William J. Wenner

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.

Normal Thiopurine Methyltransferase Levels Do Not Eliminate 6-mercaptopurine or Azathioprine Toxicity in Children with Inflammatory Bowel Disease

6-mercaptopurine (6-MP) and azathioprine (AZA) are used to treat inflammatory bowel disease (IBD). Side effects include infection, leukopenia, hepatitis, and pancreatitis. The level of thiopurine methyltransferase (TPMT), which metabolizes 6-MP to 6-methylmercaptopurine, may reflect the risk of side effects. We sought to evaluate the relationship between the side effects of these medications and the TPMT level of pediatric patients with IBD. The medical records of our patients who were diagnosed with IBD and who received 6-MP or AZA were reviewed for measured TPMT levels. All red blood cell (RBC) TPMT levels were determined at the Mayo Medical Laboratories, Rochester, MN. The occurrence of leukopenia, elevated aminotransferases, and pancreatitis was evaluated. Twenty-two patients, mean age 13.7 years, received 6-MP or AZA and had TPMT levels measured. The TPMT levels ranged 10.7-27.5 U/mL RBC with a mean of 17.2 +/- 3.2 U/mL RBC. Two children had levels below the accepted norm of 13.8 U/mL RBC. One of these patients (50%) developed both elevation of aminotransferases and leukopenia. Of all, 20 children had normal levels, 3 (15.0%) exhibited side effects: hepatitis (n = 2) and leukopenia (n = 1). We conclude that side effects of 6-MP or AZA occur despite normal TPMT levels.

Placebo-controlled trial assessing the use of oral midazolam as a premedication to conscious sedation for pediatric endoscopy

BACKGROUND This study was performed to evaluate the effect of midazolam, as premedication before intravenous conscious sedation, on preprocedural, procedural, and post-procedural patient comfort and anxiety in children undergoing endoscopy. METHODS A placebo-controlled, double-blind, randomized study was conducted in 123 children (age 7.75 +/- 4.46 years, 56% male) using oral midazolam (0.5 mg/kg, maximum 20 mg) as a premedication before insertion of an intravenous access device (i.v.) and upper endoscopy. Patients were evaluated with regard to changes in vital signs, level of sedation during i.v. placement, level of pre- and post-procedure conscious sedation, ease of separation from parents, ease and duration of procedure, recovery time, and amnesia to objects shown before i.v. placement and immediately before the start of the procedure. RESULTS A significant difference was noted in the study group for the following parameters: level of sedation for i.v. placement (p < 0.0001), pre-procedural sedation (p < 0.001), ease of i.v. insertion (p < 0.003), ease of separation from parents (p = 0.022), and ease of the nursing personnels ability to monitor the patient during the procedure (p = 0.0012). The patients amnesia to an object shown immediately before beginning the endoscopy was increased (p < 0.001). Patients and parents were also more satisfied with the procedure process (p < 0.05). No significant difference was noted with regard to the length or performance of the procedure or recovery time or in the dose of i.v. medication required for successful completion of the endoscopy. CONCLUSION Oral midazolam is an effective and safe premedication for children undergoing upper endoscopy and should be used in all anxious children and in patients previously judged to be difficult to sedate.

HIV as a cause of giant cell hepatitis

The 9-month-old daughter of human immunodeficiency virus (HIV)-seropositive parents presented with cholestasis and was found on liver biopsy to have giant cell hepatitis. No viral inclusions or particles were seen by light or electron microscopy. Ultrastructural studies of the liver biopsy demonstrated tubuloreticular structures in the endothelium and cylindrical confronting cisternae in inflammatory cells in the portal tracts. Serologic studies for hepatitis B, hepatitis A, and Epstein-Barr viruses were negative. Cytomegalovirus (CMV) was cultured from the urine, but buffy coat, nasopharyngeal, and liver cultures were negative and CMV antibody titer was low. The hepatitis responded dramatically to prednisone therapy. A repeat biopsy several months later revealed similar morphologic findings. AIDS was suspected on clinical and immunologic grounds, and was confirmed by the demonstration of HIV-specific IgG and IgM in serum. Five months after initial presentation, the infant developed Pneumocystis pneumonia, disseminated CMV infection, and died. This appears to be the first reported association of infantile giant cell hepatitis with HIV infection.

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.

