Can 2 Different Fecal Calprotectin Assays be Used Interchangeably in IBD Treatment?

BACKGROUND: Fecal calprotectin (FC) is a biomarker for inflammation in inflammatory bowel disease (IBD). Interpretation of results can be complicated because of the use of different assays to determine FC. GOALS: To assess the agreement between 2 different assays for determining FC in patients with IBD. METHODS: Samples from adults and children with IBD were tested with 2 assays: (1) EliA 2 Calprotectin and (2) EK-Cal. Samples were uniformly tested on the same day. Interassay variability was displayed in a Bland-Altman plot. The difference in categorization of the FC result (1: 0 to 250 mg/kg, 2: 250 to 500 mg/kg, 3: >500 mg/kg) was assessed with the linear weighted κ for adults and children separately. RESULTS: A total of 171 patients [mean age: 33 (range: 7 to 81); 92 (54%) female; 117 (68%) Crohn's disease; 53 (31%) ulcerative colitis] were included. Median (interquartile ranges) FC levels were 281 mg/kg (70 to 971) (EK-Cal) and 159 mg/kg (31 to 778) (EliA 2), and the mean delta FC was 89 mg/kg. In the adult population, there was substantial agreement between the 2 assays (κ: 0.72; SE: 0.06; 95% confidence interval, 0.60-0.83) and for pediatric patients, the agreement was almost perfect (κ: 0.83; SE: 0.06; 95% confidence interval: 0.70-0.95). Five of 171 patients (all aged ≥17 y and all with colonic disease) had a difference of 2 categories (1 vs. 3) between assays. Interassay variability was the highest in category 3. CONCLUSIONS: The agreement between the EliA 2 and EK-Cal assay in this cohort of IBD patients is substantial to almost perfect. Interassay variability is higher in the highest FC category.

Quality of life and colorectal function in Crohn's disease patients that underwent ileocecal resection during childhood.

Psychosocial and functional outcomes after intestinal resection in pediatric Crohn's disease (CD) are lacking. Therefore, we (I) assessed health-related quality of life (HRQOL), colorectal function, and satisfaction with surgery and (II) investigated their relationship with surgical outcomes, after ileocecal resection for CD. Crohn's patients that underwent ileocecal resection during childhood were included. HRQOL and colorectal function were assessed using SF-36 and COREFO, respectively, and compared with reference values. Satisfaction was scored on a 5-point Likert scale. In total, 80 patients (50% male, median age 23.0 years) were included. Physical HRQOL was impaired (SF-36 [mean]: CD, 47 vs. general, 54; p < 0.001), while mental HRQOL was similar to that in the general population. Overall colorectal function was impaired (COREFO [mean]: CD, 12.6 vs. normal, 7.2; p < 0.001). Worse colorectal function was associated with increasing clinical disease activity and longer interval since resection. Majority of patients was satisfied with surgery (81% satisfied/very satisfied, 11% neither satisfied nor dissatisfied, 8% dissatisfied/very dissatisfied). Decreased satisfaction with surgery was associated with increased clinical disease activity but not related to colorectal function.Conclusions: Physical HRQOL and colorectal function in CD patients who underwent ileocecal resection during childhood seem impaired and related to adverse surgical outcomes. This emphasizes the need for post-operative monitoring and prophylactic therapies. What is Known: • Up to 25% of pediatric-onset Crohn's disease (CD) patients undergo an intestinal resection within 5 years from diagnosis. • Many children and adults with CD experience disruption of their daily activities and health-related quality of life (HRQOL). What is New: • Physical HRQOL and colorectal function are impaired in patient with CD that underwent ileocecal resection during childhood. • Increasing clinical disease activity, a longer interval since surgery, severe complications related to surgery, and recurrent surgeries are all associated with worse colorectal function.

Parental Distress and Quality of Life in Pediatric Inflammatory Bowel Disease: Implications for the Outpatient Clinic.

