Sex- and corticotropin-releasing factor receptor 2- dependent actions of urocortin 1 during inflammation.

We investigated whether corticotropin-releasing factor receptor 2 (CRF2) and its high-affinity agonist urocortin 1 (Ucn1) mediate sex-specific signaling and immune responses. Intrarectal trinitrobenzene sulfonic acid was used to induce experimental colitis in wild-type, CRF2 knockout (CRF2KO), and heterozygous (CRF2Ht) mice of both sexes. Changes in plasma extravasation, organ weight, survival, immune cell numbers, inflammatory cytokines, and the MAPK signaling pathway were assessed. Stored intestinal biopsies from patients with Crohn's disease (CD) and age- and sex-matched individuals without inflammatory bowel disease (IBD) were examined by immunofluorescence and confocal microscopy to characterize Ucn1 and CRF receptor expression. CRF2Ht mice of both sexes showed decreased survival during colitis compared with other genotypes. Ucn1 improved survival in male mice alone. Ucn1 restored colon length and spleen and adrenal weight and decreased colonic TNF-α, IL-6, and IL-1ß levels in male CRF2Ht mice alone. CRF2Ht mice of both sexes showed decreased phosphorylation of MAPK p38 and heat shock protein 27 (Hsp27) levels. Ucn1 restored p-Hsp27 levels in male CRF2Ht mice alone. Expression of the chaperone protein Hsp90 decreased during colitis, except in male CRF2Ht mice. Taken together, our data indicate that sex shows significant interaction with genotype and Ucn1 during colitis. Human duodenal and colonic biopsies revealed that sex-specific differences exist in levels of CRF receptors and Ucn1 expression in patients with CD compared with the matched non-IBD subjects. To conclude, Ucn1 mediates sex-specific immune and cellular signaling responses via CRF2, emphasizing the need for inclusion of females in preclinical studies.

Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota.

The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis.

Addition of Histology to the Paris Classification of Pediatric Crohn Disease Alters Classification of Disease Location.

OBJECTIVES: The aim of the study was to investigate the value of microscopic findings in the classification of pediatric Crohn disease (CD) by determining whether classification of disease changes significantly with inclusion of histologic findings. METHODS: Sixty patients were randomly selected from a cohort of patients studied at the Pediatric Inflammatory Bowel Disease Clinic at the University of California, San Francisco Benioff Children's Hospital. Two physicians independently reviewed the electronic health records of the included patients to determine the Paris classification for each patient by adhering to present guidelines and then by including microscopic findings. RESULTS: Macroscopic and combined disease location classifications were discordant in 34 (56.6%), with no statistically significant differences between groups. Interobserver agreement was higher in the combined classification (κ = 0.73, 95% confidence interval 0.65-0.82) as opposed to when classification was limited to macroscopic findings (κ = 0.53, 95% confidence interval 0.40-0.58). When evaluating the proximal upper gastrointestinal tract (Paris L4a), the interobserver agreement was better in macroscopic compared with the combined classification. CONCLUSIONS: Disease extent classifications differed significantly when comparing isolated macroscopic findings (Paris classification) with the combined scheme that included microscopy. Further studies are needed to determine which scheme provides more accurate representation of disease extent.

The natural course of inflammatory bowel disease-indeterminate from childhood to adulthood: within a 25 year period.

BACKGROUND: Inflammatory bowel disease (IBD)-indeterminate is a subgroup of IBD that has features of both ulcerative colitis (UC) and Crohn's disease (CD). AIMS: To determine the clinical course of IBD-indeterminate in children over a 25 year period. METHODS: We performed a retrospective investigation on children diagnosed with IBD. Diagnosis and disease distribution of IBD was based on clinical, radiologic, endoscopic, and histologic examinations. RESULTS: Four hundred and twenty children diagnosed with IBD between 1986 and 2003 were identified from the IBD registry, 78 (22%) of whom were diagnosed with IBD-indeterminate. The mean age at diagnosis was 9.2 ± 4 years and the mean follow-up period was 4.1 ± 2 years. In 2003, 18 of 78 children (23%) were reclassified by the same physician based on the endoscopic and pathologic findings as follows: eight children with CD, five children with UC, and five children with non-IBD (eg, eosinophilic colitis). During 2011, 20 of the 60 patients who had maintained an IBD-indeterminate diagnosis were located and contacted, and detailed telephone interviews were conducted by the corresponding author. Two patients were reclassified as having CD (10%), one patient was reclassified as having eosinophilic colitis (5%), six patients remained with IBD-indeterminate (30%), and eleven patients (55%) reported a complete resolution of their symptoms. The follow-up period ranged from 10-18 years (mean 12.5 ± 3 years). Children who were reclassified as having CD were significantly younger than those who maintained an IBD-indeterminate diagnosis (6.4 ± 4 years versus11.2 ± 3 years, respectively, P = 0.05). CONCLUSION: Children with IBD-indeterminate remain classified as IBD-indeterminate, or were clinically reclassified as CD or non-IBD, or became asymptomatic as they transitioned into adulthood. The need for IBD-indeterminate classification is of importance, especially when deciding on management and treatment.

