Kurt A. Brown

Primary eosinophilic esophagitis in children : Successful treatment with oral corticosteroids

BACKGROUND The histologic appearance of esophageal eosinophils has been correlated with esophagitis and gastroesophageal reflux disease in children. Esophageal eosinophilia that persists despite traditional antireflux therapy may not represent treatment failure, but instead may portray early eosinophilic gastroenteritis or allergic esophagitis. In this study, a series of pediatric patients with severe esophageal eosinophilia who were unresponsive to aggressive antireflux therapy were examined and their clinical and histologic response to oral corticosteroid therapy assessed. METHODS Of 1809 patients evaluated prospectively over 2.5 years for symptoms of gastroesophageal reflux, 20 had persistent symptoms and esophageal eosinophilia, despite aggressive therapy with omeprazole and cisapride. These patients were treated with 1.5 mg/kg oral methylprednisolone per day, divided into twice-daily doses for 4 weeks. All patients underwent clinical, laboratory, and histologic evaluation before and after treatment. RESULTS Histologic findings in examination of specimens obtained in pretreatment esophageal biopsies in children with primary eosinophilic esophagitis indicated significantly greater eosinophilia (34.2+/-9.6 eosinophils/high-power field [HPF]) compared with that in children with gastroesophageal reflux disease who responded to medical therapy (2.26+/-1.16 eosinophils/HPF; p < 0.001). After corticosteroid therapy, all but one patient with primary eosinophilic esophagitis had dramatic clinical improvement, supported by histologic examination (1.5 +/-0.9 eosinophils/HPF, p < 0.0001). CONCLUSIONS Pediatric patients in a series with marked esophageal eosinophilia and chronic symptoms of gastroesophageal reflux disease unresponsive to aggressive medical antire-flux therapy had both clinical and histologic improvement after oral corticosteroid therapy.

Severity of Esophageal Eosinophilia Predicts Response to Conventional Gastroesophageal Reflux Therapy

ABSTRACT Pediatric patients who present with symptoms of gastroesophageal reflux and severe eosinophilic esophagitis may be unresponsive to aggressive anti-reflux medical therapy. In order to determine whether the degree of eosinophilia predicts anti-reflux treatment response and possibly distinguishes different etiologies, we reviewed the initial biopsies of patients with esophageal eosinophilia and compared the number of eosinophils with the response to anti-reflux treatment. Over a 1-year period, 102 patients with a biopsy demonstrating at least 1 intraepithelial eosinophil were identified among patients undergoing initial endoscopy for symptoms of reflux. All patients were treated with H2 blockers and prokinetic agents. Treatment response was classified into three categories: improvement, relapse, and failure. There were significant differences between the group who improved (mean eosinophil count [MEC] 1.1 ± 0.3 SEM) and those who failed (24.5 ± 6.1 SEM, P < 0.0025) or relapsed 6.4 ± 2.4 SEM, P < 0.05). A threshold MEC value of ≥7 provided a sensitivity of 61.3%, a specificity of 95.7%, and a predictive value for treatment failure of 86.1. A MEC value of <7 provided an 85% predictive value of successful therapy. From these data we made the following conclusions: (1) The number of eosinophils has a predictive value of treatment response with ≥7 per high power field offering a valuable clinical threshold for predicting outcome of conventional therapy. (2) The variable response to conventional reflux treatment may reflect different etiologies. (3) Alternate medical treatment modalities may be appropriate in the presence of severe eosinophilia, before considering surgical intervention.

Inflammatory bowel disease in children 5 years of age and younger

OBJECTIVES:Clinicians are becoming increasingly aware that inflammatory bowel disease (IBD) can affect all age groups, although it has not been well described in infants and young children. Our aim was to evaluate early onset IBD in patients 5 yr of age and younger.METHODS:Medical records of patients diagnosed with early onset IBD at The Childrens Hospital of Philadelphia between 1977 and 2000 were reviewed. Patients were divided into three categories: those with Crohns disease (CD), those with ulcerative colitis (UC), and those with indeterminant colitis (IC).RESULTS:A total of 82 patients fulfilled the criteria. In 12 patients (15%), the IBD diagnosis was changed during the course of illness. At the end of the follow-up period, linear growth failure was present in 10 of 35 (29%) children with CD, one of 30 (3%) with UC, and three of 17 (18%) with IC. Failure to thrive was a frequent presenting symptom in children with CD (44%) and IC (39%), whereas in all four patients with UC and failure to thrive the diagnosis was subsequently changed to CD or IC. A high proportion of patients with CD had large bowel (89%), and perianal (34%) disease. None of the tested patients were positive for anti-Saccharomyces cerevisiae antibody (ASCA), and 10 tested positive for perinuclear antineutrophil cytoplasmic antibody (three of five patients with CD, five of seven with UC, and two of three with IC).CONCLUSIONS:Failure to thrive, at the time of presentation, is indicative of a final diagnosis of CD or IC, not UC. Linear growth failure is a common finding in patients with early onset CD. A high proportion of patients with CD have failure to thrive, colonic, and perianal disease. The IBD serology panel is of limited clinical relevance in providing definitive diagnostic information in this pediatric population.

