Probiotic supplementation modifies the gut microbiota profile of very low birth weight preterm infants during hospitalization.

BACKGROUND: Probiotic supplementation is increasingly being given to very low birth weight (VLBW) preterm infants. This preliminary observational study aimed to investigate the effects of multiple-strain probiotics on the gut microbiota of VLBW preterm infants. METHODS: We collected meconium and stool samples on days 14, 30, and 60 after birth from 49 VLBW infants with a gestational age of <32 weeks. The infants were divided into the probiotics (n = 24) and control (n = 25) groups. The microbial composition and diversity in the gut of the two groups were analyzed using 16 S rRNA gene sequencing. RESULTS: The relative abundance of Bifidobacterium and Lactobacillus was significantly higher in the probiotics group than in the control group on days 14, 30, and 60 (Bifidobacterium: p = 0.002, p < 0.0001, and p < 0.0001, respectively; Lactobacillus: p = 0.012, p < 0.0001, and p < 0.0001, respectively). The control group exhibited a significantly higher proportion of participants with a low abundance (<1%) of Bifidobacterium or Lactobacillus on days 14, 30, and 60 than those in the probiotic group. Moreover, the probiotics group exhibited a significantly lower abundance of Klebsiella on days 14 and 30 (2.4% vs. 11.6%, p = 0.037; and 7.9% vs. 16.6%, p = 0.032, respectively) and of Escherichia-Shigella on day 60 than the control group (6.1% vs. 12.3%, p = 0.013). Beta diversity analysis revealed that the microbiota profile was clearly divided into two groups on days 30 and 60 (p = 0.001). CONCLUSION: Probiotic supplementation significantly increased the relative abundance of Bifidobacterium and Lactobacillus and inhibited the growth of potential pathogens. Furthermore, probiotic supplementation led to a distinct gut microbiota profile. Further research is needed to identify probiotic strains that exert significant influence on the gut microbiome and their long-term health implications in preterm infants.

Quality improvement of pediatric colonoscopy by application of bundle and centralization: A single-center review.

BACKGROUND: To assess the quality change of our single-center pediatric colonoscopy after applying bundle for bowel preparation and general anesthesia and centralize the procedure using terminal ileum (TI) intubation rate as the main indicator. METHODS: All elective colonoscopies performed for patients younger than 18 years old in MacKay Memorial Hospital from July 2015 through June 2020 (assigned to group 1, before bundle) and from August 2020 through July 2021 (assigned to group 2, after bundle) were retrospectively reviewed for demographic characteristics, indications, bowel preparation agent and cleansing level, diagnostic and therapeutic procedures, maximum intestinal level reached, and cecal intubation and total procedure time. Statistical analysis was done using P value < 0.05 considered to be significant. RESULTS: Analysis included 45 and 32 colonoscopies in group 1 and 2, respectively. Bloody stool was the most frequent indication in both groups. Both TI intubation rate (42.2 % vs. 75.0 %, P = 0.004) and biopsy rate (45.0 % vs. 75.9 %, P = 0.01) increased significantly from group 1 to group 2. The narrower standard deviation of bowel preparation score (1.93 vs. 1.15) and total procedure time (37.71 vs. 22.29) in group 2 indicated a more stable quality, although the mean showed no difference. There was no statistical difference in age, gender, body weight, cecal intubation rate, or cecal intubation time. CONCLUSION: A higher TI intubation rate and biopsy rate indicated an improved quality of pediatric colonoscopy after applying bundle including bowel preparation and general anesthesia, with additional centralization.

Localization and Laparoscopic Excision of Gastric Heterotopic Pancreas in a Child by Endoscopic SPOT® Tattooing.

