Angela Noble

Risk Factors for Short- and Long-Term Morbidity in Children with Esophageal Atresia

OBJECTIVE To describe short- (first year of age) and long-term (after 1 year of age) outcome in patients with esophageal atresia and identify early predictive factors of morbidity in the first month of life. STUDY DESIGN Charts of children with esophageal atresia born January 1990 to May 2005 were reviewed. A complicated evolution was defined as the occurrence of at least 1 complication: severe gastroesophageal reflux, esophageal stricture requiring dilatations, recurrent fistula needing surgery, need for gavage feeding for >or=3 months, severe tracheomalacia, chronic respiratory disease, and death. RESULTS A total of 134 patients were included. Forty-nine percent of patients had a complicated evolution before 1 year of age, and 54% had a complicated evolution after 1 year. With bivariate analysis, predictive variables of a complicated evolution were demonstrated, including twin birth, preoperative tracheal intubation, birth weight <2500 g, long gap atresia, anastomotic leak, postoperative tracheal intubation >or=5 days, and inability to be fed orally by the end of the first month. After 1 year of age, the complicated evolution was only associated with long gap atresia and inability to be fed orally in the first month. A hospital stay >or=30 days was associated with a risk of a complicated evolution at 1 year and after 1 year of age (odds ratio, 9.3 [95% CI, 4.1-20.8] and 3.5 [95% CI, 1.6-7.6], respectively). CONCLUSION Early factors are predictive of morbidity in children with esophageal atresia.

Is Visceral Hypersensitivity Correlated With Symptom Severity in Children With Functional Gastrointestinal Disorders

Background: Abdominal pain related to irritable bowel syndrome (IBS) and functional abdominal pain (FAP) is frequent in children and can be of variable severity. Both IBS and FAP are associated with rectal hypersensitivity. We hypothesized that in children with IBS and FAP, the rectal sensory threshold for pain (RSTP) is associated with symptom severity. Paitents and Methods: A total of 47 patients (34 girls; median age, 14.2 years) with IBS (n = 29) and FAP (n = 18), according to the Rome II criteria, underwent a rectal barostat examination to determine their RSTP. Gastrointestinal symptom severity was assessed by validated questionnaires. During the rectal barostat exam, symptoms were documented using a visual analog scale and by measuring the area coloured on a human body diagram corresponding to painful sensations. Results: The median RSTP was 16 mmHg and was similar in IBS and FAP patients. Eighty-three percent of the patients had rectal hypersensitivity (RSTP ≤ 30.8 mmHg, the 5th percentile of control children studied in our laboratory). Fifty-one percent and 36%, respectively, reported missing school and social activities at least once per week. Increased frequency of pain, missed days of school, missed social activities, and pain during the barostat examination were not associated with lower RSTP values in either the whole group or in the subset of children with rectal hypersensitivity. Conclusions: Rectal hypersensitivity is not proportional to the severity of symptoms in children with IBS and FAP, indicating that symptom severity is influenced by other factors in addition to visceral hypersensitivity.

Methotrexate in the treatment of inflammatory bowel disease: An 8‐year retrospective study in a Canadian pediatric IBD center

Background: Methotrexate (MTX) is used as an alternative immunosuppressive treatment for patients with inflammatory bowel disease (IBD). The aim of the study was to evaluate effectiveness and tolerance of MTX for children with IBD. Methods: A retrospective study was conducted in our pediatric IBD center of all children having received MTX for the treatment of their IBD between 2000 and 2008. Remission was defined as discontinuation of steroids and Harvey–Bradshaw Index <4 for Crohns disease (CD) patients or Pediatric Ulcerative Colitis Activity Index (PUCAI) <10 for ulcerative (UC) or indeterminate colitis (IC) patients. Results: Seventy‐five patients had CD, 5 UC, and 13 IC. Mean age at diagnosis was 11 (0.6–17.4) years. Ninety patients were previously treated with purine analogs and 26 with anti‐tumor necrosis factor (TNF). Among patients assessed for effectiveness of MTX (n = 79), clinical remission was observed in 29, 37, 25, and 16% of CD patients (n = 63) and 19, 25, 13, and 7% of patients with UC or IC (n = 16), respectively, 3, 6,12, and 24 months after initiation of MTX. The 1‐year remission rate for CD patients was significantly higher in patients with colonic disease. Forty‐six patients (49%) experienced side effects but only 13 (14%) had to discontinue treatment. Conclusions: The long‐term remission rate with MTX in our pediatric IBD population was low. However, MTX was generally well tolerated and induced and maintained remission in some patients who previously had failed a purine analog and/or anti‐TNF. Prospective controlled trials are indicated to determine the place of MTX in the management of pediatric IBD.