The natural history of ulcerative colitis in a pediatric population: a follow-up population-based cohort study.

BACKGROUND: The natural history of ulcerative colitis (UC) has been poorly studied in children. METHODS: We performed a retrospective study in children diagnosed with UC with a follow-up. The diagnosis of UC was based on clinical, radiologic, endoscopic, and histologic examinations. We estimated the occurrence of colectomy, proctitis, and extraintestinal manifestations (EIMs) at the onset of the diagnosis and at the end of the study period. RESULTS: We identified 115 UC patients between 1986 and 2003 with a mean age at diagnosis of 10.6 ± 5.1 years. The cumulative rate of colectomy was 4.1% at 1 year, and 16% at 10 years. EIMs were experienced by 20% of the children; 48% had arthritis, 35% had sclerosing cholangitis, and 17% had aphthous stomatitis. Proctitis was noted in 29 patients and it was not associated with an increased risk of colectomy (relative risk = 1.4; 95% CI = 0.7-4.5), and girls were twice more likely to develop proctitis. The pathologic reading for disease extensions was recorded for all children at entry and only 62 children had pathological results at maximum follow-up. At entry, 25% of the children only had ulcerative proctitis (E1) localization, 40% had left-sided UC (E2), and 35% had extensive UC (E3). Among the patients with E1 localization, 20% had progressed to E2 and 80% had progressed to E3; among the patients with E2 localization, 40% had progressed to E3. Age, gender, and EIMs at time of diagnosis were not associated with extension of disease at maximal follow-up. The Z score of body mass index (BMI) of children was significantly higher at the end of the study. At diagnosis, 85% of patients received 5-aminosalicyclic acid, 60% received steroids, and 11% received an immunomodulator. The majority of patients were still using systemic steroids at and after 5 years from their entry date. Only 32 of the 91 children on steroids did not receive an immunomodulator. CONCLUSION: Pediatric UC is associated with high rates of EIMs and colectomy that are not dependent on age, gender, or race, but is associated with a high rate of proctitis among girls. Understanding the clinical course of UC can optimize therapeutic interventions.

High-dose infliximab for treatment of pediatric ulcerative colitis: a survey of clinical practice.

AIM: To assess attitudes and trends regarding the use of high-dose infliximab among pediatric gastroenterologists for treatment of pediatric ulcerative colitis (UC). METHODS: A 19-item survey was distributed to subscribers of the pediatric gastroenterology (PEDSGI) listserv. Responses were submitted anonymously and results compiled in a secure website. RESULTS: A total of 113 subscribers (88% based in the United States) responded (101 pediatric gastroenterology attendings and 12 pediatric gastroenterology fellows). There were 46% in academic medical institutions and 39% in hospital-based practices. The majority (91%) were treating >10 patients with UC; 13% were treating >100 patients with UC; 91% had prescribed infliximab (IFX) 5 mg/kg for UC; 72% had prescribed IFX 10 mg/kg for UC. Using a 5-point Likert scale, factors that influenced the decision not to increase IFX dosing in patients with UC included: "improvement on initial dose of IFX" (mean: 3.88) and "decision to move to colectomy" (3.69). Lowest mean Likert scores were: "lack of guidelines or literature regarding increased IFX dosing" (1.96) and "insurance authorization or other insurance issues" (2.34). "Insurance authorization or other insurance issues" was identified by 39% as at least somewhat of a factor (Likert score ≥ 3) in their decision not to increase the IFX dose. IFX 10 mg/kg was more commonly used for the treatment of pediatric UC among responders based in the United States (75/100) compared to non-United States responders (6/13, P = 0.047). Induction of remission was reported by 78% of all responders and 81% reported maintenance of remission with IFX 10 mg/kg. One responder reported one death with IFX 10 mg/kg. CONCLUSION: IFX 10 mg/kg is more commonly used in the United States to treat pediatric UC. Efficacy and safety data are required to avoid insurance barriers for its use.