Heterotopic pancreas (HP) is defined as pancreatic tissue lacking vascular or anatomic connection with the normal pancreas. Surgical resection is often indicated for symptomatic gastric HP. However, intraoperative identification of gastric HP is often difficult during laparoscopic surgery. Herein, we describe a patient with gastric HP, which was marked with SPOT® dye (GI Supply, Camp Hill, PA, USA). The dye was seen clearly laparoscopically facilitating total excision of the lesion. The final pathology report confirmed the presence of heterotopic pancreatic tissue including pancreatic acini, small pancreatic ducts tissue with islets of Langerhans in the deep gastric submucosal area. There were no postoperative complications, and the patient was symptom-free. To the best of our knowledge, this was the first case report in the literature in which endoscopic tattooing of gastric HP before laparoscopic resection was performed. This method of localization was simple and reliable in children.

Associations between Vitamin D Deficiency and Carbohydrate Intake and Dietary Factors in Taiwanese Pregnant Women.

This cross-sectional observation study investigated the vitamin D (VD) status in Taiwanese pregnant women and the effects of VD supplementation and macronutrient intake on serum 25-hydroxy-vitamin D (25[OH]D) level. Data on VD intake, daily sunlight exposure, and carbohydrate intake were obtained from 125 pregnant women at 30−37 weeks' gestation. Serum 25[OH]D level was measured before delivery in all enrolled women; and the mean 25(OH)D level was 43 nmol/L or 17.2 ng/mL. The 25(OH)D level was significantly correlated with total VD intake of pregnant women (r = 0.239; p = 0.007). The severe VD deficiency group (n = 16; mean of 25(OH)D level = 8.5 ng/mL) had significantly lower total VD intake and supplementation than the groups with VD deficiency (n = 69), insufficiency (n = 32), and sufficiency (n = 8). Those with ≥400 IU/day total VD intake (including VD from food and supplementation) had significantly higher 25(OH)D concentration than those with <400 IU/day total VD intake. Those with 400 IU/day VD supplementation could significantly increase serum 25(OH)D concentrations for pregnant women. Among 85 pregnant women with carbohydrate intake of ≥300 g/day, serum 25(OH)D levels were negatively correlated with carbohydrate intake (p = 0.031). In conclusion, VD deficiency was highly prevalent in Taiwanese pregnant women. VD supplementation was the most effective method for increasing 25(OH)D concentration in pregnant women. Higher carbohydrate intake might reduce 25(OH)D levels.

Associations of metal mixtures in the meconium with birth outcomes in northern Taiwan.

Previous studies investigated prenatal exposure to neurotoxic metals in relation to birth anthropometrics. However, limited information has been developed on associations with birth outcomes of fetal exposure to metal mixtures using the meconium as a biomarker. The purpose of this study was to evaluate relationships of the combined effects of mercury (Hg), lead (Pb), cadmium (Cd), and arsenic (As) concentrations in the meconium on birth outcomes (i.e., birth weight, birth length, and head circumference). This cross-sectional study was conducted in northern Taiwan between January 2007 and December 2009. We collected 526 meconium samples within the first 24 h after birth to measure the in utero mixed-metal exposure determined using inductively coupled plasma/mass spectrometry (ICP-MS). We used a multivariable regression and Bayesian kernel machine regression (BKMR) to estimate associations of the combined effects and identify important mixture components with growth impairments. Our results revealed Hg, Pb, Cd, and As concentrations in the meconium and enhanced the quantity of research on meconium analyses. The overall effects of Hg, Pb, Cd, and As concentrations in the meconium as prenatal exposure biomarkers were negatively associated with birth growth. Fetal exposure to Hg and Pb was correlated with decreased birth weights. Hg and Pb concentrations in the meconium were linearly inversely related to the birth weight, birth length, and head circumference. Effects of fetal exposure to As and Cd on birth outcomes were not obvious. A significant increasing relationship was detected between Hg concentrations in the meconium and maternal fish consumption during pregnancy. Higher Pb concentrations in the meconium were observed among infants of mothers who consumed Chinese herbal medicines. Reducing maternal fish consumption and Chinese herbal medicine consumption during pregnancy could limit infant exposure to metals.