Safety and Steroid-Sparing Experience Using Infliximab for Crohn's Disease at a Pediatric Inflammatory Bowel Disease Center

OBJECTIVES:The published experience using infliximab (Remicade, Centocor, Malvern, PA) for the treatment of pediatric Crohns disease is limited but suggests utility in the treatment of refractory disease. Experience using infliximab at a large pediatric center is reviewed.METHODS:A retrospective review of all infliximab infusions administered to patients with Crohns disease (CD) was undertaken. Data were obtained from database and pharmacy records. Chart review and interviews with physicians, patients, and families were used to obtain missing data.RESULTS:A total of 432 infusions were administered to 82 patients (34 female and 48 male) with CD. The number of infusions each patient received ranged from one to 18, with a mean of 5.3 (SD 4.6) and median of 3. Of 33 patients, 19 (57.6%) became independent and remained free of corticosteroids. There was a statistically significant difference in the steroid dose between 0 and 4 wk and 0 and 8 wk. In all, 23 infusion reactions occurred (5.3%). Three patients developed herpes zoster, and one developed Listeria monocytogenes meningitis. No patients were documented to have delayed hypersensitivity reactions or malignancies.CONCLUSIONS:Infliximab is safe and effective for treating pediatric patients with CD. A steroid-sparing effect was demonstrated. The most common adverse reaction to infliximab was infusion reaction. These reactions did not preclude further use of the agent. Serious infections were seen in a small number of patients.

Infliximab as a novel therapy for pediatric ulcerative colitis.

Objectives The role of infliximab (anti–tumor necrosis factor &agr; antibody) therapy in ulcerative colitis (UC) is not well defined. There are only two reports published describing its use in UC. The authors describe their experience with open-label use of infliximab in children with moderate to severe UC. Methods The authors collected data on all consecutive pediatric patients with UC who received infliximab at The Childrens Hospital of Philadelphia until July 2001. The primary measured outcome was clinical response at 2 days and 2 weeks after infliximab infusion, as measured by the Lichtiger colitis activity index (LCAI) score and the Physician Global Assessment (PGA). Tolerance of the infusions and adverse events were recorded. Results Nine patients qualified for clinical response analysis. The median Lichtiger colitis activity index score decreased from 11 before the infusion to 1 at 2 days and 2 weeks after the infusion, respectively (P = 0.01 for 2 days and 2 weeks). Seven of nine (77%) patients had decreased activity of their disease measured by the Physician Global Assessment. Corticosteroid therapy was discontinued in six (66%) patients. An infusion reaction developed (generalized pruritus and facial flushing) in two patients and an elevated anti-nuclear antibody (ANA) titer of 1:1280 developed in one patient. Conclusion Infliximab is associated with short-term clinical improvement in children and adolescents with moderate to severe UC.

Lamina propria and circulating interleukin-6 in newly diagnosed pediatric inflammatory bowel disease patients.

OBJECTIVES:Understanding cytokine production patterns in early mucosal lesions of pediatric patients newly diagnosed with inflammatory bowel disease (IBD) may be critical to understanding IBD pathogenesis. Interleukin-6 (IL-6) has a central role in a multitude of immune system reactions; however, inconsistent lamina propria and serum IL-6 has been reported in IBD patients. Newly diagnosed pediatric IBD patients have not previously been evaluated for lamina propria or serum IL-6.METHODS:Serum and intestinal lamina propria biopsy whole organ culture supernatants were evaluated by ELISA for IL-6 obtained from newly diagnosed IBD patients, before initiation of immunomodulatory therapies.RESULTS:Levels of lamina propria IL-6 demonstrated significant correlation with graded severity of histological inflammation (p < 0.001). Log-transformed serum and organ culture IL-6 levels demonstrated significant correlation (p < 0.0001, R2= 0.6226). Assigning a demarcation level of >400 pg/ml, serum IL-6 concentrations were a superior marker for the presence of microscopic intestinal inflammation than erythrocyte sedimentation rate (ESR), with a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 82%. When evaluating subtypes of IBD, serum IL-6 levels were correlated more significantly with active disease in ulcerative colitis patients (p = 0.01, R2= 0.74) than in Crohns disease patients (p = 0.21, R2= 0.33).CONCLUSIONS:This study outlines graded production of IL-6 in intestinal lamina propria and serum of newly diagnosed pediatric IBD patients, confirming the presence of IL-6 in early IBD patients. In addition, serum IL-6 may be a good predictor of IBD in pediatric patients with suspected or newly diagnosed IBD.

Intestinal cytokines in children with pervasive developmental disorders.