OBJECTIVES: The interrelation between the course of inflammatory bowel disease (IBD) in children and parent's distress, and the subsequent impact this may have on health-related quality of life (HRQOL) of the child is unclear. Therefore, we investigated patient's HRQOL and parental distress and the association between the course of IBD, parental distress, and HRQOL of pediatric patients with IBD. METHODS: Pediatric patients with IBD (8-18 years) and parents were invited. Patients completed the Pediatric Quality of Life Inventory, and parents the Distress Thermometer for Parents, simultaneously. Disease course was expressed as current clinical disease activity or months since last IBD flare. Patient's HRQOL and parental distress were compared to healthy controls. RESULTS: In total, 87 patients (71% response rate, 59% boys, median age 15.2 years) and parents were included. Patients had an impaired total HRQOL (ß = 0.125, P = 0.010), driven by lower physical (0.196, P = 0.001) and school (ß = 0.232, P < 0.001) functioning. Parents of children with IBD exhibited comparable levels of distress to parents of healthy children on the total problem and most subdomain problem scores (practical, social, emotional, physical, and cognitive), yet experienced more frequent parenting problems (P = 0.025). More severe disease course (months since last IBD flare) was indirectly associated, through parental distress, with decreased HRQOL of patients. CONCLUSIONS: Worse disease course is directly associated with increased distress of parents and indirectly with lower HRQOL of children and adolescents with IBD. Distress of parents may be considered in management of pediatric IBD to improve HRQOL of children.

Do Children and Adolescents With Inflammatory Bowel Disease Complete Clinical Disease Indices Similar to Physicians?

OBJECTIVES: The degree to which children and adolescents with inflammatory bowel disease (IBD) complete clinical disease activity indices in accordance with their physician is indefinite. Therefore, we investigated the agreement between patient- and physician-based clinical indices in children and adolescents with a previous diagnosis of IBD. METHODS: In this cross-sectional study, IBD patients (8-18 years) were included prospectively. Patients completed a patient-based short Pediatric Crohn's Disease Activity Index (shPCDAI) for Crohn disease or the Pediatric Ulcerative Colitis Activity Index (PUCAI) for ulcerative or indeterminate colitis. Physicians completed the original physician-based shPCDAI or PUCAI. Agreement was calculated with linear weighted kappa. RESULTS: In total, 154 pairs of clinical indices were collected: 89 pairs of shPCDAI's (median age at assessment 15.6 years, 61% men) and 55 pairs of PUCAI's (median age at assessment 14.0 years, 44% men). The shPCDAI disease activity category only fairly agreed between patient- and physician-based indices (kappa: 0.40 [95% confidence interval 0.24-0.55], P < 0.001), with perfect agreement in 58% of pairs. In the majority of disagreement (81%), patients scored in a higher shPCDAI disease activity category. The PUCAI disease activity category substantially agreed between patient- and physician-based indices (kappa: 0.64 [95% confidence interval 0.45-0.83], P < 0.001), with perfect agreement in 78% of pairs. In the majority of disagreement (75%), patients scored in a higher PUCAI disease activity category. CONCLUSIONS: Patient- and physician-based shPCDAI and PUCAI do not always agree, particularly the shPCDAI, and therefore, should not be interpreted equivalently in management and research on children and adolescents with IBD.

Fecal Amino Acid Analysis Can Discriminate De Novo Treatment-Naïve Pediatric Inflammatory Bowel Disease From Controls.