First-trimester urinary extracellular vesicles as predictors of preterm birth: an insight into immune programming.

Background: The programming of innate and adaptive immunity plays a pivotal role in determining the course of pregnancy, leading to either normal term birth (TB) or preterm birth (PB) through the modulation of macrophage (M1/M2) differentiation. Extracellular vesicles (EVs) in maternal blood, harboring a repertoire of physiological and pathological messengers, are integral players in pregnancy outcomes. It is unknown whether urinary EVs (UEVs) could serve as a non-invasive mechanistic biomarker for predicting PB. Methods: This study investigated first-trimester UEVs carrying M1 messengers with altered immune programming, aiming to discern their correlation to subsequent PB. A birth cohort comprising 501 pregnant women, with 40 women experiencing PB matched to 40 women experiencing TB on the same day, was examined. First-trimester UEVs were isolated for the quantification of immune mediators. Additionally, we evaluated the UEV modulation of "trained immunity" on macrophage and lymphocyte differentiations, including mRNA expression profiles, and chromatin activation modification at histone 3 lysine 4 trimethylation (H3K4me3). Results: We found a significant elevation (p < 0.05) in the particles of UEVs bearing characteristic exosome markers (CD9/CD63/CD81/syntenin) during the first trimester of pregnancy compared to non-pregnant samples. Furthermore, UEVs from PB demonstrated significantly heightened levels of MCP-1 (p = 0.003), IL-6 (p = 0.041), IL-17A (p = 0.007), IP-10 (p = 0.036), TNFα (p = 0.004), IL-12 (p = 0.045), and IFNγ (p = 0.030) relative to those from TB, indicative of altered M1 and Th17 differentiation. Notably, MCP-1 (>174 pg/mL) exhibited a sensitivity of 71.9% and specificity of 64.6%, and MCP-1 (>174 pg/mL) and IFNγ (>8.7 pg/mL) provided a higher sensitivity (84.6%) of predicting PB and moderate specificity of 66.7%. Subsequent investigations showed that UEVs from TB exerted a significant suppression of M1 differentiation (iNOS expression) and Th17 differentiation (RORrT expression) compared to those of PB. Conversely, UEVs derived from PB induced a significantly higher expression of chromatin modification at H3K4me3 with higher production of IL-8 and TNFα cytokines (p < 0.001). Implications: This pioneering study provides critical evidence for the early detection of altered M1 and Th17 responses within UEVs as a predictor of PB and early modulation of altered M1 and Th17 polarization associated with better T-cell regulatory differentiation as a potential prevention of subsequent PB.

Rare presentation in a rare case of pancreatic extraosseous Ewing's sarcoma: A case report.

RATIONALE: Extraosseous Ewing's sarcoma is a rare tumor which is aggressive with poor prognosis; it can occur anywhere in the body, but scantily in the pancreas. Pancreatic Ewing's sarcoma is not reported commonly, with inconsistent clinical manifestations. In this regard, early recognition of this disease is very important for the patient's sake. PATIENT CONCERNS: A 16-year-old boy presented with left lower quadrant abdominal pain for 2 months, and left flank pain with dysuria for 1 month. DIAGNOSIS: Abdominal and renal ultrasonography found a mass between the spleen and left kidney as well as left renal pelvic dilatation. Abdominal computed tomography found a heterogenous mass derived from the tail of the pancreas. Serial examinations revealed that the mass was a pancreatic Ewing's sarcoma. Furthermore, no metastasis was documented. INTERVENTIONS: The tumor was totally excised after 6 months of chemotherapy, which included 10 courses of neoadjuvant chemotherapy with vincristine, epirubicin, and cyclophosphamide, alternating with ifosfamide and etoposide. The patient completed consolidation chemotherapy with vincristine, epirubicin, and cyclophosphamide, alternating with ifosfamide and etoposide for 5 courses. Radiotherapy was applied to the tumor-involved region and tumor bed. OUTCOMES: To date, the malignancy has not recurred since the treatment was completed 4 years ago. There are no complications from the treatment for the patient. LESSONS: The pancreas is a very rare extraosseous location for Ewing's sarcoma. Pancreatic extraosseous Ewing's sarcoma should be regarded as a differential diagnosis of non-urinary originated left flank pain with dysuria in adolescents.

