viral negativity (2.7 vs. 1.0 months; p = 0.0031). CONCLUSIONS: Approximately 10% of Japanese children infected by mother-to-child transmission achieve spontaneous resolution of HCV infection. Our findings indicate that DAA therapy is safe and highly effective in Japanese children, achieving higher sustained virologic response rates and shorter time to clearance of the virus compared with interferon-based therapy.

The role of serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in the assessment of fibrosis in children with chronic hepatitis C.

At present, noninvasive fibrosis markers are not available for the assessment of liver fibrosis in children with chronic hepatitis C. Sixty-three children with chronic hepatitis C were included. Changes in Wisteria floribunda agglutinin-positive Mac-2 binding protein (M2BPGi) levels were evaluated in l3 of 27 treatment-naive patients during the natural course of disease (median 4, range 3-6 years). Changes during treatment were evaluated in 27 of 36 patients for 4 (2-9) years of posttreatment follow-up. There were significant differences in the levels of M2BPGi between control group and HCV F0 group (P = 0.002) and between control group and HCV F1 group (P < 0.001). Receiver operating characteristic curve analysis showed that to discriminate stage F1 fibrosis from F0, the cut-off value was 0.95 for M2BPGi with a sensitivity of 52%, specificity of 90%, and area under the curve of 0.687. A substantial decrease in M2BPGi levels by treatment was shown from 0.98 ± 0.57 at pretreatment to 0.42 ± 0.15 at posttreatment (P < 0.001) in the 27 treated patients. Our study shows new findings that M2BPGi may be useful to predict the presence of a mild degree of fibrosis in children with chronic hepatitis C, and such mild fibrosis may be quickly resolved by treatment.

Whipple disease mimicking inflammatory bowel disease.

Whipple disease is a systemic chronic infection caused by Tropheryma whipplei. Although chronic diarrhea is a common gastrointestinal symptom, diagnosis is often difficult because there are no specific endoscopic findings, and the pathogen is not detectable by stool culture. We present a female patient with Whipple disease who developed chronic bloody diarrhea and growth retardation at the age of 4 years. Colonoscopy showed a mildly edematous terminal ileum and marked erythema without vascular patterns throughout the sigmoid colon and rectum. Subsequently, a primary diagnosis of ulcerative colitis was made. Histopathological analysis of the terminal ileum showed the presence of foamy macrophages filled with periodic acidSchiff-positive particles. Polymerase chain reaction using DNA from a terminal ileum biopsy sample amplified a fragment of 16S rRNA from T. whipplei. Antibiotic treatment relieved the patient's symptoms. There was no evidence of immunodeficiency in the present case. Since Whipple disease worsens after anti-tumor necrosis factor inhibitor therapy, considering this infection in the differential diagnosis may be important in patients with inflammatory bowel disease, especially before initiation of immunotherapy.

Serological cytokine signature in paediatric patients with inflammatory bowel disease impacts diagnosis.

Endoscopy is a central tool for diagnosing and evaluating paediatric inflammatory bowel diseases (PIBD), but is too invasive to be frequently repeated in young children. Furthermore, it is challenging to distinguish Crohn's disease (CD) from ulcerative colitis (UC) endoscopically. This study aimed to determine biomarkers useful for the diagnosis of PIBD. Cytokines, chemokines, and growth factors were quantified in the sera of 15 patients with CD or UC, at disease onset prior to treatment, and 26 age-matched controls. Correlation of cytokine levels with the paediatric CD activity index (PCDAI) and the paediatric UC activity index (PUCAI) was analysed. Interleukin (IL)-6, IL-13, IL-7, and vascular endothelial growth factor were higher in the CD group than in the UC group. The receiver operating characteristic curve analysis showed that IL-7 was a putative biomarker for distinguishing CD from UC (area under the curve: 0.94). Granulocyte-macrophage colony-stimulating factor was associated with PCDAI, and an IL-1 receptor antagonist, IL-6, and macrophage inflammatory protein-1ß were associated with PUCAI. These findings indicate significant differences in cytokine signatures among patients with new-onset PIBD, which may improve accuracy in diagnosing PIBD.

Standard protocol devised by the Japanese Pediatric Impedance Working Group for combined multichannel intraluminal impedance-pH measurements in children.