OBJECTIVES: Endoscopy remains mandatory in the diagnostic work-up of inflammatory bowel disease (IBD), but is a costly and invasive procedure. Identification of novel, noninvasive, diagnostic biomarkers remains a priority. The aim of the present study was to explore the potential of fecal amino acid composition as diagnostic biomarker for pediatric IBD. METHODS: In this case-control study, treatment-naïve, de novo pediatric patients with IBD from two tertiary centers were included. Endoscopic severity of ulcerative colitis (UC) and Crohn's disease (CD) was based on physician global assessment scores, substantiated by levels of fecal calprotectin and C-reactive protein at study inclusion. Patients were instructed to collect a fecal sample prior to bowel cleansing. Healthy controls (HCs) were recruited from primary schools in the same region. Dedicated amino acid analysis was performed on all samples. RESULTS: Significant differences between 30 IBD patients (15 UC, 15 CD) and 15 age and sex-matched HCs were found in six amino acids (histidine, tryptophan, phenylalanine, leucine, tyrosine, and valine; all area under the curve >0.75 and P < 0.005), displaying higher levels in IBD. When distributing the patients according to type of IBD, a similar spectrum of amino acids differed between UC and HC (histidine, tryptophan, phenylalanine, leucine, valine, and serine), whereas three amino acids were different between CD and HC (histidine, tryptophan, and phenylalanine). CONCLUSIONS: Significantly increased levels of six different fecal amino acids were found in patients with IBD compared to controls. Whether these differences reflect decreased absorption or increased loss by inflamed intestines needs to be elucidated.

Relationship of clinical symptoms with biomarkers of inflammation in pediatric inflammatory bowel disease.

UNLABELLED: In adult inflammatory bowel disease (IBD) patients, there is a strong discrepancy between symptoms and biomarkers of inflammation. Data on pediatric IBD patients are conflicting. Therefore, we aimed to investigate the relationship between clinical symptoms and biomarkers of inflammation in pediatric IBD. Patients aged <18 years with previously diagnosed Crohn's disease (CD) or ulcerative colitis (UC) were included. Clinical disease activity was determined using the abbreviated Pediatric CD Activity Index (aPCDAI) or Pediatric UC Activity Index (PUCAI). Biochemical disease activity was assessed using fecal calprotectin (FC) and C-reactive protein (CRP). In total, 127 patients (62 male; median age 14.9 years) were included (82 CD, 45 UC). FC correlated weakly with total aPCDAI score (r s = 0.32; 95 % CI 0.12-0.51; p = 0.003) and total PUCAI score (r s = 0.36; 95 % CI 0.07-0.62; p = 0.015). Only aPCDAI components abdominal examination and perirectal disease and PUCAI component activity level had a significant correlation with levels of FC. CRP correlated weakly with total aPCDAI score (r s = 0.28; 95 % CI 0.05-0.46; p = 0.012) and aPCDAI components abdominal examination and activity level. No significant correlation was observed between CRP and total PUCAI score (r s = 0.01; 95 % CI -0.34-0.29; p = 0.961) or individual PUCAI components. CONCLUSION: There is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD. WHAT IS KNOWN: • A substantial proportion of asymptomatic pediatric inflammatory bowel disease (IBD) patients have elevated biomarkers of inflammation. • There is a strong discrepancy between symptoms and biomarkers of inflammation in adults with IBD. What is New: • Clinical symptoms are only weakly associated with levels of fecal calprotectin and serum C-reactive protein in children and adolescents with previously diagnosed IBD. • Similarly to adult IBD patients, there is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD.

Current treatment practice of functional abdominal pain disorders in children: A multicenter survey.

BACKGROUND: Approximately 90% of the children with chronic abdominal pain are diagnosed as having functional abdominal pain disorder (FAPD). The Dutch guideline "functional abdominal pain" provides a stepwise approach to treat FAPD. The aim of this survey was twofold first, to determine adherence to the Dutch guideline, and second to determine current management of FAPDs in clinical practice. METHODS: A multicenter survey was designed. The survey was sent to pediatricians and pediatric residents in December 2020. The study ran from October 2020 until March 2021. Participants in ten hospitals in the western region of The Netherlands were invited to complete this survey. Respondents who indicated not to treat children with FAPDs or respondents who completed less than 3 steps of the survey were excluded. RESULTS: In total, 85/174 (48.9%) respondents completed the survey. We included 80 respondents, 68 pediatricians and 12 pediatric residents, for analysis. Overall, self-reported guideline adherence was 85%. Self-reported adherence was higher than actual adherence. Only 50% of all respondents followed the first three steps of the guideline. The reported non-pharmacological and pharmacological treatments were diverse and varied between different age groups. The average follow-up duration was between 2 and 6 months, and the most regularly used outcome measures were attendance at school, quality of life, and adequate pain relief/reassurance. CONCLUSION: We reportedly observed a large variation in the management of children with FAPDs, due to low guideline adherence among clinicians. Improved guideline adherence may be accomplished by updating the guideline with specific recommendations per subtype, follow-up and outcome measures as well measures to improve guideline implementation.

Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn's disease.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn's disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.

Diet and Anthropometrics of Children With Inflammatory Bowel Disease: A Comparison With the General Population.

Background: There is a lack of knowledge regarding the diet of children with inflammatory bowel disease (IBD). Therefore, we investigated dietary intake in pediatric IBD compared to the general population and assessed anthropometrics and food avoidance. Methods: In this cross-sectional cohort study, patients younger than 18 years with IBD were included (2014-2017). Dietary intake (total energy, macro nutrients, food types) was assessed using a Food Frequency Questionnaire (FFQ) and compared with a matched reference population (n = 306). Results: There were 102 patients included (55% male, median age 15.0 years). Median height Z-score was -0.39 (interquartile range [IQR]: -1.17 to 0.26). Growth failure (height Z-scores<-1.64) was present in 11% of patients. Median BMI Z-score was 0.36 (IQR: -0.70 to 0.96). Acute malnutrition (weight-for-height Z-score<-2) was present in 3% of patients. Energy intake was lower in pediatric IBD compared to the reference population (mean kilojoule/day: 8286 vs 9794, P < 0.001). Protein intake did not differ, while fat intake was higher in pediatric IBD (mean gram/day: 101 vs 91, P < 0.001), with higher intake of vegetable oils/fats. Carbohydrate intake was lower in pediatric IBD (mean gram/day: 267 vs 305, P < 0.001), with lower intake of food types high in sugar. Food avoidance was reported in 53% of patients, with frequent avoidance of spicy (46%), high-fat food (30%), and dairy (30%). Conclusions: The diet of children with IBD differs from the general pediatric population, with lower energy intake and high rates of food avoidance. Evaluation of the dietary intake alongside anthropometrics may be important to prevent nutrition deficiencies and promote health.

Complications and Disease Recurrence After Primary Ileocecal Resection in Pediatric Crohn's Disease: A Multicenter Cohort Analysis.

BACKGROUND: Studies on the outcome of ileocecal resection in pediatric Crohn's disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. METHODS: This is a retrospective cohort analysis of all children (<18 years) that underwent ileocecal resection as first intestinal resection for CD derived from 7 tertiary hospitals in the Netherlands (1990-2015). Risk factors were identified using multivariable analysis. RESULTS: In total, 122 children were included (52% male; median age 15.5 years [interquartile range 14.0-16.0]). Severe postoperative complications rate was 10%. Colonic disease (odds ratio: 5.6 [95% confidence interval {CI}: 1.3-26.3], P = 0.024), microscopically positive resection margins (odds ratio: 10.4 [95% CI: 1.1-100.8] P = 0.043), and emergency surgery (odds ratio: 6.8 [95% CI: 1.1-42.2], P = 0.038) were risk factors for severe complications. Clinical and surgical recurrence rates after 1, 5 and 10 years were 19%, 49%, 71% and 2%, 12%, 22%, respectively. Female sex (hazard ratio [HR]: 2.1 [95% CI: 1.1-3.8], P = 0.023) was a risk factor for clinical recurrence, whereas ileocecal disease (HR: 3.9 [95% CI: 1.2-12.5], P = 0.024) and microscopically positive resection margins (HR: 9.6 [95% CI: 1.2-74.5], P = 0.031) were risk factors for surgical recurrence. Immediate postoperative therapy reduced the risk of both clinical (HR: 0.3 [95% CI: 0.1-0.6], P = 0.001) and surgical (HR: 0.5 [95% CI: 0.1-0.9], P = 0.035) recurrence. CONCLUSIONS: Ileocecal resection is an effective and durable treatment of pediatric CD, although postoperative complications occur frequently. Postoperative therapy may be started immediately to prevent disease recurrence.