Characteristics of Gut Microbiota in Small for Gestational Age Infants with Very Low Birth Weight.

Small for gestational age (SGA) birth is associated with high rates of mortality and morbidity in preterm infants. The aim of this preliminary observational study was to investigate the difference in gut microbiota between SGA and appropriate for gestational age (AGA) preterm infants with very low birth weight (VLBW). We included 20 VLBW preterm infants (SGA, n = 10; AGA, n = 10) in this study. Stool samples were collected on days 7, 14, and 30 after birth. We performed 16S ribosomal DNA sequencing to compare microbiota composition between both groups. The SGA group exhibited a lower abundance of Klebsiella on day 14 (SGA, 0.57%; AGA, 7.42%; p = 0.037). On day 30, the SGA group exhibited a lower abundance of Klebsiella (SGA 3.76% vs. AGA 16.05%; p = 0.07) and Enterobacter (SGA 5.09% vs. AGA 27.25%; p = 0.011) than the AGA group. Beta diversity demonstrated a separation of the bacterial community structure between both groups on day 30 (p = 0.019). The present study revealed that a distinct gut microbiota profile gradually develops in SGA preterm infants with VLBW during the early days of life. The role of changes in gut microbiota structure warrants further investigation.

A rare case of pancreatic macrocystic serous cystadenoma in an adolescent: a case report and literature review.

While serous cystadenomas of the pancreas usually consist of small cysts, one rare variant has been reported to be composed of macrocysts. Herein, we present the case of the youngest patient with macrocystic serous cystadenoma (MSC) to be reported in the literature. The patient was a 17-year-old girl who presented with the major symptoms of a palpable abdominal mass accompanied by epigastric pain and vomiting for several months. A potential malignancy could not be excluded on the basis of imaging studies, which showed a large macrocystic pancreatic tumor that was 7 cm in diameter. Owing to the patient's symptoms, after diagnosing the mass as a pancreatic cystic tumor with potential malignancy and large tumor size, surgical intervention was arranged. Pathological analysis of the biopsy sample suggested MSC. By reviewing the literature, we found several unique characters of MSCs that cause them to be frequently misdiagnosed as potential malignancies. Additionally, the age of MSC occurrence was found to be lower than of general serous cystadenomas. The potential of MSC should be kept in mind by clinicians when diagnosing young people with pancreatic macrocystic lesions.

Rapid Weight Loss and Severe Failure to Thrive Mimicking Lipodystrophy Syndrome in a 1-Year-Old Taiwanese Girl with Costello Syndrome.

Costello syndrome (CS) is a type of RASopathy caused mainly by de-novo heterozygous pathogenic variants in the HRAS gene located on chromosome 11p15.5. The phenotype of CS is characterized by prenatal overgrowth, postnatal failure to thrive, curly or sparse fine hair, coarse facial features, and multisystem involvement, including cardiovascular, endocrine, and gastroenterological disorders. We present a one-year-old girl with rapid weight loss and severe failure to thrive. She had gastroesophageal reflux at the age of four months with subsequent rapid weight loss. The loss of fat tissue over the whole body, refractory to a hypercaloric diet, mimicked the presentation of progressive lipodystrophy and masked the dysmorphic features of CS. The final diagnosis of CS was made by whole exome sequencing, which demonstrated a hot-spot, heterozygouspathogenic variant in the HRAS gene (c.34G > A, rs104894229). Our patient illustrates that the excessive energy needs in CS patients may lead to severe failure to thrive and cause challenges in diagnosing CS. This case also highlights the importance of recognizing CS in patients with a history of prenatal overgrowth, polyhydramnios presenting with severe failure to thrive refractory to pharmacotherapy and tube feeding.

