Michal Kori

Comparison of two dosing methods for induction of response and remission with oral budesonide in active pediatric Crohn's disease: A randomized placebo-controlled trial†

Background: Oral budesonide has been found to be comparable to systemic corticosteroids in mild to moderately active Crohns disease (CD). Remission rates in pediatric studies to date have been suboptimal (47%–55%), even though patients with colonic involvement were excluded in some studies. In addition, the optimal pediatric dosing regimen has never been evaluated before. Methods: This was a randomized, controlled, double‐blind study in 70 children with mild or moderately active CD randomized to 1 of 2 groups: Group 1: Standard dose budesonide (9 mg/day) for 7 weeks followed by 6 mg budesonide daily for an additional 3 weeks. Group 2: Induction with 12 mg/day for the first month followed by the same regimen as Group 1. Outcome measures included a decrease in Pediatric Crohns Disease Activity Index and remission rates. Patients with colonic disease were not excluded. Results: At week 7 a clinical response was obtained in 51.4% in Group 1 versus 74.3% in Group 2. A significant decrease in C‐reactive protein was seen only in Group 2. At the end of treatment, remission was obtained in 42.9% in Group 1 versus 65.7% in Group 2 (P = 0.054). There was no significant difference in adverse events or serum cortisol. Conclusions: Use of an induction dose of budesonide followed by a budesonide taper resulted in a trend to higher rates of clinical remission and a decrease in inflammation, without an increase in steroid‐associated side effects. Budesonide was also useful for patients with ileocolonic disease.

Helicobacter pylori infection in young children detected by a monoclonal stool antigen immunoassay.

The prevalence of Helicobacter pylori infection in young children attending day care facilities was studied using a monoclonal stool antigen test. Of 316 samples, 78 (24.7%) were positive. Only 7/98 (7.1%) of the 3- to 12-month-old infants tested positive compared with 71/218 (32.5%) of the 13- to 60-month-old group. We conclude that approximately 30% of infants may become infected with H. pylori after the first year of life.

Homozygous deletion of TRMT10A as part of a contiguous gene deletion in a syndrome of failure to thrive, delayed puberty, intellectual disability and diabetes mellitus

Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17‐year‐old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%–6.2%). RT‐PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.

Inflammatory Bowel Disease: An Emergent Disease Among Ethiopian Jews Migrating to Israel

Background:The development and characteristics of inflammatory bowel disease (IBD) in Ethiopian Jewish immigrants to Israel were investigated. Methods:A case-control study was conducted in 7 tertiary care hospitals in Israel. Patients of Ethiopian origin with IBD >6 months were included. Time of disease onset after immigration and age at diagnosis were recorded. Randomly chosen patients with IBD of Ashkenazi Jewish origin served as controls. Demographics and clinical parameters were compared between the 2 cohorts. Results:Thirty-two Ethiopian patients with IBD were compared with 33 Ashkenazi Jewish patients with IBD. Crohns disease (CD) was more prevalent than ulcerative colitis (UC) in the Ethiopian group compared with the Ashkenazi group (94% versus 73%, P = 0.02). No Ethiopian-origin patient had a positive family history of IBD compared with 42% of Ashkenazi-origin patients (P < 0.001). Arthritis was more common in Ashkenazi than in Ethiopian patients (27% versus 3%, P < 0.01). One Ashkenazi patient with CD had upper gastrointestinal involvement compared with 7 (23%) in the Ethiopian group (P < 0.02). All other clinical measures were similar between the 2 cohorts. The Ethiopian group lived in Israel with a mean of 13 ± 5 years, and 75% were born in Ethiopia. The shortest time between immigration and developing IBD was 8 years (range, 8–26; median 16 yrs). No Ethiopian patient was diagnosed before immigration. Conclusions:Ethiopian Jews migrating to Israel are at risk of developing IBD. Larger cohorts are needed to determine the relative importance of environmental and genetic factors that cause IBD in these patients.

Once- Versus Twice-daily Mesalazine to Induce Remission in Paediatric Ulcerative Colitis: A Randomised Controlled Trial.

Background Trials in adults suggested that, in ulcerative colitis [UC], once-daily [OD] dosing of 5-ASA [5-amino salicylic acid] may be as or more effective than twice-daily [BD] dosing. In this induction of remission, investigator-blinded, randomised controlled-trial, we aimed to compare effectiveness and safety of once- versus twice-daily mesalazine in paediatric UC. Methods Children, aged 4-18 years with a PUCAI [Paediatric Ulcerative Colitis Activity Index] of 10-55 points at inclusion, were randomised in blocks of six with blinded allocation to OD or BD mesalazine, using a weight-based dosing table. The primary outcome was mean PUCAI score at Week 6. Results A total of 83/86 randomised children were eligible and analysed: 43 in the OD group and 40 in the BD group (mean age 14 ± 2.7 years, 43 [52%] males, 51 [62%] extensive colitis). The groups did not differ with regard to disease activity or any other parameter at baseline. There was no difference in median PUCAI score between the OD group and BD group at Week 6: 15 ( interquartile range [IQR] 5-40) versus 10 [0-40]; p = 0.48]. Response was seen in 25 [60%] OD versus 25 [63%] BD dosing [p = 0.78]. Proportion of children in remission [PUCAI < 10] at Week 6 was 13 [30%] OD versus 16 [40%] BD; p = 0.35]. Most adverse events were related to disease aggravation; the rates of serious adverse events were similar [p > 0.2]. Conclusions In this first randomised controlled trial in children, no differences were found between OD and BD dosing for any clinical outcome. Remission was achieved in 35% of children treated with mesalazine for active UC.