Clinical features distinguish eosinophilic and reflux-induced esophagitis.

Background and Objectives : Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of ≥15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true “criterion standard” criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis. Methods: Adult and pediatric patients with EoE were identified by present diagnostic guidelines including an esophageal biopsy finding of ≥15 eosinophils/HPF. Patients with GERD were age-matched one to one with patients with EoE. Clinical, endoscopic, and histologic information at the time of diagnosis was obtained from the medical record and compared between pairs by McNemar test. A conditional logistic regression model was created using 6 distinguishing disease characteristics. This model was used to create a nomogram to differentiate EoE from reflux-induced esophagitis. Results: Patients with EoE were 75% men and 68% had a history of atopy. Many aspects of EoE were statistically distinct from GERD when controlling for age. Male sex, dysphagia, history of food impaction, absence of pain/heartburn, linear furrowing, and white papules were the distinguishing variables used to create the logistic regression model and scoring system based on odds ratios. The area under the curve of the receiver-operator characteristic curve for this model was 0.858. Conclusions: EoE can be distinguished from GERD using a scoring system of clinical and endoscopic features. Prospective studies will be needed to validate this model.

Increased dosing requirements for 6‐mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger

Background: 6‐Mercaptopurine (6‐MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6‐MP is 1.0–1.5 mg/kg/day and for AZA is 2.0–2.5 mg/kg/day. The aim of this study was to determine whether IBD patients 6 years of age and younger require higher than standard doses of 6‐MP/AZA to achieve clinical remission. Methods: Clinical data was collected retrospectively for all IBD patients 6 years of age or younger treated with 6‐MP/AZA at The Childrens Hospital of Philadelphia. Results: Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25–75th %ile 2.3–4.6 years) and 6‐MP/AZA was initiated at a median age of 3.9 years (range 0.8–6.8 years). After dose escalation, the median AZA‐equivalent dose was 3.1 mg/kg/day (25–75th %ile 2.5–3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2–3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA‐equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%–93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6‐MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction. Conclusions: The standard dose of 6‐MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well‐tolerated.

A novel enteral nutrition protocol for the treatment of pediatric Crohn's disease.

Background:Enteral nutritional therapy (EN) is an effective modality for inducing and maintaining remission in pediatric patients with Crohn’s disease (CD). The standard protocol for EN provides patients with 100% of their caloric needs for induction of remission. The aim of this study was to determine the efficacy of delivering 80% to 90% of patient’s caloric needs through EN, to induce remission in pediatric patients with CD. This approach allows patients to consume remaining calories from a normal diet. Methods:A retrospective review of charts from 1998 to 2010 was conducted at The Children’s Hospital of Philadelphia. Remission (Pediatric Crohn’s Disease Activity Index <10) and response (decrease in Pediatric Crohn’s Disease Activity Index score of ≥12.5 points) were calculated before and after treatment with EN. Weight z scores and laboratory parameters were evaluated in all participants. Results:Forty-three charts were evaluated. Mean age of participants was 12.8 years (5.1–17.4), 67% were male and 33% female patients. Remission and response were evaluated in a group of 23 participants, with no missing data. There were reductions in erythrocyte sedimentation rate (P < 0.0001) and C-reactive protein (P < 0.02), and increases in albumin (P < 0.03). Mean Pediatric Crohn’s Disease Activity Index score at baseline was 26.9 and was reduced to a score of 10.2 at follow-up (P < 0.0001). Induction of remission was achieved in 65% and response in 87% at a mean follow-up of 2 months (1–4 months). Conclusions:This novel EN protocol seems to be effective for the induction of remission in pediatric patients with CD and contributes to increasing weight and improving laboratory markers. This protocol may result in improved EN acceptance and compliance and will be evaluated prospectively.