Coexisting gastrointestinal and hepatobiliary tract anomalies in omphalocele and gastroschisis: A twenty-year experience in a single tertiary medical center.

BACKGROUND: Omphalocele and gastroschisis are the two most common congenital abdominal wall defects; however, no previous study has focused on gastrointestinal and hepatobiliary tract malformations in these two conditions. This study aimed to investigate the demographic characteristics, coexisting congenital gastrointestinal and hepatobiliary tract anomalies, hospital course, and outcomes of patients with gastroschisis and omphalocele. METHODS: This is retrospective chart review of all patients admitted to one tertiary medical center in Taiwan between January 1, 2000 and June 30, 2020 with a diagnosis of gastroschisis or omphalocele. The medical records were reviewed to obtain demographic data regarding coexisting gastrointestinal and hepatobiliary tract anomalies and outcomes. RESULTS: Of the 51 patients included, 21 had gastroschisis and 30 had omphalocele. Gastroschisis was associated with a significantly younger maternal age and a higher incidence of small for gestational age. Of the 30 patients with omphalocele, twelve had associated gastrointestinal and hepatobiliary anomalies. Seven of the 21 patients with gastroschisis had gastrointestinal anomalies, and none had hepatobiliary anomalies. Among the omphalocele patients, three (10%) had documented malrotation, and one developed midgut volvulus. Among gastroschisis patients, four patients (19%) had malrotation, and two developed midgut volvulus. There were no statistically significant differences in postoperative complications or mortality rates between those with and without gastrointestinal/hepatobiliary tract anomalies. CONCLUSION: The diversity of coexisting gastrointestinal and hepatobiliary tract anomalies is higher in the omphalocele than in gastroschisis. In addition, we demonstrate that patients with gastroschisis or omphalocele have a higher rate of intestinal malrotation and midgut volvulus.

Effect of Oral Vitamin D3 Supplementation in Exclusively Breastfed Newborns: Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.

Exclusively breastfed infants are at a high risk of vitamin D deficiency. Few studies have evaluated the effects of vitamin D supplementation. Hence, we conducted a prospective randomized controlled trial investigating the effects of oral vitamin D3 400 IU/d supplementation in exclusively breastfed newborns. Serum 25-hydroxy-vitamin D (25[OH]D) levels in pregnant women and their newborns were evaluated. Breastfed newborns were randomized to one of two regimens at age 10 days. One group received vitamin D3 supplementation at a dose of 400 IU/d (vD-400 group), whereas the placebo group received a liquid product without vitamin D3. Outcomes were assessed at 4 months of age. A total of 92 pregnant women and their infants were enrolled, and the data of 72 infants (37 in the vD-400 group and 35 in the placebo group) who completed the study at 4 months of age were assessed. The results showed severe vitamin D deficiency in 15.2% of mothers before delivery, while 54.3% had vitamin D deficiency. Moreover, 15.2% of newborns presented with severe vitamin D deficiency at birth, while 52.2% had vitamin D deficiency. Maternal vitamin D levels were significantly correlated with infant vitamin D levels at birth (r = 0.816, p < 0.001). At 4 months of age, weight, head circumference, serum 25(OH)D, phosphorus, and intact parathyroid hormone levels significantly differed between the vD-400 and placebo groups. However, the body length and bone mineral density of the two groups did not differ significantly. Regardless of vitamin D supplementation, participants with severe vitamin D deficiency had significantly higher intact parathyroid hormone levels and lower bone mineral content. In conclusion, among exclusively breastfed infants, oral supplementation with vitamin D3 at a dose of 400 IU/d from age 10 days increased 25(OH)D concentrations at 4 months of age, but it did not affect bone mineralization. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Blue Rubber Bleb Nevus Syndrome (BRBNS): A Rare Cause of Refractory Anemia in Children.

