Aubrey J. Katz

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

Background and Objectives: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. Methods: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. Results: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean ± SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 ± 10.4, 32.2 ± 12.7, and 47.8 ± 14.9, respectively (P < 0.001 for all comparisons). Mean ± SD PCDAI for inactive disease after treatment was 5.2 ± 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of ≥30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of ≥12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. Conclusions: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of ≥30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Prospective Evaluation of MR Enterography as the Primary Imaging Modality for Pediatric Crohn Disease Assessment

OBJECTIVE The objectives of this study were prospective evaluation of MR enterographic accuracy for detecting Crohn disease imaging features in pediatric patients, compared with a CT reference standard, as well as determination of MR enterographic accuracy for detecting active bowel inflammation and fibrosis using a histologic reference standard. SUBJECTS AND METHODS The study group for this blinded prospective study included 21 pediatric subjects with known Crohn disease scheduled for clinical CT and histologic bowel sampling for symptomatic exacerbation. All subjects and their parents gave informed consent to also undergo MR enterography. CT and MR enterography examinations were independently reviewed by two radiologists and were scored for Crohn disease features. All bowel histology specimens were reviewed by a single pathologist for the presence of active mucosal inflammation and mural fibrosis, followed by correlation of imaging and histologic findings. RESULTS All 21 subjects underwent MR enterography and histologic sampling, 18 of whom also underwent CT. MR enterography had high sensitivity for detecting Crohn disease imaging features (e.g., bowel wall thickening, mesenteric inflammation, lymphadenopathy, fistula, and abscess) compared with CT, with individual sensitivity values ranging from 85.1% to 100%. Of a total of 53 abnormal bowel segments with correlation of MRI and histologic findings, MR enterography showed 86.7% accuracy (90.0% sensitivity and 82.6% specificity) for detecting active inflammation (p < 0.001). The accuracy of MR enterography for detecting mural fibrosis overall was 64.9%, compared with histology, but increased to 83.3% (p < 0.05) for detecting fibrosis without superimposed active inflammation. CONCLUSION MR enterography can substitute for CT as the first-line imaging modality in pediatric patients with Crohn disease, on the basis of its ability to detect intestinal pathologic abnormalities in both small and large bowel as well as extraintestinal disease manifestations. Additionally, MR enterography provides an accurate noninvasive assessment of Crohn disease activity and mural fibrosis and can aid in formulating treatment strategies for symptomatic patients and assessing therapy response.

Milk-sensitive and eosinophilic gastroenteropathy: Similar clinical features with contrasting mechanisms and clinical course

We studied 12 children with peripheral eosinophilia, iron deficiency anemia secondary to blood loss in the stools, protein-losing enteropathy, and eosinophilic infiltration of the stomach and small intestine. On the basis of immunologic features and responses to therapy, these patients could be divided into two groups. In the first group the disease was transient, presented in the first year of life, remitted on withdrawal of milk from the diet, and was not associated with IgE-mediated immediate hypersensitivity (milk-sensitive enteropathy). In contrast, the second group, which we termed eosinophilic gastroenteropathy, represented patients with a chronic disease that had its onset later in childhood, did not respond to dietary manipulations, was associated with atopy and IgE-mediated immediate hypersensitivity reactions to food, and required corticosteroid therapy to establish remission and control. The mechanism by which food causes gastrointestinal damage appears to be different in these two groups even though the clinical syndromes are similar.

Relationship of common laboratory parameters to the activity of Crohn's disease in children

The Pediatric Crohns Disease Activity Index (PCDAI) has been proposed as a simple instrument to aid in the classification of patients by disease severity. The PCDAI includes subjective patient reporting of symptoms, physical examination, nutritional parameters, and several common laboratory tests (hematocrit, erythrocyte sedimentation rate, albumin). In this report we examine the relationship of each of the laboratory parameters to the PCDAI, as well as to a modified Harvey-Bradshaw Index score and physician global assessment of disease activity. Data were gathered from the clinical and laboratory observations from 133 children and adolescents at 12 pediatric gastroenterology centers in North America. A statistically significant relationship (p < 0.05) was noted between each of the laboratory tests and the PCDAI for patients with either disease limited to the small bowel or in those with colonic in volvement. For patients with disease limited to the small bowel, a statistically significant (p < 0.05) relationship was also noted between the three laboratory parameters and the modified Harvey-Bradshaw Index and global assessment. For patients with large-bowel involvement, the erythrocyte sedimentation rate was statistically related to the modified Harvey-Bradshaw Index and global assessment (p < 0.01), as was hematocrit to global assessment (p < 0.01). Although the laboratory parameters used in the PCDAI appear to generally reflect disease activity in most patients, no single laboratory test is adequate to reflect disease activity in all patients. Future work will need to identify additional laboratory measures to reflect the inflammatory process and serve as important adjuncts in the assessment of disease activity.