Abstract Objective A relationship between autism and gastrointestinal (GI) immune dysregulation has been postulated based on incidence of GI complaints as well as macroscopically observed lymphonodular hyperplasia and microscopically determined enterocolitis in pediatric patients with autism. To evaluate GI immunity, we quantitatively assessed levels of proinflammatory cytokines, interleukin (IL)-6, IL-8, and IL-1β, produced by intestinal biopsies of children with pervasive developmental disorders. Methods Fifteen patients, six with pervasive developmental disorders and nine age-matched controls, presenting for diagnostic colonoscopy were enrolled. Endoscopic biopsies were organ cultured, supernatants were harvested, and IL-6, IL-8, and IL-1β levels were quantified by ELISA. Tissue histology was evaluated by blinded pathologists. Results Concentrations of IL-6 from intestinal organ culture supernatants of patients with pervasive developmental disorders (median 318.5 pg/ml, interquartile range 282.0–393.0 pg/ml) when compared with controls (median 436.9 pg/ml, interquartile range 312.6–602.5 pg/ml) were not significantly different ( p = 0.0987). Concentrations of IL-8 (median 84,000 pg/ml, interquartile range 16,000–143,000 pg/ml) when compared with controls (median 177,000 pg/ml, interquartile range 114,000–244,000 pg/ml) were not significantly different ( p = 0.0707). Concentrations of IL-1β (median 0.0 pg/ml, interquartile range 0.0–94.7 pg/ml) when compared with controls (median 0.0 pg/ml, interquartile range 0.0–60.2 pg/ml) were not significantly different ( p = 0.8826). Tissue histology was nonpathological for all patients. Conclusions We have demonstrated no significant difference in production of IL-6, IL-8, and IL-1β between patients with pervasive developmental disorders and age-matched controls. In general, intestinal levels of IL-6 and IL-8 were lower in patients with pervasive developmental disorders than in age-matched controls. These data fail to support an association between autism and GI inflammation.

Circulating Rotavirus-Specific Antibody-Secreting Cells (ASCs) Predict the Presence of Rotavirus-Specific ASCs in the Human Small Intestinal Lamina Propria

Rotaviruses are the most important cause of infectious diarrhea in children throughout the world. Protection is most likely mediated by small-intestinal virus-specific IgA. However, neither fecal nor serum virus-specific IgA clearly correlates with protection against challenge. The capacity of rotavirus-specific antibodies and rotavirus-specific antibody-secreting cells (ASCs) in the circulation to predict the presence of ASCs in the intestines of children was evaluated. Mononuclear cells from intestinal biopsy samples and blood from 21 children were enriched for CD38, a marker of terminally differentiated B cells, and evaluated for the presence of virus-specific and total IgA- and IgG-secreting cells, by ELISPOT assay. Serum virus-specific IgA and IgG levels were determined by ELISA. The ratio of virus-specific to total IgA-secreting cells in the blood correlated with that found in the small, but not large, intestine. In contrast, serum rotavirus-specific IgA correlated less well with the presence of virus-specific ASCs in the small intestine.

Intestinal interleukin-13 in pediatric inflammatory bowel disease patients.

Background:Interleukin-13 (IL-13) is a multifunctional cytokine whose net principle action is to diminish inflammatory responses. Dysregulation of IL-13 production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies implicate IL-13 in IBD pathogenesis; however, they fail to accurately reflect in vivo intestinal IL-13 production. We evaluate IL-13, IL-6, and IL-1β elaborations from colonic organ cultures of pediatric IBD patients Methods:Endoscopic lamina propria biopsies or surgical specimens from pediatric patients with IBD were organ cultured and supernatants evaluated by enzyme-linked immunosorbent assay for IL-1β, IL-6, and IL-13. Results:IL-13 concentrations were significantly reduced in ulcerative colitis (UC) patients when compared with normal controls (P = 0.002) and Crohn disease (CD) patients (P = 0.001). End-stage UC patients at colectomy had lower intestinal IL-13 production than all other UC patients (P = 0.002). No significant correlation was found between IL-13 concentration and histologic disease severity (P = 0.134). Conclusions:Diminished intestinal IL-13 production is present in UC patients and wanes further with clinical disease progression. These findings suggest that UC patients may be differentiated from CD patients by intestinal IL-13 quantitation, and UC patients may benefit from IL-13 enhancing therapies.

Aqueous-based microcapsules are detected primarily in gut-associated dendritic cells after oral inoculation of mice

We previously found that aqueous-based microencapsulation enhanced virus-specific humoral immune responses after oral inoculation of mice. However, the mechanism by which microencapsulation enhances immunogenicity remains unclear. We found that spermine-alginate microcapsules were detected primarily in gut-associated dendritic cells (i.e. CD11c/CD18+, Ia+, CD11b-, CD45R-) after oral inoculation of adult mice. Microencapsulation may enhance immunogenicity by involving antigen presenting cells which are more efficient than those recruited during natural infection.