Quality of life in patients postcolectomy for pediatric-onset ulcerative colitis.

BACKGROUND: Ulcerative colitis in children can have a negative effect on quality of life (QOL). METHODS: We included 16 of 31 patients who underwent colectomy for ulcerative colitis before 20 years of age between 1980 and 2005 at University of California in San Francisco Benioff Children's Hospital. A disease-specific QOL questionnaire (Inflammatory Bowel Disease Questionnaire-32), validated for adults, was used to determine QOL and an additional questionnaire addressing bowel function and reproductive health in long-term follow-up of these patients. RESULTS: Median age at the time of survey was 20.3 years (17.9-25.3), and time postcolectomy was 6.9 years (4.8-9.0). Mean total score was 159.7 ± 43.3 (58-210). Two patients (12.5%) had scores of ≥ 200, 12 (75.0%) had 101 to 199, and 2 (12.5%) had ≤ 100. Patients ages 18 years or younger at the time of survey showed higher QOL, particularly in emotional health (P=0.020), social function (P=0.014), and overall QOL (P=0.009). Social function scored highest of all of the systems (median 7; interquartile range 4-7). Patients with scores ≤ 100 had repeated episodes of pouchitis (16-30) compared with the other 14 patients (0-3). Children who were diagnosed ages 12 years or younger tended to have higher QOL (p=0.072). Years postcolectomy did not correlate to QOL. Eleven patients were sexually active. Two males had feelings of impotence and decreased libido, and 6 females experienced dyspareunia. Three women tried unsuccessfully to conceive after colectomy. One woman became pregnant 4 times, each leading to miscarriage. CONCLUSIONS: Younger age at time of colectomy, diagnosis, and survey show higher QOL. Highest satisfaction was found in ability to attend school, work, and social engagements. Pouchitis continued to be an issue for a small number of the patients, with 2 patients having recurring episodes that severely affected QOL. Patients reported decreased sexual activity and fertility at the time of survey due to colectomy, especially for females.

Cytokine profiles in peripheral blood of children and adults with Crohn disease.

BACKGROUND: Increasing evidence suggests that cytokine dysregulation in T-helper 1 and T-helper 2 (TH1/TH2) subsets contributes to the pathogenesis of Crohn disease (CD). The present pilot study examines the hypothesis that cytokine profiles differ between pediatric and adult patients with CD. METHODS: Production of TH1 cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and of TH2 cytokines interleukin-4 (IL-4) and IL-6 was analyzed in peripheral blood of patients with CD and healthy controls (n=20) using flow cytometry after in vitro stimulation. RESULTS: In both pediatric and adult subjects, frequencies of TNF-α CD4+ T cells were higher in patients with CD than in controls (P=0.009 and P=0.047, respectively). Percentages of cells expressing IL-4 were slightly increased (P=0.036), whereas those for IFN-γ were decreased (P=0.009) in pediatric patients with CD compared with controls. As expected, the overall production of TH1 cytokines was higher in adults compared with pediatric subjects. When memory CD4+CD45RO+ T cells were considered, lower IFN-γ expression was observed in pediatric subjects with CD compared with controls (P=0.009), matching the trend seen in the general CD4+ T cell population. The percentage of CD4+CD45RO+ T cells was increased in adult patients with CD compared with pediatric patients with CD (P=0.016). CONCLUSIONS: The present study describes a peripheral blood TH1/TH2 cytokine imbalance in CD and suggests different immunological mechanisms in children and adults for disease pathogenesis.

Postoperative outcome of colectomy for pediatric patients with ulcerative colitis.

BACKGROUND: Few studies have reported on the surgical outcomes of colectomy in pediatric patients with ulcerative colitis (UC). PATIENTS AND METHODS: We conducted a retrospective chart review of all pediatric patients diagnosed with UC who underwent colectomy at UCSF between 1980 and 2005 to identify early (within 30 days) and later complications of surgery. RESULTS: Complete medical records were available for 31 patients [12.4 +/- 3.3 (range 6-19) years] with UC who underwent colectomy at UCSF Children's Hospital. Total colectomy with ileal pouch anal anastomosis (IPAA) was performed in 21 of the 31 patients (12 without diverting ileostomy). Five of the 31 patients had an initial colectomy with IPAA and J-pouch performed later; 4 had an initial subtotal colectomy for urgent indications. Only one of 31 had IPAA with S-pouch. The median number of early postoperative complications was 1.0; 4 required additional surgery to treat complications. The most common early complications were small intestinal obstruction in 6 (19%) and wound infection in 4 (13%). Preoperative medications included corticosteroids in 25 (81%), 6-mercaptopurine/azathioprine in 10 (32%), and 5-aminosalicylates in 19 (61%). Medication exposure was not related to postoperative complications. Late complications included pouchitis in 12 (39%), anastomotic, anal, or rectal strictures in 5 (16%), and fistulas in 5 (16%); 1 (3%) was subsequently diagnosed as having Crohn disease. CONCLUSIONS: Postcolectomy morbidity is common among pediatric patients with UC. Preoperative medications were not associated with postoperative complications. Investigations to determine preoperative factors affecting surgical outcomes and long-term satisfaction following this surgery in a large pediatric cohort are needed.

