Jonathan E. Markowitz

Eosinophilic Esophagitis: A 10-Year Experience in 381 Children

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is a disorder characterized by a severe, isolated eosinophilic infiltration of the esophagus unresponsive to aggressive acid blockade but responsive to the removal of dietary antigens. We present information relating to our 10-year experience in children diagnosed with EoE. METHODS We conducted a retrospective study between January 1, 1994, and January 1, 2004, to evaluate all patients diagnosed with EoE. Clinical symptoms, demographic data, endoscopic findings, and the results of various treatment regimens were collected and evaluated. RESULTS A total of 381 patients (66% male, age 9.1 +/- 3.1 years) were diagnosed with EoE: 312 presented with symptoms of gastroesophageal reflux; 69 presented with dysphagia. Endoscopically, 68% of patients had a visually abnormal esophagus; 32% had a normal-appearing esophagus despite a severe histologic esophageal eosinophilia. The average number of esophageal eosinophils (per 400 x high power field) proximally and distally were 23.3 +/- 10.5 and 38.7 +/- 13.3, respectively. Corticosteroids significantly improved clinical symptoms and esophageal histology; however, upon their withdrawal, the symptoms and esophageal eosinophilia recurred. Dietary restriction or complete dietary elimination using an amino acid-based formula significantly improved both the clinical symptoms and esophageal histology in 75 and 172 patients, respectively. CONCLUSIONS Medications such as corticosteroids are effective; however, upon withdrawal, EoE recurs. The removal of dietary antigens significantly improved clinical symptoms and esophageal histology in 98% of patients.

Elemental Diet Is an Effective Treatment for Eosinophilic Esophagitis in Children and Adolescents

OBJECTIVE:Eosinophilic esophagitis (EoE), a disorder characterized by eosinophilic infiltration of the esophageal mucosa, has been defined in large part through published case reports and series leading to ambiguity in both diagnostic and treatment options. Corticosteroids, cromolyn, and elemental diet have all been reported as successful treatments for EoE. In this study, we sought to accurately define a population of patients with EoE and then assess their response to elemental diet.METHODS:A series of patients with chronic symptoms of gastroesophageal reflux disease and an isolated esophageal eosinophilia on esophagogastroduodenoscopy (EGD) were identified. Therapy with a proton pump inhibitor was instituted for 3 months, followed by repeat EGD when symptoms persisted. A 24-h pH probe study was performed, and those with significantly abnormal studies were excluded. The remaining patients were diagnosed with EoE and placed on an elemental diet for 1 month, followed by a repeat EGD.RESULTS:Of 346 patients with chronic gastroesophageal reflux disease symptoms and eosinophils on esophageal biopsy, 51 (14.7%) were ultimately diagnosed with EoE. There was significant improvement in vomiting, abdominal pain, and dysphagia after the elemental diet. The median number of esophageal eosinophils per high-powered field (HPF) decreased from 33.7 before the diet to 1.0 after the diet (p <0.01). The average time to clinical improvement was 8.5 days.CONCLUSIONS:Elemental diet resulted in striking improvement in both symptoms and histologic evidence of disease in children and adolescents with EoE, as identified by strict diagnostic criteria.

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.

Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease.

INTRODUCTIONThe risk of malignancy as a complication of Crohn disease has been well described (1-3). In addition to the established risk of colorectal cancer associated with inflammatory bowel disease, extraintestinal malignancies such as lymphoma have been reported. Areas of intestine with chronic

Inflammatory bowel disease in early childhood and adolescence: special considerations

Several aspects of IBD overlap between pediatric and adult population. Those include nutritional issues, bone density, and medical and surgical therapies. Some aspects like natural course of the disease, and epidemiology and genetics are more easily examined and researched in the pediatric population. Others like pubertal and growth delay, and transition of health care are unique to pediatric patients. This article examines some of the similarities, as well as differences of IBD in these two populations.

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.

Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab.

