Faecal Bacteriome and Metabolome Profiles Associated with Decreased Mucosal Inflammatory Activity Upon Anti-TNF Therapy in Paediatric Crohn's Disease.

BACKGROUND AND AIMS: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA]. METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab. RESULTS: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test. CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.

Etiology and classification of acute pancreatitis in children admitted to ICU using the Pediatric Sequential Organ Failure Assessment (pSOFA) score.

BACKGROUND: Pediatric acute pancreatitis (AP) is rare but increasing. Severe AP is associated with higher morbidity and mortality. However, there are no universally accepted prognostic criteria for AP. METHODS: This retrospective study included children with AP admitted to an intensive care unit (ICU) of our tertiary pediatric center between January 2009 and December 2018. The severity of organ dysfunction in AP was assessed according to the modified Atlanta criteria using the Pediatric Sequential Organ Failure Assessment (pSOFA) and Computed Tomography Severity Index (CTSI). RESULTS: Seventy acute episodes of AP were evaluated in 55 children with primary pancreatitis. In addition, secondary AP was diagnosed in 15 patients originally admitted to ICU for different indications. Mild AP [no organ dysfunction, normal computed tomography (CT) finding] was the most prevalent (64/85 episodes in 49 children), followed by moderate AP (15 children; pSOFA 2-9 points, CTSI 3-4 points on admission). Severe AP (pSOFA 4-17 points, CTSI 6-10 points) was diagnosed in 6 children with traumatic or secondary AP. The most frequent etiologies of primary AP episodes were idiopathic (39%) and biliary (31%). Children with idiopathic AP had frequent relapses and comorbidities. Hereditary AP was typically mild, but presented with high pancreatic enzyme levels and recurrence rates. Admission at ICU and an interval without enteral nutrition (EN) were relatively short in drug-induced AP and relatively long in secondary and traumatic AP. Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 13 patients with biliary AP and in 4 patients with traumatic AP. No AP-related death was observed. CONCLUSION: pSOFA score accurately reflects the severity and prognosis of AP in children.

Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis as a Complication of Home Parenteral Nutrition.

Patients on long-term home parenteral nutrition (HPN) occasionally develop glomerulonephritis due to chronic central venous catheter (CVC)-related infection. Most previously reported cases were membranoproliferative glomerulonephritis (MPGN). This is a case report of a 16-year-old girl receiving HPN for short bowel syndrome. After 11 years on HPN, she developed acute kidney injury with macroscopic hematuria, nephrotic-range proteinuria, and a reduced glomerular filtration rate (GFR). Initially, MPGN associated with chronic bacteremia was suspected with the assumption that the condition would be treated with antibiotics and CVC replacement. However, her kidney biopsy revealed antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAG). This was consistent with the fact that the patient tested positive for proteinase 3-ANCA. Immunosuppressive therapy with methylprednisolone pulses (followed by oral prednisone) and rituximab led to remission. Her GFR and protein excretion returned to normal. Chronic bacteremia as a complication of long-term HPN may cause various types of glomerulonephritis including, rarely, AAG requiring immunosuppressive therapy.

Is It Useful to Monitor Thiopurine Metabolites in Pediatric Patients with Crohn's Disease on Combination Therapy? A Multicenter Prospective Observational Study.

BACKGROUND: The additional value of azathioprine concomitant treatment on infliximab pharmacokinetics in children is not well described yet. AIMS: In the present study, we aimed to describe the relationship between thiopurine metabolite levels, infliximab trough levels, anti-IFX antibody formation, and clinical and laboratory markers of disease activity in pediatric patients with Crohn's disease, and to assess non-adherence. METHODS: Data were collected prospectively during repeated visits from pediatric patients followed for Crohn's disease in two Czech pediatric inflammatory bowel disease centers between January 2016 and June 2017. Thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine) were measured by high-performance liquid chromatography. Infliximab trough levels and anti-IFX antibody serum levels were measured routinely by ELISA. The risk of loss of response to infliximab therapy was also assessed. RESULTS: A significant association between infliximab serum levels and 6-thioguanine erythrocyte levels was observed when tested as categorical variables (63 patients, 321 observations). To predict infliximab levels > 5 µg/mL, we propose a 6-thioguanine cutoff of 278 pmol/8 × 108 erythrocytes (sensitivity, 0.799; specificity, 0.347). A higher loss-of-response-to-infliximab rate (tested in a subgroup of 51 patients) was observed in patients with undetectable 6-thioguanine levels than in those with detectable levels (p = 0.026). Non-adherence to azathioprine therapy was suspected in 20% of patients. CONCLUSION: Thiopurine metabolite monitoring in pediatric patients with Crohn's disease is useful when optimizing combination therapy. Pediatric patients with undetectable 6-thioguanine levels are more likely to lose response to infliximab therapy. When targeting optimal infliximab levels, the 6-thioguanine cutoff levels in children appear to be higher than in adults.

Giant post-inflammatory polyposis in a child with ulcerative colitis: A case report.