Impact of gluten-free camp on quality of life of children and adolescents with celiac disease.

OBJECTIVE: A gluten-free camp allows children with celiac disease (CD) to enjoy a camp experience without concern and preoccupation with foods they eat or the stigma of their underlying disease. The objective of this study was to evaluate the impact of gluten-free camp on quality-of-life indicators for children and adolescents with CD. METHODS: Children aged 7 to 17 years with CD were administered a 14-question survey at the beginning and the end of a 7-day gluten-free camp. Surveys used a Likert scale to examine general well-being, emotional outlook, and self-perception for the week before each survey. Differences between the time points were compared. Data were analyzed by paired t test. RESULTS: Of the 104 campers who attended camp, 77 (21 male) completed the survey at both time points. Most (70%) had been on a gluten-free diet (GFD) for <4 years. All seemed to benefit from camp, no longer feeling different from other kids or feeling frustrated with a restricted diet. A more beneficial impact was found for campers who were on a GFD for <4 years. Overall, campers reported an improvement in 11 of 14 questions, statistically significant (P < .05) for 8 of those 11 questions. Improvement was observed in each of the 3 categories of questions: well-being, self-perception, and emotional outlook. CONCLUSIONS: Children who had CD and attended a week-long gluten-free camp demonstrated improvement in well-being, self-perception, and emotional outlook. The positive effects of camp were more apparent among campers who had been on a GFD for <4 years compared with those who had been on a GFD for > or =4 years, suggesting an adaptation to CD with time. A gluten-free camp that provides an environment of unrestricted foods can at least temporarily alleviate stress and anxiety around food and social interactions. Durability of these observations on return to daily life requires additional study.

Folate concentrations in pediatric patients with newly diagnosed inflammatory bowel disease.

BACKGROUND: Folate is postulated to protect against cell injury and long-term risk of cancer. Folate deficiency has been shown to be associated with inflammatory bowel disease (IBD). However, folate concentrations are poorly delineated in children with IBD. OBJECTIVE: The objective was to compare folate concentrations between children with newly diagnosed IBD and healthy controls. DESIGN: Red blood cell folate (RBCF) and whole-blood folate (WBF) concentrations were measured in 78 children (mean age: 12.8 +/- 2.7 y): 22 patients with newly diagnosed untreated Crohn disease, 11 patients with ulcerative colitis, 4 patients with indeterminate colitis, and 41 controls. Vitamin supplementation and dietary intakes determined by food-frequency questionnaire were recorded for 20 IBD patients and 28 controls. RESULTS: RBCF concentrations were 19.4% lower in controls (587.0 +/- 148.6 ng/mL) than in patients (728.7 +/- 185.8 ng/mL; P = 0.0004), and WBF concentrations were 11.1% lower in controls (218.2 +/- 49.7 ng/mL) than in patients (245.3 +/- 59.1 ng/mL; P = 0.031). Total folate intake was 18.8% higher in controls (444.7 +/- 266.7 microg/d) than in IBD patients (361.1 +/- 230.6 microg/d), but this difference was not statistically significant (P = 0.264). Folate intakes were below the Recommended Dietary Allowance (200-400 microg/d), adjusted for age and sex, in 35.4% of study subjects. CONCLUSIONS: In contrast with previous evidence of folate deficiency in adult IBD patients, our data indicate higher folate concentrations in children with newly diagnosed untreated IBD than in controls. This finding was unexpected, especially in light of the higher dietary folate intakes and hematocrit values in children without IBD. The influence of IBD therapy on folate metabolism and the long-term clinical implications of high RBCF and WBF concentrations at the time of IBD diagnosis should be explored further.

Use of complementary medicine in pediatric patients with inflammatory bowel disease: results from a multicenter survey.