Infliximab is effective in acute but not chronic childhood ulcerative Colitis

Purpose: The authors report their experience with infliximab in pediatric patients with ulcerative colitis (UC). Methods: Fourteen patients were reviewed. Group 1 included five patients with newly diagnosed, fulminant colitis refractory to 7 to 10 days of intravenous steroids. Group 2 included four patients with ulcerative colitis in remission off steroid therapy who experienced relapse and were hospitalized with fulminant colitis refractory to intravenous steroids for 7 to 10 days. Group 3 included five patients chronically dependent on steroids with colitis refractory to medical management. All patients were treated on an open-label basis with infliximab infusions of 5 mg/kg/dose at 0, 2, and 6 weeks and every 6 to 8 weeks thereafter. Follow-up was maintained for at least 6 weeks. Clinical status was scored with the Lichtiger Colitis Activity Index (LCAI) at each visit. LCAI ≥10 was considered treatment failure. We defined success as LCAI ≤2, a score consistent with UC remission. Response was categorized for each group. Results: All patients began the study with LCAI ≥11 before infliximab treatment. All group 1 patients experienced response to infliximab. All but one (75%) patient in group 2 had a response. Only one (20%) group 3 patient had a response to infliximab. Conclusion: Infliximab was an effective agent in the treatment of acute UC in our patients. Long-term steroid use and emergency colectomy were avoided. Infliximab was less effective in patients who were dependent on steroids.

Short- and long-term response to and weaning from infliximab therapy in pediatric ulcerative colitis.

Objectives: We evaluated the response to infliximab in pediatric patients with ulcerative colitis (UC) and their long-term follow-up. We expanded our previous study of 14 patients and furthermore evaluated the success of weaning patients from infliximab. Patients and Methods: We reviewed the charts of 27 pediatric patients with UC who were treated with infliximab instead of undergoing a colectomy. Patients with new-onset UC refractory to intravenous steroids for 5 to 10 days and patients with non–steroid-dependent UC with an acute exacerbation were classified as acutely ill (n = 16); patients with chronic steroid-dependent UC were classified as chronically ill (n = 11). The Lichtiger Colitis Activity Index (LCAI) was measured for all patients at baseline and at 1 and 2 months after treatment with infliximab was initiated. Patients were regarded as successfully treated if they remained off steroids and avoided colectomy. Results: The acutely ill group had a mean LCAI score of 11.4 at induction and 0.3 after 2 months. The chronically ill group had a mean LCAI score of 11.2 at induction and 5.5 after 2 months. Treatment with infliximab was successful in 75% of acutely ill patients and in 27% of chronically ill patients. Infliximab was discontinued in 80% of successfully treated patients (83% of acutely ill, 67% of chronically ill). These patients had an average of 10 infusions and a mean follow-up time of 10 months from their last infliximab infusion. Conclusions: Our results suggest that infliximab is more effective in acutely ill UC patients than in patients with chronic steroid-dependent UC. In addition, some patients treated with infliximab can be weaned from infliximab and maintain remission.

Horizontal Nonparenteral Spread of Hepatitis B Among Children

Two families with an unusually high incidence of hepatitis B infection (15 of 21 persons) were investigated over an 18-month period. Serologic evidence of past or present infection--hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), or antibody to hepatitis B core antigen (anti-HBc)--was found in 11 of the 12 members of one family, four of whom were chronic HBsAg carriers, and in four of nine members of a contact family. Anti-HBc was the only serologic marker of infection in five persons. Histocompatibility leukocyte antigen (HLA) typing failed to show an association between carriage of HBsAg and specific HLA markers. Chewing gum was a potential vehicle as HBsAg was detected in gum samples from three of four children who were chronic HBsAg carriers. Horizontal, nonparenteral transmission of hepatitis B virus probably accounted for the clustering of infection in these families, especially via the exchange among children of objects contaminated with oral secretions.