Introduction: Pediatric studies on immunogenicity of infliximab have not been published. The aim of the study was to evaluate the prevalence of human antichimeric antibody (HACA), relationship to infusion reactions (IR), and the role of concomitant immunomodulatory therapies. Methods: An inflammatory bowel disease (IBD) database was queried, and a retrospective review of patients who had HACA performed was undertaken. Results: HACA was conclusively determined in 34 patients with IBD (14 male, Crohn disease/ulcerative colitis: 30/4), median age 14.8 years (range, 6.4–22.5 years). Twenty-nine (85.3%) patients were receiving immunomodulatory therapy. A total of 234 infliximab infusions were administered (mean, 6.9; range, 1–26). HACA was detected in 12 (35.3%) patients. IR occurred in 8 (23.5%) patients. HACA-positive patients had a higher proportion of infusions associated with IR than did HACA-negative patients (P < 0.01). HACA levels ≥ 8.0 μg/mL were more likely to be associated with IR (P = 0.03). Levels of ≥ 8.0 μg/mL were more common in patients who had an average interval between infliximab infusions of 8 weeks or less (P = 0.04). Concomitant immunomodulatory therapy was associated with a lower risk of developing HACA (P = 0.02) and lower titer of HACA (P = 0.04). Patients did not have HACA at a greater rate when there was an extended interval (more than 12 weeks) between infliximab infusions (P = 0.89). Conclusions: In children and adolescents with IBD, HACA formation is related to IR and to the duration of response to treatment. Immunomodulatory agents seem to have a protective role against development of HACA or high titers of antibodies. The interval between infusions does not influence the development of HACA.

Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response

Objective To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. Methods This was a prospective multicentre cohort study. Stool samples from 101 children (13.3±3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72±12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physicians global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. Results Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 μg/g (2297–8808); lactoferrin 212 μg/g (114–328); M2-pyruvate kinase (M2-PK) 363 U/g (119–3104); and S100A12 469 μg/g (193–1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearmans rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). Conclusions The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.

Listeria meningitis after treatment with infliximab.

Tumor necrosis factor (TNF)– is a proinflammatory cytokine with a pivotal role in the pathophysiology of chronic inflammatory conditions such as Crohn disease and rheumatoid arthritis (1,2). The use of infliximab, a chimeric anti–TNFmonoclonal antibody, has shown clinical efficacy in treating moderate to severe Crohn disease in adult and pediatric patients (3–5). Several studies in patients with Crohn disease have cited low rates of adverse effects in comparison with placebo (6,7). The exact mechanisms of the action of infliximab are unclear. Although infliximab clearly neutralizes the biologic activity of TNF, the complete picture is more complex. A recent study examined the antiinflammatory and immunomodulatory activity of infliximab in patients with Crohn disease and concluded that infliximab exerts its immunologic effects at a local level in the bowel mucosa without generally suppressing systemic immune function (8). This implies that patients treated with infliximab are not at increased risk of serious opportunistic infections. We describe an adolescent with Crohn disease in whom listeria meningitis developed 3 days after an infusion of infliximab. Listeria monocytogenes (L. monocytogenes) infection has been well documented in pregnant women, neonates, and immunosuppressed patients (9,10). Furthermore, listeria septicemia has been reported in an adult patient with Crohn disease 4 days after the administration of infliximab (11). However, infection with listeria after infliximab administration has never been reported in the pediatric population.

Infliximab in pediatric ulcerative colitis: two-year follow-up.

Objectives: The role of infliximab in treating pediatric ulcerative colitis (UC) is not defined. The authors previously have described their experience with the open label use of infliximab in nine children with moderate to severe UC. The aim of this study was to describe the outcome of these patients after a minimum 2-year follow-up and to describe the responses of eight additional patients to this medication. Methods: The authors reviewed all pediatric patients with UC who received infliximab at The Childrens Hospital of Philadelphia from its first use until February 2003. Tolerance of the infusions and adverse events were recorded. Results: Follow-up information for a minimum of 2 years was reviewed for the nine initial patients. A total of 73 infliximab infusions were administered to these patients. Seven of nine (78%) patients were considered to be responders to the initial dose of infliximab. Two of these patients became nonresponders within 9 months of the first dose of infliximab and underwent colectomy. Of the remaining five (56%) patients with sustained response, two continue to receive infliximab infusions and three are doing well without infliximab. One patient experienced an infusion reaction, and one experienced herpes zoster infection. We have treated eight additional UC patients with infliximab. Seven (88%) patients were considered responders. One responder experienced relapse within 2 months. Overall, a short-term improvement was seen in 14 of 17 (82%) patients, and sustained improvement in 10 of 16 (63%) patients followed up for more than 9 months. All five patients with severe or fulminant UC, unresponsive to 2 weeks of intravenous corticosteroid therapy, experienced improvement with infliximab. Infliximab was well tolerated. Conclusion: Infliximab is associated with short- and long-term clinical improvement in children and adolescents with moderate to severe UC.