The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis

Abstract.The purpose of this study was to evaluate the effects of cysteamine on gastric acid output and serum gastrin levels in children with nephropathic cystinosis. We studied four children with nephropathic cystinosis receiving a dose of free base cysteamine of 14.35 mg/kg four times a day (range 12.30 – 18.80 mg/kg). Gastric acid was measured for the hour before and after administration of the medication. Serum gastrin levels were obtained at 0, 30, 60, and 90 min following the medication. Gastrointestinal anatomy was evaluated by endoscopy and biopsy. Following administration of the medication, all subjects showed an increase in gastric acid output. Mean acid output increased from 0.79 to 2.22 mEq/h. Mean gastric acid output adjusted for body weight increased from 0.03 to 0.09 mEq/kg per hour. Following administration of the medication, all subjects showed an increase in serum gastrin. The mean increase above the base value was 38.3 pg/dl. Two of the four subjects demonstrated visual and histological evidence of inflammation. Cysteamine has a marked effect on gastric acid production and serum gastrin, even at the dose used in children with nephropathic cystinosis. The clinical effect of this acid production is unknown but may be significant.

Significance of Lymphoid Follicles and Aggregates in Gastric Mucosa of Children

ABSTRACT This study was designed to evaluate the significance of gastric lymphoid follicles (LF) and aggregates (LA) in children with and without Helicobacter pylori (HP) infection. All 605 antrum biopsies performed during 1994 were reviewed and classified according to the presence or absence of inflammation, LF, or LA. HP was searched with a DiffQuik stain in all biopsies showing gastritis, LF, or LA. Gastritis was diagnosed in 80 biopsies (16 with LF, 18 with LA and 46 without LA or LF). Identification of HP in these biopsies was as follows: (a) cases with LF: 12/16; (b) cases with LA: 3/18; (c) cases without LF or LA: 8/46. The biopsies without gastritis had a higher frequency of LA (65/525) than of LF (2/525). HP was not identified in any case without gastritis. The presence of LF with histologic gastritis had the strongest correlation with HP (R = 0.5, p < 0.00001). LF with gastritis had a positive predictive value of 75% for HP and the absence of LF had a negative predictive value of 82.8% (sensitivity 52%; specificity 92%). LA with gastritis had no significant correlation with HP. From these results we conclude that lymphoid follicles should be distinguished from lymphoid aggregates. Lymphoid follicles can rarely be present in an otherwise normal gastric mucosa; however, they are more frequently found in cases of gastritis and are strongly associated with HP infection. Lymphoid aggregates are not significantly associated with HP infection and may be a component of the normal gastric lymphoid tissue.

Colonic inflammation found at diagnosis of juvenile retention polyps in pediatric patients

OBJECTIVE:The finding of colonic inflammation concurrently with a juvenile retention polyp (JRP) may have prognostic value. However, the significance of abnormal mucosal histology with JRP has not been evaluated. We evaluated the significance of mucosal histology at the time of JRP removal with respect to future development of inflammatory bowel disease (IBD) and polyp recurrence.METHODS:The medical records of patients who had an endoscopic polypectomy performed at the Childrens Hospital of Philadelphia (CHOP) from 1/1/87 through 4/30/98 were retrospectively reviewed.RESULTS:JRP was histologically identified in 96 patients. A total of 54 patients had colonic mucosal biopsies: 30 (55.6%) had normal histology and 24 (44.4%) had colitis. Of the 24 patients with colitis, 14 patients (58.3%) had inflammation at the polyp site. Twelve of these patients had additional inflammation elsewhere in the colon. Nine (37.5%) had inflammation elsewhere in the colon; however, biopsies around the polyp site were not obtained. One patient with inflammation did not have the location of the polyp documented. Four patients (16.7%) had IBD at the time of polypectomy; two were diagnosed prior and two coincident with JRP. None have subsequently been diagnosed with IBD. There was no difference in polyp recurrence between those with or without inflammation (16.7% [4/24] vs 10.0% [3/30]). The mean follow-up period was 72.4 months (range, 5–142 months).CONCLUSIONS:In our experience, histological mucosal inflammation is a common finding with JRP. This inflammation may be a precursor for the development of JRP but has no predictive value for polyp recurrence. This colitis does not seem to be associated with IBD.

Delayed Diagnosis of Infantile Meningitis Medical and Legal Outcomes

While the diagnosis of meningitis in the infant can be difficult due to the lack of definitive signs, a delay in the diagnosis can markedly increase morbidity and mortality. Eighteen cases of meningitis that were re ported to a malpractice carrier over 75 months were evaluated for medical and legal outcome. Fourteen had a delay in diagnosis that was judged to have occurred due to substandard care. All had a poor outcome; one half died and the other half had neuro logic complications. Four cases resulted in payment to the patient. Median payment was