Gluten-sensitive Enteropathy: INFLUENCE OF HISTOCOMPATIBILITY TYPE ON GLUTEN SENSITIVITY IN VITRO

Gluten-sensitive enteropathy is a disease characterized by villous atrophy related to the ingestion of wheat protein, gluten. In the present series of studies it was shown that gluten ingestion in affected patients is promptly followed by a local immune reaction involving the production of antigluten antibodies. An in vitro model of gluten enteropathy involving the organ culture of biopsy tissue has been developed which has led to the conclusion that gluten is not directly toxic to the gastrointestional mucosa but, instead, brings about tissue damage through the activation of an endogenous mechanism, presumably the immune system. An additional insight into the pathogenesis of gluten-sensitive enteropathy is afforded by the fact that some 90% of patients carry the HL-A8 histocompatibility type. This may be a marker for the presence of an abnormal immune response gene or may determine the presence of abnormal gluten-protein receptor sites on epithelial cells. Either of these abnormalities could result in a propensity to respond immunologically to gluten, with destructive consequences.

Infliximab therapy in pediatric Crohn's pouchitis

Objective:We describe the prolonged clinical benefit of murine chimeric antitumor necrosis factor (TNF)–alpha monoclonal antibody, infliximab, on pediatric patients with Crohns disease and ileal pouch anal anastomosis (IPAA). Methods:A retrospective review of patients originally diagnosed with ulcerative colitis, status post colectomy and IPAA, who developed findings compatible with Crohns disease was undertaken. Refractory pouchitis developed in all patients as well as protracted symptoms of diarrhea, abdominal pain, joint pain, and incontinence. All patients received infliximab. Results:Four pediatric patients (2 males and 2 females) with mean age of 14.5 years (range 11–18 years) were studied. The development of perianal fistulas in 2 patients, granuloma on biopsy in 1 patient and perianal skin tag in 1 patient, led to a diagnosis change of CD. After failure to respond to antibiotics, aminosalicylates and immunomodulators such as azathioprine and 6-mercaptopurine (6-MP), all patients were treated with infliximab. Patients received infliximab infusions at a dose of 5 mg/kg, initially at weeks 0, 2 and 6 and subsequently at 8 weeks intervals in combination with an immunomodulator drug. All patients showed marked improvement clinically, endoscopically, and histologically. Conclusion:Infliximab can be used successfully for the treatment of pediatric patients with Crohns disease and IPAA who are refractory to conventional therapies.

Predictors of Gluten Avoidance and Implementation of a Gluten-Free Diet in Children and Adolescents without Confirmed Celiac Disease

OBJECTIVES To determine independent predictors of gluten avoidance and of a physicians decision to initiate a gluten-free diet (GFD) in children and adolescents without confirmed celiac disease. STUDY DESIGN We performed a structured medical record review of 579 patients aged 1-19 years presenting for evaluation of celiac disease between January 2000 and December 2010 at a large Boston teaching hospital. We collected data including demographic information, medical history, serology, small intestinal biopsy, history of gluten avoidance, and the postworkup recommendation of implementation of a GFD. Predictors of gluten-related issues were identified by multivariate logistic regression. RESULTS Among 579 children without a previous diagnosis of celiac disease (mean age, 8.7 years), 43 (7.4%) had ever avoided gluten. Independent predictors of gluten avoidance were irritability or poor temper (OR, 3.2), diarrhea (OR, 2.5), weight issues (OR, 0.4), pervasive developmental disorder (OR, 5.3), and family history of celiac disease (OR, 2.2). Among 143 children without confirmed celiac disease who underwent diagnostic evaluation, several predictive factors were associated with a physician- recommended/parent-initiated GFD: irritability (OR, 6.4), diarrhea (OR, 3.4), pervasive developmental disorder (OR, 7.9), and positive serology before the referral (OR, 4.3). CONCLUSION Gluten avoidance among children and adolescents without a previous diagnosis of celiac disease is relatively common. The identified predictors suggest that gluten avoidance is associated with nonspecific behavioral and gastrointestinal complaints and perhaps with the perceived dietary responses in another family member thought to have celiac disease.