Multichannel intraluminal impedance-pH measurements (MII-pH) are useful for evaluating acid and non-acid gastroesophageal reflux (GER). However, the use of MIH-pH is not yet established in Japan. The Japanese Pediatric Impedance Working Group (Japanese-PIG) convened to devise a standard protocol for MII-pH in Japanese children. The expert members of the Japanese-PIG collected data on pediatric MII-pH from the relevant literature in English, including the standard protocol of MII-pH presented by the European PIG, and the insights of international experts. The resultant consensus was included in the contents of the standard protocol of MII-pH. The standard protocol included standardization of the indication, methodology, and interpretation of MII-pH in Japanese children. The criteria for abnormal GER by MII-pH were defined using the Reflux Index and number of total reflux episodes independently in children aged < 1 year and those aged ≥ 1 year. Moreover, a significant relationship between GER and symptoms was identified using the symptom index and symptom association probability approach. We conclude that the current version of the protocol for MII-pH is tentative because it is not based on data from Japanese children. Further studies are needed to render this protocol clinically beneficial and expand its use in Japan.

Correction to: Standard protocol devised by the Japanese Pediatric Impedance Working Group for combined multichannel intraluminal impedance-pH measurements in children.

The authors would like to add the following sentence in Acknowledgements in the original publication of this paper.

Severity scales of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GI-FAs) are one type of food allergy found in neonates and infants. Few reports have defined the severity of non-IgE-GI-FAs in these populations. METHODS: Grading scales of the severity of non-IgE-GI-FAs according to extra-GI symptoms, such as poor weight gain, as well as systemic symptoms, including fever and shock, were developed and retrospectively applied to patients with non-IgE-GI-FAs. The relationship between the severity of non-IgE-GI-FAs and both clinical and laboratory findings were examined. RESULTS: Elevation of C-reactive protein levels and a decrease in total protein and albumin were observed in accordance with allergy severity. In an endoscopic examination, inflammatory findings were confirmed in large areas of the colonic mucosa in case of higher severity levels, and infiltration of inflammatory cells other than eosinophils was found in the severest grade. Extensively hydrolyzed milk or amino acid-based milk was required for all patients with the severest grade. In addition, the timing of acquiring tolerance tended to be late for this grade. CONCLUSIONS: Classification and determination of the severity of non-IgE-GI-FAs in neonates and infants may not only contribute to elucidation of the pathogenesis but may also be useful in the clinical setting.

IL-10RA Mutation as a Risk Factor of Severe Influenza-Associated Encephalopathy: A Case Report.

Influenza-associated encephalitis and encephalopathy (IAE) is a severe complication of influenza infection with high morbidity and mortality. We present the case of a patient with IL-10RA mutation who developed encephalopathy after influenza infection. A 10-day-old boy developed recurrent fever and anal fistula. Growth failure gradually became apparent. He had been treated with antibiotics and elemental nutrition. However, the patient did not respond to the treatments. At 11 months, he suddenly developed shock with encephalopathy and multiple organ failures. He was then diagnosed with IAE. A cytokine study revealed elevated levels of IL-1 receptor antagonist, IL-2, IL-6, IL-8, IP-10, eotaxin, G-CSF, MCP-1, and IL-10. These cytokines are normally downregulated by IL-10. Genetic testing revealed a IL-10RA mutation at the 3' end of exon 4 (c.537G→A). These findings might reflect an increased risk of severe IAE in patients with IL-10RA mutation.

Temporal Trend of Pediatric Inflammatory Bowel Disease: Analysis of National Registry Data 2004 to 2013 in Japan.

Increased incidence and prevalence of pediatric inflammatory bowel disease (IBD) have been reported in Western countries. Changes in the prevalence of pediatric IBD in Asian countries, however, remain unclear. We evaluated the changes in the prevalence of IBD among Japanese adults and children from 2004 to 2013, by using the Japanese national registry data of patients receiving financial aid. Data from children (ages 0-19 years) were compared with those from young adults (ages 20-39 years). In 2004, age-standardized prevalences of Crohn disease (CD) and ulcerative colitis (UC) among children were 4.2 of 100,000 and 11.0 of 100,000, respectively. The corresponding prevalences among young adults were 41.0 of 100,000 and 89.8 of 100,000, respectively. In 2013, age-standardized prevalences of pediatric CD and UC were 7.2 of 100,000 and 15.0 of 100,000, respectively. During this period, prevalence of pediatric CD increased by 73.8% among children and by 49.0% in young adults. The prevalence of UC increased by 45.0% among children, and by 73.7% among young adults.

Fecal retention in childhood: Evaluation on ultrasonography.