INTRODUCTION: Post-inflammatory pseudopolyps (PIPs) develop in connection with an inflammatory process in the bowel. Masses larger than 15 mm are classified as giant PIPs. They are very rare, especially in children. PRESENTATION OF CASE: A case of 13-year-old girl suffering from ulcerative colitis (UC) and treated with corticosteroids and azathioprine is reported. Colonoscopic examination after achieving clinical remission revealed multiple giant PIPs. During endoscopic surveillance subsequent spontaneous regression of pseudopolyps was documented. DISCUSSION: Patients with prolonged relapses of inflammatory bowel disease (IBD) are predisposed to PIPs. Giant PIPs may be related to post inflammatory mucosal regeneration or hyperplastic proliferation of the colonic mucosa between ulcerations after recurrent acute disease flares. Partial regression of giant polyps is uncommon, but has been reported. Some of these pseudopolyps are suitable for endoscopic polypectomy, but resection of PIPs is not generally advisable, because they usually regrow. Surgical intervention is advocated in symptomatic cases such as those with abdominal pain, severe hemorrhage or intestinal obstruction. CONCLUSION: The present case report of giant PIPs in an adolescent girl describes rare course of severe ulcerative colitis complicated by development of multiple giant PIPs. Due to asymptomatic course of the disease a conservative therapeutic approach was decided upon. Gradual regression of giant PIPs was observed during consecutive several year surveillance.

Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis.

BACKGROUND: Sclerosing cholangitis (SC) is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate long-term results in children with SC according to the types of SC. METHODS: We retrospectively followed up 25 children with SC over a period of 4-17 years (median 12). The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis (ASC); other patients were included in a group of primary sclerosing cholangitis (PSC). The incidence of the following complications was studied: obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease. RESULTS: Fourteen (56%) patients had PSC and 11 (44%) had ASC. Patients with ASC were significantly younger at the time of diagnosis (12.3 vs 15.4 years, P=0.032) and had higher IgG levels (22.7 vs 17.2 g/L, P=0.003). The mentioned complications occurred in 4 (16%) patients with SC, exclusively in the PSC group: one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, two other children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications. CONCLUSION: In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.

Unmet psychosocial needs in adolescents with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel diseases (IBD) are severe medical conditions with adverse impact on the quality of life of both children and their caregivers. IBD are associated with many limitations in personal and interpersonal functioning, and it also restricts the patients' ability to use the full potential (extent) of their capabilities. With the progress and humanization in society, the issue of patients' needs became an important topic; however, the psychosocial functioning and quality of life of adolescents suffering from IBD and their caregivers have been understudied. The aim of this article is to provide a comprehensive, up-to-date literature review of the unmet needs of patients with IBD and their caregivers. METHOD: A computerized search of MEDLINE publications from 1990 to 2016 using the keywords "inflammatory bowel disease", "Crohn disease", "ulcerative colitis" and "unmet needs". In the period 1990-2016, the MEDLINE searches identified 54 publications. Articles cited in the papers from these searches were also used. The total number of 132 particular articles were collected, sorted by their relevance and key articles (n=72) listed in reference lists were searched. RESULTS: Patients' needs differ at various stages of the illness and may have different origins and goals. Thus, we divided the needs into five groups according to their nature; i.e. needs to be connected with symptoms, treatment, quality of life, family and age-related challenges. We provide implications of the patients' needs for pharmacotherapy and psychotherapy. CONCLUSION: Following the needs of patients with IBD may be a crucial part of the therapeutic process. Due to the better understanding and cooperation, the impact of disease could be reduced, and the physical and mental condition of the patient could be improved. However, many needs remain unmet due to both medical and social factors.

Heart rate variability in children with inflammatory bowel diseases.

OBJECTIVE: Heart rate variability (HRV) oscillations are used in the detection of autonomic instabilities in various clinical disorders. METHODS: We compared the HRV as a possible marker of chronic distress in children with inflammatory bowel disease (IBD) with HRV frequencies in the healthy controls. Participants were 29 children with IBD (19 Crohn's disease and 10 ulcerative colitis), 25 children were in remission and 4 presented mild disease activity. They were compared with the control group of 35 healthy children of the same age (13-16 years-old). RESULTS: In HRV assessment, adolescents with IBD had significantly lower levels of the spectral activity in an LF band in all three positions; lower levels of VLF in both supine positions; and the ratio of the spectral activity at LF/HF was significantly lower in the second post (standing). CONCLUSION: These results indicate children with IBD have less adaptability to stress.

Quality of life in adolescents with inflammatory bowel disease and their parents--comparison with healthy controls.

OBJECTIVE: Inflammatory bowel diseases (IBD) are chronic diseases with a significant impact on quality of life (QoL). The aim of the study was to examine the QoL in children with IBD and their families, depression and anxiety for both the children and their parents. METHODS: Participants were 29 adolescents with IBD (19 individuals suffered from the Crohn disease, another ten had ulcerative colitis) and 40 healthy controls of the same age (13-16 years). The probands and their parents completed questionnaires measuring the quality of life (KidScreen-10, PedsQL), depression (CDI, BDI-II), and anxiety (SAD, BAI). RESULTS: The QoL measured by questionnaires did not differ between the adolescent participants, but it was significantly lower in the parents of the children with IBD than in the parents of the healthy controls. The parents of the IBD children scored lower in the Family Impact Module Total Scale Score and the parental Health-Related QoL Summary Score. The fathers of the IBD children also had a lower level of the Family Functioning Summary Score. There wasn't any difference in the levels of anxiety and depressive symptoms among the IBD adolescents and the controls. CONCLUSIONS: The parents of the children with IBD experience lower QoL than the parents with the healthy children. The children with IBD show similar symptoms of depression, anxiety, and QoL as the healthy controls.