Look-back study of Hepatitis C in teenagers after blood transfusions as neonates

Aim: To conduct a single‐centre “look‐back” study of the prevalence of hepatitis C in teenagers who had received blood products as newborns, prior to hepatitis C virus (HCV) blood donor screening.

Treatment-Specific Composition of Gut Microbiota Is Associated with Disease Remission in a Pediatric Crohn\'s Disease Cohort

Objectives The beneficial effects of antibiotics depend in part on the gut microbiota but are inadequately understood. We investigated the impact of metronidazole (MET) and metronidazole plus azithromycin (MET+AZ) on the microbiota in pediatric CD, and the use of microbiota features as classifiers or predictors of disease remission. Methods 16S rRNA-based microbiota profiling was performed on stool samples from a multinational, randomized, controlled, longitudinal, 12-week trial of MET vs. MET+AZ in children with mild to moderate CD. Profiles were analyzed together with disease activity, and then used to construct Random Forest classification models to classify remission or predict treatment response. Results Both MET and MET+AZ significantly decreased diversity of the microbiota and caused large treatment-specific shifts in microbiota structure at week 4. Disease remission was associated with a treatment-specific microbiota configuration. Random Forest models constructed from microbiota profiles pre- and during antibiotic treatment with metronidazole accurately classified disease remission in this treatment group (AUC of 0.879, 95% CI 0.683, 0.9877; sensitivity 0.7778; specificity 1.000, P < 0.001). A Random Forest model trained on pre-antibiotic microbiota profiles predicted disease remission at week 4 with modest accuracy (AUC of 0.8, P = 0.24). Conclusions MET and MET+AZ antibiotic regimens lead to distinct gut microbiota structures at remission. It may be possible to classify and predict remission based in part on microbiota profiles, but larger cohorts will be needed to realize this goal. Study Highlights What is known The composition of the intestinal microbiota of pediatric Crohn’s disease patients is altered, and has low diversity Antibiotics disturb the intestinal microbiota in an individualized fashion that may help explain different clinical responses The combination of metronidazole and azithromycin (MET+AZ) is more effective than metronidazole alone (MET) for inducing disease remission in some CD patients What is new MET and MET+AZ cause distinct changes in the gut microbiota of pediatric CD patients Each regimen induces a specific remission-associated microbiota community configuration mDisease remission after either antibiotic regimen is characterized by a higher abundance of Lactobacillus

Helicobacter pylori and some aspects of gut microbiota in children

Helicobacter pylori infection in children differs from infection in adults in many aspects. The rate of infection, epidemiology, clinical presentations and complications, the applicability of diagnostic tests, antibiotic resistance, treatment options, and success rates differ significantly. Due to all these differences, management guidelines for children and adults differ also substantially. In 2017, the Updated ESPGHAN and NASPGHAN Guidelines on the management of H. pylori infection in children were published, emphasizing the differences in clinical presentation and indications for treatment, stating that the primary goal of clinical investigation in children is to identify the cause of upper gastrointestinal symptoms rather than the presence of H. pylori infection. Therefore, the diagnosis should be based on upper endoscopy, and the “test and treat strategy” should not be used in children. Due to an increasing rate of antibiotic resistance worldwide, the updated guidelines recommend broader use of antimicrobial susceptibility testing for H. pylori strains in order to tailor eradication treatment accordingly. Moreover, treatment in children should be prescribed only when indicated and should be based on the rate of eradication in local populations aiming for treatment success above 90%. During the last two decades there has been a steady decrease in the rate of H. pylori infection in both children and adults in the Western world. Two recent publications studying the incidence of H. pylori infection confirmed that early childhood is a time for acquisition of infection both in industrialized and nonindustrialized countries. In addition, they showed that H. pylori could be acquired outside the family. In respect to the inverse association between H. pylori and allergy, a longitudinal study demonstrated that early exposure to H. pylori at any age was inversely associated with atopy and allergic conditions.

Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease : a randomised controlled trial

Objective Crohn’s disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD. Design This blinded randomised controlled trial allocated children 5–18 years with 10<Pediatric Crohn’s Disease Activity Index (PCDAI)≤40 to azithromycin 7.5 mg/kg, 5 days/week for 4 weeks and 3 days/week for another 4 weeks with metronidazole 20 mg/kg/day (group 1) or metronidazole alone (group 2), daily for 8 weeks. Failures from group 2 were offered azithromycin as open label. The primary end point was response defined by a decrease in PCDAI>12.5 or remission using intention to treat analysis. Results 73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%). Conclusions The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin. Trial registration number NCT01596894.

Intestinal granulomatous disease: what is the first call

A 15-year-old girl presented with erythema nodosum and mild abdominal complaints. Her intestinal granulomatous disease was erroneously diagnosed as Crohn’s disease despite the fact that the possibility of tuberculosis was considered. The final diagnosis of tuberculosis was made only when an anti-tumour necrosis factor therapy resulted in further deterioration. The patient was treated with isoniazid, rifampin, pyrazinamide and ethambutol, with slow and steady clinical improvement until complete recovery was achieved.