BACKGROUND: To assess the usefulness of rectal diameter measurement on ultrasonography as a diagnostic tool for fecal retention in children. METHODS: One hundred children (median age, 5.0 years), consisting of 80 with functional constipation and 20 without constipation, participated in the study. All patients underwent physical examination that included digital rectal examination. Forty-five children underwent ultrasonography in three differential planes: transection above the symphysis; under the ischial spine; and at the bladder neck. The measurement of the rectal diameter at the transection above the symphysis could most easily detect fecal retention and had the closest correlations with retention among the three planes. RESULTS: Rectal diameter was wider at all measuring points (35.2 vs 20.9 mm above the symphysis, P < 0.0001; 35.7 vs 24.0 mm under the ischial spine, P < 0.0001; and 19.4 vs 8.7 mm at the bladder neck, P < 0.0001) in children with fecal retention than in those with no fecal retention. With regard to presence of constipation, children with fecal retention had a wider rectal diameter above the symphysis than those with no fecal retention (children with functional constipation, 35.3 vs 20.0 mm, P < 0.0001; children without constipation: 32.6 vs 14.6 mm, P = 0.0026). The cut-off for the rectal diameter measured above the symphysis to identify fecal retention was 27 mm, with high sensitivity and specificity (95.5% and 94.1%, respectively). CONCLUSION: Ultrasound rectal diameter measurement can be used to detect fecal retention in children.

The effects of intestinal ischemia on colonic motility in conscious rats.

BACKGROUND: The present study aimed to examine whether and how colonic motility is affected by mild ischemia-induced intestinal injury in conscious rats through in vivo monitoring of colonic contractions, specifically with regard to the interstitial cells of Cajal (ICC) and the effect of nitric oxide (NO). METHODS: Using miniature strain-gauge transducers, colonic motility with or without ischemia was recorded in conscious rats on the 4th, 7th, and 14th days after surgery. Histological examination for c-kit-positive cells was performed. RESULTS: In control nonischemic rats, the number and duration of contractions (NC and DC, respectively) decreased gradually, but the mean amplitude of contractions (MC) and motility index (MI) did not change. On the 7th day, the NC in the ischemic group increased significantly when compared with that in the control group (P = 0.037). The DC in the ischemic group was lower than that in the control group; the difference was significant on the 4th day (P = 0.008). The MIs in the ischemic group were lower than those in the control group. In both groups, administration of NGnitro-L: -arginine methyl ester on the 7th day increased only the resting cecal motility. Pathological examinations revealed c-kit-positive cells in both groups. CONCLUSIONS: Changes such as increased NC with shortened DC accompanied with decreased MI must have occurred at the ischemic site and might have been induced by an ischemic event. However, there exists a possibility that ICC and NO do not play a role in mild ischemia-induced dysmotility.

In vivo recording of colonic motility in conscious rats with deficiency of interstitial cells of Cajal, with special reference to the effects of nitric oxide on colonic motility.

BACKGROUND: We recorded in vivo colonic motility in rats with a deficiency of interstitial cells of Cajal (ICC) (Ws/Ws rats) and in wild-type rats (+/+ rats), with special reference to the effects of nitric oxide (NO) on colonic motility in both types of rats, in order to ascertain the role of ICC in colonic motility, and the relationship between NO and ICC in regard to colonic motility. METHODS: Miniature strain-gauge force transducers were sutured on the surface of the ascending and sigmoid colon of Ws/Ws rats and +/+ rats as controls. After 1 week and a fasting period of 24 h, colonic motility in +/+ and Ws/Ws rats was recorded. We also studied the effect of NO on colonic motility in both types of rats, by means of the administration of N-nitro-L-arginine methyl ester (L-NAME) or L-arginine. RESULTS: In +/+ rats, there were contractions with high amplitude and long duration in both the ascending and sigmoid colon. The number, amplitude, and duration of contractions in the ascending colon were 9.9/20 min, 6.1 g, and 22.7 s, respectively. These findings in the sigmoid colon were 5.2/20 min, 5.2 g, and 23.0 s, respectively. The number of contractions in the ascending and sigmoid colon in Ws/Ws rats (2.3 and 1.0/20 min) was significantly lower than that in +/+ rats (P < 0.05). The number of contractions in the ascending and sigmoid colon in +/+ rats (9.7 and 5.1/20 min before treatment) was significantly increased by L-NAME administration (28.7 and 13.9/40-60 min after treatment; P < 0.05), but that in Ws/Ws rats was not influenced. The number of contractions in the ascending and sigmoid colon in +/+ rats (10.2 and 5.2/20 min before treatment) was significantly decreased by L-arginine administration (3.6 and 2.1/40-60 min after treatment; P < 0.05), but that in Ws/Ws rats was not influenced. CONCLUSIONS: ICC must be related to the occurrence of a normal number of colonic contractions. NO may be involved in the inhibitory regulation of colonic motility, and the effect of NO on the occurrence of contractions appears to be mediated by ICC.