The child's perspective on discomfort during medical research procedures: a descriptive study.

OBJECTIVE: The evaluation of discomfort in paediatric research is scarcely evidence-based. In this study, we make a start in describing children's self-reported discomfort during common medical research procedures and compare this with discomfort during dental check-ups which can be considered as a reference level of a 'minimal discomfort' medical procedure. We exploratory study whether there are associations between age, anxiety-proneness, gender, medical condition, previous experiences and discomfort. We also describe children's suggestions for reducing discomfort. DESIGN: Cross-sectional descriptive study. SETTING: Paediatric research at three academic hospitals. PATIENTS: 357 children with and without illnesses (8-18 years, mean=10.6 years) were enrolled: 307 from paediatric research studies and 50 from dental care. MAIN OUTCOME MEASURES: We measured various generic forms of discomfort (nervousness, annoyance, pain, fright, boredom, tiredness) due to six common research procedures: buccal swabs, MRI scans, pulmonary function tests, skin prick tests, ultrasound imaging and venepunctures. RESULTS: Most children reported limited discomfort during the research procedures (means: 1-2.6 on a scale from 1 to 5). Compared with dental check-ups, buccal swab tests, skin prick tests and ultrasound imaging were less discomforting, while MRI scans, venepunctures and pulmonary function tests caused a similar degree of discomfort. 60.3% of the children suggested providing distraction by showing movies to reduce discomfort. The exploratory analyses suggested a positive association between anxiety-proneness and discomfort. CONCLUSIONS: The findings of this study support the acceptability of participation of children in the studied research procedures, which stimulates evidence-based research practice. Furthermore, the present study can be considered as a first step in providing benchmarks for discomfort of procedures in paediatric research.

Efficacy and safety of prucalopride in adults and children with chronic constipation.

INTRODUCTION: Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro-intestinal prokinetic activity and has been evaluated for the treatment of CC. AREAS COVERED: A PubMed search (1965 - 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children. EXPERT OPINION: Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders.

Epidemiology of pediatric functional abdominal pain disorders: a meta-analysis.

OBJECTIVE: We aimed to review the literature regarding epidemiology of functional abdominal pain disorders in children and to assess its geographic, gender and age distribution including associated risk factors of developing functional abdominal pain. METHODS: The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsychInfo databases were systematically searched up to February 2014. Study selection criteria included: (1) studies of birth cohort, school based or general population samples (2) containing data concerning epidemiology, prevalence or incidence (3) of children aged 4-18 years (4) suffering from functional abdominal pain. Quality of studies was rated by a self-made assessment tool. A random-effect meta-analysis model was used to estimate the prevalence of functional abdominal pain in childhood. RESULTS: A total of 58 articles, including 196,472 children were included. Worldwide pooled prevalence for functional abdominal pain disorders was 13.5% (95% CI 11.8-15.3), of which irritable bowel syndrome was reported most frequently (8.8%, 95% CI 6.2-11.9). The prevalence across studies ranged widely from 1.6% to 41.2%. Higher pooled prevalence rates were reported in South America (16.8%) and Asia (16.5%) compared to Europe (10.5%). And a higher pooled prevalence was reported when using the Rome III criteria (16.4%, 95% CI 13.5-19.4). Functional abdominal pain disorders are shown to occur significantly more in girls (15.9% vs. 11.5%, pooled OR 1.5) and is associated with the presence of anxiety and depressive disorders, stress and traumatic life events. CONCLUSION: Functional abdominal pain disorders are a common problem worldwide with irritable bowel syndrome as most encountered abdominal pain-related functional gastrointestinal disorder. Female gender, psychological disorders, stress and traumatic life events affect prevalence.