Yigael Finkel

Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult patients with Crohn's colitis.

Aims: To test the assumption that epithelioid granulomas found in colonoscopic biopsy specimens in patients with Crohn’s colitis are markers of a different clinical behaviour. Methods: Sections from colonoscopic biopsy specimens from 352 consecutive patients (119 children and 233 adults) were investigated. Results: A total of 1117 colonoscopies were performed: 293 in children (mean 2.46 per patient) and 824 in adults (mean 3.53 per patient) (p<0.05). Granulomas at initial colonoscopy were recorded in 67.2% (43/64) of children and 65.9% (27/41) of adults (p>0.6), and at subsequent colonoscopies in 53.8% (64/119) of children and 17.6% (41/233) of adults (p<0.05). Surgical intervention was required in 6.3% (4/64) of the children having previous granuloma, but also in 14.5% (8/55) of those without previous granuloma, the rate for operated adults being 26.8% (11/41) and 24.5% (47/192), respectively (p>0.6). Conclusions: Granulomas in entry and/or in subsequent colonoscopic biopsy specimens in patients with Crohn’s colitis did not predict the need for subsequent surgical intervention. The fact that the frequency of granulomas was significantly higher in children than in adults with Crohn’s colitis (despite a higher mean number of colonoscopic biopsies in adults), and that granulomas were present in colonoscopic biopsy specimens but not in the subsequent surgical specimens from 50% of the paediatric and 36% of the adult patients strengthen the conviction that granulomas in Crohn’s colitis might evolve or regress at different time intervals during the course of the disease. This behaviour would reflect a particular immunological reaction, an epiphenomenon from immature tissues—as in children—when challenged by the so far elusive aetiological agent responsible for Crohn’s disease.

Improved Outcome in Neonatal Short Bowel Syndrome Using Parenteral Fish Oil in Combination With ω-6/9 Lipid Emulsions

BACKGROUNDnNewborn infants with short bowel syndrome (SBS) represent a high-risk group of developing intestinal failure-associated liver disease (IFALD), which may be fatal. However, infants have a great capacity for intestinal growth and adaptation if IFALD can be prevented or reversed. A major contributing factor to IFALD may be the soybean oil-based intravenous lipid emulsions used since the introduction of parenteral nutrition (PN) 40 years ago.nnnMETHODSnThis retrospective study compares the outcome in 20 neonates with SBS treated with parenteral fish oil (Omegaven) in combination with ω-6/9 lipid emulsions (ClinOleic) with the outcome in a historical cohort of 18 patients with SBS who received a soybean oil-based intravenous lipid emulsion (Intralipid).nnnRESULTSnMedian gestational age was 26 weeks in the treatment group and 35.5 weeks in the historical group. All patients were started on PN containing Intralipid that was switched to ClinOleic/Omegaven in the treatment group at a median age of 39 gestational weeks. In the treatment group, direct bilirubin levels were reversed in all 14 survivors with cholestasis (direct bilirubin >50 umol/L). Median time to reversal was 2.9 months. Only 2 patients died of liver failure (10%). In the historical cohort, 6 patients (33%) died of liver failure, and only 2 patients showed normalization of bilirubin levels.nnnCONCLUSIONSnParenteral fish oil in combination with ω-6/9 lipid emulsions was associated with improved outcome in premature neonates with SBS. When used instead of traditional soybean-based emulsions, this mixed lipid emulsion may facilitate intestinal adaptation by increasing the IFALD-free period.

Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome

BackgroundThe composition of the intestinal microbiota seems to be an important factor in determining the clinical outcome in children with short bowel syndrome (SBS). Alterations in the microbiota may result in serious complications such as small bowel bacterial overgrowth (SBBO) and intestinal mucosal inflammation that lead to prolonged parenteral nutrition (PN) dependency with subsequently increased risk of liver failure and sepsis. To date, there are no reported mappings of the intestinal microbiome in children with SBS. Here, we present the first report on the intestinal microbial community profile in children with SBS.FindingsThe study includes children diagnosed with SBS in the neonatal period. Healthy siblings served as controls. Fecal samples were collected, and microbial profiles were analyzed by using 16S rRNA gene sequencing on the Illumina MiSeq platform. We observed a pronounced microbial dysbiosis in children with SBS on PN treatment with an increased and totally dominating relative abundance of Enterobacteriacae in four out of five children compared to children with SBS weaned from PN and healthy siblings.ConclusionsThe overall decreased bacterial diversity in children with SBS is consistent with intestinal microbiome mappings in inflammatory bowel diseases such as Crohn’s disease and necrotizing enterocolitis in preterm infants. Our findings indicate that intestinal dysbiosis in children with SBS is associated with prolonged PN dependency.

Prevention and reversal of intestinal failure–associated liver disease in premature infants with short bowel syndrome using intravenous fish oil in combination with omega-6/9 lipid emulsions

Although premature infants with short bowel syndrome are at the highest risk of developing intestinal failure-associated liver disease (IFALD), they have great capacity for intestinal growth and adaptation if IFALD can be prevented. Conventional soybean oil-based intravenous lipid emulsions have been associated with IFALD. This study presents data on 5 premature neonates with short bowel syndrome treated with a combination of parenteral fish oil- and olive/soybean-based lipid emulsion for periods ranging between 7 and 17 months. Despite an enteral tolerance of less than 50% in 4 of these patients during their first year of life, direct bilirubin levels normalized while on this combination of ClinOleic (Baxter, Maurepas, France)/Omegaven (Fresenius Kabi, Bad Homburg, Germany) at a 1:1 ratio. None of our patients developed irreversible IFALD even though all of them were premature, had undergone multiple major surgical procedures, and had experienced several episodes of sepsis. Thus far, we have not seen any adverse effects of this mixed lipid emulsion in these preterm infants. All 5 patients are growing and developing well and have normal liver function.

Virulence and colonization-associated properties of Helicobacter pylori isolated from children and adolescents.

Helicobacter pylori isolates from 32 children and adolescents were characterized with respect to putative virulence and colonization-associated properties. Only 3 of the subjects had duodenal ulcer. All but 2 of the remaining 29 had various degrees of chronic gastric inflammation. No significant correlation between degree of inflammation and presence of the cag-pathogenicity island, cytotoxin production, vacA alleles associated with cytotoxin expression, and binding ability to the Lewis(b) (Le[b]) oligosaccharide was found. Only 4 isolates expressed the Le(b)-specific adhesin, of which 3 were also cag region-positive. This is in contrast to adults with gastritis or peptic ulcer disease (or both), in whom most of the H. pylori isolates bind Le(b). In an in situ binding assay H. pylori were less able to adhere to gastric surface mucous cells in biopsies taken from children compared with adults, suggesting a lower expression of the Le(b) oligosaccharide in the children.

Pediatric Crohn’s disease from onset to adulthood: granulomas are associated with an early need for immunomodulation

Abstract Objective. Childhood onset Crohn’s disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood. Material and methods. Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed. Results. We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up – 12.3 years, range 9.3–18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0–75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2–105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas. Conclusions. Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.

Human Enterovirus Species B in Ileocecal Crohn's Disease

OBJECTIVES:Advanced ileocecal Crohn’s disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.METHODS:We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.RESULTS:All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.CONCLUSIONS:The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.