Rectal Sensory Threshold for Pain is a Diagnostic Marker of Irritable Bowel Syndrome and Functional Abdominal Pain in Children

OBJECTIVE To evaluate the diagnostic value of the rectal sensory threshold for pain (RSTP) in children and adolescents with chronic abdominal pain. STUDY DESIGN Fifty-one patients (25 girls; median age 14.2 years; range 8.4-17.6) with abdominal pain >2 months underwent a series of rectal distensions with an electronic barostat. RSTP and viscerosomatic referrals were assessed. Three months after the barostat, the final diagnosis was documented. RESULTS Thirty-five patients had a functional gastrointestinal disorder (FGID) (irritable bowel syndrome or functional abdominal pain), and 16 had an organic disease. RSTP was lower in the FGID group than in the organic disease group (25.4mm Hg vs 37.1mm Hg; P = .0002). At the cutoff of 30mm Hg, the RSTP measurement for the diagnosis of FGID had a sensitivity of 94% and a specificity of 77%. Both groups similarly reported aberrant viscerosomatic projections. CONCLUSION In children, RSTP is a diagnostic marker of irritable bowel syndrome and functional abdominal pain. Viscerosomatic referrals are similar in children with FGID and organic diseases.

Efficacy of oral methotrexate in paediatric Crohn’s disease: a multicentre propensity score study

Background Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn’s disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD. Methods 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and ‘doubly robust’ weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups. Results 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test). Conclusions In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

Eosinophilic Esophagitis and Gastritis in Rubinstein-Taybi Syndrome

Rubinstein-Taybi syndrome is a rare disorder associated with mutations in the CREB-binding protein gene (1). It is characterized by broad thumbs and toes, characteristic facies, postnatal failure to thrive, and delayed development (2). These children often have chronic gastrointestinal problems, including gastroesophageal reflux, feeding difficulties, and chronic constipation (2–4). They are not reported to have an increased incidence of atopic disease. Herein is the first report, to the authors’ knowledge, of eosinophilic gastrointestinal disease presenting as dysphagia in this population.

Design of predictive models for positive outcomes of upper and lower gastrointestinal endoscopies in children and adolescents.

Objectives: To develop models to accurately determine the outcomes of diagnostic endoscopies performed in children and adolescents without known gastrointestinal disease. Materials and Methods: Retrospective chart review of all endoscopies performed in children 2 to 18 years of age without known gastrointestinal disease from January 1 to December 31, 2000. The association between age, presenting symptoms, physical examination findings, laboratory investigations, and endoscopy outcomes was assessed. Predictive models for positive outcomes on endoscopy were estimated for upper and lower endoscopies separately by use of multiple logistic regression. Receiver operating curves were constructed to evaluate the performance of the models. A model with a sensitivity of 95% and specificity of 40% was considered clinically significant. Results: Positive findings on endoscopy were found in 191 (55%) of 346 and in 120 (59%) of 204 upper and lower endoscopies, respectively. Age above 13 years, vomiting, and hypoalbuminemia were significant predictors of positive upper endoscopies. Rectal bleeding, hypoalbuminemia, and elevated erythrocyte sedimentation rate were significant predictors of positive lower endoscopies. Extrapolating from the receiver operating curves, a sensitivity of 95% corresponded to a specificity of 10% for the upper endoscopy model and 30% for the lower endoscopy model. Conclusions: In our population of children and adolescents, several clinical characteristics were predictive of positive upper and lower endoscopy outcomes. Predictive models composed of these clinical variables were statistically, but not clinically, significant. The inclusion of additional clinical characteristics that could be assessed in prospective studies will likely improve the clinical significance of endoscopy outcome prediction.