Refractory anemia is not uncommon in pediatric patients, and anemia caused by gastrointestinal tract bleeding should always be kept in mind. Aside from infection or intestinal malrotation related bleeding, vascular malformation should also be considered. Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder consisting of multiple venous malformations. Lack of experience in pediatric BRBNS might lead to delayed diagnosis or misdiagnosis. Herein, we report a case of an eleven-year-old boy with recurrent pallor appearance and weakness diagnosed with BRBNS. After a thorough examination, he was treated with endoscopic polypectomy, and further iron supplements and folic acid. He is now under regular follow-up at our outpatient department. No complication is noted for six months. BRBNS is a rare venous malformation syndrome that mostly involves skin and the gastrointestinal tract. Multidisciplinary approach should be arranged for diagnosis and management. Up to date, no consensus for BRBNS treatment has been reached. Management usually depends on clinical symptoms and severity of damage of involved organs. The options of treatment include conservative, medical, endoscopic, and surgical management.

Corrigendum: Phenotype, Susceptibility, Autoimmunity, and Immunotherapy Between Kawasaki Disease and Coronavirus Disease-19 Associated Multisystem Inflammatory Syndrome in Children.

[This corrects the article DOI: 10.3389/fimmu.2021.632890.].

Effects of Vitamin D-Deficient Diet on Intestinal Epithelial Integrity and Zonulin Expression in a C57BL/6 Mouse Model.

Background and Aims: Vitamin D (VD) plays an important role not only in mineral balance and skeletal maintenance but also in immune modulation. VD status was found correlated with the pathophysiology and severity of inflammatory bowel diseases and other autoimmune disorders. Epithelial barrier function is primarily regulated by the tight-junction (TJ) proteins. In this study, we try to establish an animal model by raising mice fed VD-deficient diet and to investigate the effects of VD-deficient diet on gut integrity and zonulin expression. Methods: Male C57BL/6 mice were administered either VD-deficient [VDD group, 25(OH)2D3 0 IU/per mouse] or VD-sufficient [VDS group, 25(OH)2D3 37.8 IU/per mouse] special diets for 7 weeks. Body weight and diet intake were recorded weekly. Serum VD levels were detected. After sacrifice, jejunum and colon specimens were collected. The villus length and crypt depth of the jejunum as well as mucosa thickness of the colon were measured. Various serum pro-inflammatory cytokines and intestinal TJ proteins were assessed. The serum level of zonulin and the mRNA expression of jejunum zonulin were also investigated. Results: We found that mice fed a VDD diet had a lower serum level of VD after 7 weeks (p < 0.001). VDD mice gained significant less weight (p = 0.022) and took a similar amount of diet (p = 0.398) when compared to mice raised on a VDS diet. Significantly decreased colon mucosa thickness was found in VDD mice compared with the VDS group (p = 0.022). A marked increase in serum pro-inflammatory cytokine levels was demonstrated in VDD mice. All relative levels of claudin (CLD)-1 (p = 0.007), CLD-3 (p < 0.001), CLD-7 (p < 0.001), and zonulin-1 (ZO-1, p = 0.038) protein expressions were significantly decreased in the VDD group when compared to the VDS group. A significant upregulation of mRNA expression of jejunum zonulin (p = 0.043) and elevated serum zonulin (p = 0.001) were found in the VDD group. Conclusions: We successfully demonstrated that VDD could lead to impaired barrier properties. We assume that sufficient VD could maintain intestinal epithelial integrity and prevent mucosal barrier dysfunction. VD supplementation may serve as part of a therapeutic strategy for human autoimmune and infectious diseases with intestinal barrier dysfunction (leaky gut) in the future. To our knowledge, this is the first study to demonstrate that VDD could lead to a significant upregulation in mRNA expression of the jejunum zonulin level and also a marked elevation of serum zonulin in a mouse model.