OBJECTIVES: We examined the use of complementary and alternative medicine (CAM) at 3 US pediatric medical centers, comparing a group of children with inflammatory bowel disease (IBD) with children presenting with chronic constipation. MATERIALS AND METHODS: Surveys were administered by postal mail and at pediatric IBD centers in San Francisco, Houston, and Atlanta from 2001 to 2003. A comparison group consisting of pediatric patients with chronic constipation also was surveyed. Data were analyzed by t tests and by exact tests of contingency tables. RESULTS: In all, 236 surveys were collected from the IBD group; 126 surveys were collected from the chronic constipation comparison group. CAM therapies were used by 50% in the IBD group and 23% in the chronic constipation group. The overall regional breakdown of CAM use in IBD revealed no differences, although the types of CAM therapy used varied by site. The most commonly used CAM therapies in the IBD group were spiritual interventions (25%) and nutritional supplements (25%). Positive predictors for CAM use in IBD include the patient's self-reported overall health, an increase in the number of side effects associated with allopathic medications, white ethnicity, and parental education beyond high school. CONCLUSIONS: This is the first US study to characterize CAM use in pediatric patients with IBD with another chronic gastrointestinal disorder. CAM use was twice as common with the IBD group compared with the chronic constipation group. Regional variations exist with the types of CAM therapy used. Practitioners should know that half of their pediatric patients with IBD may be using CAM in conjunction with or as an alternative to other treatments and that certain predictors can help identify those using CAM therapies.

Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease.

BACKGROUND: Extraintestinal manifestations (EIMs) in pediatric patients with inflammatory bowel disease (IBD) are poorly characterized. We examined the prevalence of EIMs at diagnosis, subsequent incidence, and risk factors for EIMs. METHODS: Data for 1649 patients from the PediIBD Consortium Registry, diagnosed with IBD before 18 years of age (1007 [61%] with Crohn's disease, 471 [29%] with ulcerative colitis, and 171 [10%] with indeterminate colitis), were analyzed using logistic regression, Kaplan-Meier, log rank tests, and Cox models. RESULTS: EIMs were reported prior to IBD diagnosis in 97 of 1649 patients (6%). Older children at diagnosis had higher rates compared with younger children, and arthritis (26%) and aphthous stomatitis (21%) were most common. Among the 1552 patients without EIM at diagnosis, 290 developed at least 1 EIM. Kaplan-Meier estimates of cumulative incidence were 9% at 1 year, 19% at 5 years, and 29% at 15 years after diagnosis. Incidence did not differ by IBD type (P = 0.20), age at diagnosis (P = 0.22), or race/ethnicity (P = 0.24). Arthritis (17%) and osteopenia/osteoporosis (15%) were the most common EIMs after IBD diagnosis. CONCLUSIONS: In our large cohort of pediatric IBD patients, 6% had at least 1 EIM before diagnosis of IBD. At least 1 EIM will develop in 29% within 15 years of diagnosis. The incidence of EIMs both before and after diagnosis of IBD differs by type of EIM and may be slightly higher in girls, but is independent of the type of IBD, age at diagnosis, and race/ethnicity.

Growth hormone treatment for growth failure in pediatric patients with Crohn's disease.

OBJECTIVE: To investigate the effect of human growth hormone (GH) injections on growth velocity in growth-impaired children with Crohn's disease (CD). STUDY DESIGN: Ten children and adolescents (mean age, 12.6 +/- 4.5 years; 6 males) with CD and poor height growth were treated with open-label recombinant GH, 0.043 mg/kg/day administered via subcutaneous injection, for 1 year. Patients were retrospectively matched with untreated patients (3 comparisons per case) by race, age, sex, and baseline height. Primary endpoint was height velocity; secondary endpoints were disease activity, body composition, and bone density determined by dual-energy x-ray absorptiometry scan. RESULTS: Mean height velocity increased by 5.33 +/- 3.40 (mean +/- standard deviation) cm/year in the GH-treated patients during the year of GH treatment, compared with 0.96 +/- 3.52 cm/year in the comparison group (P = .03). Height z-score increased by 0.76 +/- 0.38 in the treated group, compared with 0.16 +/- 0.40 in the comparison group (P < .01), and weight z-score increased by 0.81 +/- 0.89 in the treated group, compared with 0.00 +/- 0.57 in the comparison group (P < .01). Bone density revealed an increase of 0.31 +/- 0.33 in the lumbar spine z-score (P = .03 vs baseline). CONCLUSIONS: GH treatment increases height velocity and may enhance bone mineralization in children with CD. A randomized controlled trial in a large cohort of children is needed to evaluate the ultimate impact of GH treatment.