Impact of Early Empiric Antibiotic Regimens on the Gut Microbiota in Very Low Birth Weight Preterm Infants: An Observational Study.

Frequent use of antibiotics in preterm infants disturbs their gut microbial balance. In this preliminary observational study, we investigated the effect of different antibiotic regimens, administered during the first week of life, on microbial composition and diversity in very low birth weight (VLBW) preterm infants. We performed fecal sampling of breastfed VLBW infants on days 7, 14, and 30. After excluding stool samples from infants who received probiotics or who were administered antibiotics beyond the age of 7 days, we compared gut microbiota profiles between infants receiving a combination of ampicillin and gentamicin for 3 days (AG group, n = 10) and those receiving a combination of ampicillin and cefotaxime for 7 days (AC group, n = 14) using 16S ribosomal DNA community profiling. We also assessed the changes over time in each group. Compared to the AG group, Enterococcus species were significantly more abundant in the AC group (P = 0.002), especially in 7-day samples (12.3 vs. 0.6%, respectively, P = 0.032). No difference was observed at phylum and genus level over time within each group. Species richness in the AC group decreased significantly in the 14-day (P = 0.038) and 30-day (P = 0.03) samples compared to that in the 7-day sample. The same was observed for microbial evenness; in contrast, no significant difference in Shannon index and beta-diversity was detected between the two groups. Controlling for relevant confounding variables did not change the results. In conclusion, different antibiotic regimens affect the early development of gut microbiota in VLBW preterm infants. Prolonged use of ampicillin and cefotaxime might result in overabundance of Enterococcus. However, given that no significant differences were observed in 1-month samples, bacterial genera appear to continue colonizing the gastrointestinal tract despite previous exposure to antibiotics. The clinical relevance of these findings should be elucidated by further studies.

Importance of early detection of infantile inflammatory bowel disease with defective IL-10 pathway: A case report.

RATIONALE: Infantile inflammatory bowel disease (IBD) is an extremely rare subgroup of IBD that includes patients whose age of onset is younger than 2 years old. These patients can have more surgical interventions, and a severe and refractory disease course with higher rates of conventional treatment failure. Monogenic defects play an important role in this subgroup of IBD, and identification of the underlying defect can guide the therapeutic approach. PATIENT CONCERNS: In 2007, a 4-month-old girl from a nonconsanguineous family presenting with anal fistula, chronic diarrhea, and failure to thrive. She underwent multiple surgical repairs but continued to have persistent colitis and perianal fistulas. DIAGNOSIS: Crohn's disease was confirmed by endoscopic and histologic finding. INTERVENTION: Conventional pediatric IBD therapy including multiple surgical interventions and antitumor necrosis factor alpha agents were applied. OUTCOMES: The patient did not respond to conventional pediatric IBD therapy. Interleukin-10 (IL-10) receptor mutation was discovered by whole-exome sequencing and defective IL-10 signaling was proved by functional test of IL-10 signaling pathway by the age of 12. The patient is currently awaiting hematopoietic stem cell transplantation. LESSONS: Early detection of underlying genetic causes of patients with infantile-IBD is crucial, since it may prevent patients from undergoing unnecessary surgeries and adverse effects from ineffective medical therapies. Moreover, infantile-IBD patients with complex perianal disease, intractable early onset enterocolitis and extraintestinal manifestations including oral ulcers and skin folliculitis, should undergo genetic and functional testing for IL-10 pathway defect.

Tight junction protein ZO-1 in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a form of systemic febrile vasculitis that is complicated with coronary artery lesions (CAL). The tight junctions that maintain the intestinal barrier also play a role in systemic inflammatory diseases. Serum zonula occludens-1 (ZO-1) expression was found to be significantly lower in asthmatic patients, and another study reported that elevated systemic ZO-1 was positively correlated with inflammation in cirrhotic patients. A murine model of KD vasculitis demonstrated that vasculitis depended on intestinal barrier dysfunction, which is maintained by tight junctions. In this study, we aimed to investigate the role of the tight junction zonula occludens-1 (ZO-1) in the treatment response of intravenous immunoglobulin (IVIG) and the occurrence of CAL formation in KD patients. METHODS: We enrolled 40 KD patients, 12 healthy controls, and 12 febrile controls in this study. The serum levels of tight junction ZO-1 were determined by enzyme-linked immunosorbent assay. RESULTS: The serum ZO-1 level was higher in the fever control group but did not reach a statistical significance. KD patients who received a second dose of IVIG treatment due to initial IVIG unresponsiveness had a higher serum levels of tight junction ZO-1, but without statistical significance (2.15 ± 0.18 vs. 2.69 ± 0.31 ng/mL, p = 0.058). KD patients who developed a CAL demonstrated a significant lower serum tight junction ZO-1 levels than KD without CAL formation (1.89 ± 0.16 vs. 2.39 ± 0.15 ng/mL, p = 0.027). After multiple logistic regression analysis, ZO-1 levels [(95% confidence interval (CI): 0.058 ~ 0.941, odds ratio (OR) = 0.235, p = 0.041)] showed as the risk factor for CAL formation. CONCLUSION: Serum levels of tight junction ZO-1 levels were lower in KD patients than fever controls and associated with CAL formation.

Phenotype, Susceptibility, Autoimmunity, and Immunotherapy Between Kawasaki Disease and Coronavirus Disease-19 Associated Multisystem Inflammatory Syndrome in Children.

Coronavirus disease-19 (COVID-19) in children is usually mild but some are susceptible to a Kawasaki disease (KD)-like multisystem inflammatory syndrome in children (MIS-C) in the convalescent stage, posing a need to differentiate the phenotype, susceptibility, autoimmunity, and immunotherapy between KD and MIS-C, particularly in the upcoming mass vaccination of COVID-19. Patients with MIS-C are prone to gastrointestinal symptoms, coagulopathy, and shock in addition to atypical KD syndrome with fever, mucocutaneous lesions, lymphadenopathy, and/or cardiovascular events. MIS-C manifests KD-like symptoms that alert physicians to early recognize and adopt the KD treatment regimen for patients with MIS-C. MIS-C linked to COVID-19 teaches us infection-associated autoimmune vasculitis and vice versa. Studies on genetic susceptibility have identified certain human leukocyte antigen (HLA) locus and toll-like receptor (TLR) associated with KD and/or COVID-19. Certain HLA subtypes, such as HLA-DRB1 and HLA-MICA A4 are associated with KD. HLA-B*46:01 is proposed to be the risk allele of severe COVID-19 infection, and blood group O type is a protective factor of COVID-19. The autoimmune vasculitis of KD, KD shock syndrome (KDSS), or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE) resulting in hyperinflammation with T helper 17 (Th17)/Treg imbalance with augmented Th17/Th1 mediators: interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), Interferon (IFNγ), and IL-17A, and lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-ß). There are certain similarities and differences in phenotypes, susceptibility, and pathogenesis of KD, KDSS, and MIS-C, by which a physician can make early protection, prevention, and precision treatment of the diseases. The evolution of immunotherapies for the diseases has shown that intravenous immunoglobulin (IVIG) alone or combined with corticosteroids is the standard treatment for KD, KDSS, and MIS-C. However, a certain portion of patients who revealed a treatment resistance to IVIG or IVIG plus corticosteroids, posing a need to early identify the immunopathogenesis, to protect hosts with genetic susceptibility, and to combat Th17/Treg imbalance by anti-cytokine or pro-Treg for reversal of the hyperinflammation and IVIG resistance. Based on physiological and pathological immunity of the diseases under genetic susceptibility and host milieu conditions, a series of sequential regimens are provided to develop a so-called "Know thyself, enemy (pathogen), and ever-victorious" strategy for the prevention and immunotherapy of KD and/or MIS-C.