Charles C. Roberts

Clinical Efficacy and Pharmacokinetics of Montelukast in Dyspeptic Children with Duodenal Eosinophilia

Background Montelukast, a competitive cysteinyl leucotriene-1 receptor antagonist, reduces airway eosinophilia in asthmatics. We evaluated the effect of this drug in children with eosinophilic duodenitis, defined histologically as duodenal mucosa with peak eosinophil count of more than 10 eosinophils/hpf. Methods Forty children and adolescents (6–18 yr) with dyspepsia and duodenal eosinophilia were enrolled in a double blind, randomized, placebo-controlled, cross-over study of monteleukast therapy. Subjects were randomized to receive either 10 mg montelukast or an identical placebo once daily and were evaluated on day 14 for symptomatic and biochemical responses. Subjects were also randomized to one of two blood sampling schemes to evaluate montelukast pharmacokinetics. Results Using a post treatment global pain assessment, a positive clinical response was observed in 62.1% of patients receiving montelukast compared with 32.4% on placebo (p < 0.02). Pain assessment score deteriorated in 45% of montelukast responders (5/11) after cross-over to placebo and improved in 62% (8/13) of placebo non-responders on cross-over to montelukast. In patients with peak duodenal eosinophil counts between 20–29/hpf (n=19), a positive pain assessment response was observed in 84% of patients receiving montelukast compared to 42% receiving placebo (p < 0.01). Response rate did not differ by age, gender or histologic findings at baseline. Pharmacokinetic analysis yielded parameter estimates for absorption rate constant (Ka), apparent volume of distribution (Vd/F) and elimination rate constant (Kel) of 0.42 h−1, 0.19 L/kg and 0.26 h−1, respectively. The relative extent of systemic drug exposure was comparable to that observed in previous pediatric investigations with similar weight-adjusted montelukast doses. Neither dose nor calculated drug exposure were associated with the level of post treatment pain assessment or the change in biochemical markers. Conclusions These data suggest a beneficial role for montelukast in the treatment of pediatric patients with dyspepsia associated with duodenal eosinophilia.

Safety of infliximab treatment in pediatric patients with inflammatory bowel disease.

ABSTRACTBackground:Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy.Methods:A retrospective review of all infliximab infusions administered to IBD patients at a tertiary child

Mucosal Eosinophilia and Response to H1/H2 Antagonist and Cromolyn Therapy in Pediatric Dyspepsia

Both eosinophils and mast cells have been implicated in the generation of abdominal pain. The purposes of this retrospective study were to determine the prevalence of duodenal eosinophilia in pediatric dyspepsia and to determine the clinical response rate of these patients to combined H1 and H2 receptor antagonist and mast cell stabilizer therapy. Fifty-nine patients (ages 3.5–17.7 years) with dyspepsia undergoing endoscopy were evaluated. All patients had a minimum of 2 forceps biopsies obtained from each of the esophagus, antrum, and duodenal bulb. Routine histologic evaluation was performed and duodenal biopsies were additionally evaluated to determine eosinophil counts. Patients with > 10 eosinophils/hpf were treated with ranitidine and hydroxyzine (H1/H2). Nonresponders were then treated with oral cromolyn. Patients were followed up and response recorded in an abdominal pain database and/or medical chart, which were reviewed for this study. Forty-two patients (71%) had duodenal eosinophilia. Twenty-one (50%) of these were responders to H1/H2. The response rate did not differ between patients with and without noneosinophilic esophagitis, gastritis, or duodenitis, respectively. Two patients were lost to follow-up and considered nonresponders. Seventeen of the remaining 19 (89%) were responders to cromolyn. Overall, the response rate to this treatment pathway was 90%. Duodenal eosinophilia is common in pediatric patients with dyspepsia. These patients appear to be clinically amenable to combination H1/H2 therapy and/or oral cromolyn.

Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing

Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.

Activated duodenal mucosal Eosinophils in children with dyspepsia: A pilot transmission electron microscopic study

Background Activated eosinophils can be identified by electron microscopy (EM) Previous studies have shown EM evidence of eosinophil activation in a variety of gastrointestinal conditions associated with inflammation. The purpose of this study was to evaluate the activation state by EM of duodenal mucosal eosinophils in children who presented with dyspepsia and to determine if eosinophils are activated in patients with normal eosinophil counts on routine histology. Methods Twenty patients (ages 7–15 years) with dyspepsia were evaluated. All had normal gross endoscopies and Helicobacter pylori was excluded. Each patient had two endoscopic forceps biopsies taken from both the duodenal bulb (DB) and the second portion of the duodenum (DS) for routine histology to determine eosinophil counts. Two additional biopsies were taken from the adjacent mucosa of each site for EM evaluation. The eosinophil activation state was determined for each specimen and a degranulation index was calculated for DB specimens. Results On routine histology, peak eosinophil counts were greater than or equal to 20 per hpf in three patients, 11 to 19 per hpf in 12 patients, and less than or equal to 10 per hpf in 5 patients. All patients showed evidence of EM activation on DB specimens and 95% showed activation on DS specimens. The mean degranulation index was 50.5 + 12.0% with 65% of specimens revealing moderate (20 – 60%) degranulation and 30% of specimens revealing extensive (greater than 60%) degranulation. Conclusions Eosinophils present in the duodenal mucosa of children with dyspepsia are activated in a significant proportion of patients, even in those with normal eosinophil counts. The degree of degranulation is similar to that seen in other conditions where eosinophils have a pathogenic role.

Glucose Response to Discontinuation of Parenteral Nutrition in Patients Less Than 3 Years of Age

BACKGROUND The effects of abrupt discontinuation and tapering of total parenteral nutrition (TPN) on glucose concentration were compared in patients < 3 years of age. METHODS Serial glucose concentrations were measured over 120 minutes after abrupt discontinuation as compared with tapering (decreasing infusion rate by 50% for 1 hour before discontinuation). Serial insulin concentrations were measured after abrupt discontinuation. RESULTS There was a significantly greater decrease in glucose concentration from baseline at 30 minutes after abrupt discontinuation as compared with tapering. Fifty-five percent (6/11) of the patients developed hypoglycemia (glucose concentration < 40 mg/dL) after abrupt discontinuation. Age, glucose infusion rate, and serum insulin concentrations were not predictive of the development of hypoglycemia. The tapering regimen did not prevent hypoglycemia, which developed in 20% (2/10). CONCLUSION The high incidence of hypoglycemia after TPN discontinuation in children < 3 years of age requires monitoring of serum glucose concentration when initiating intermittent TPN until tolerance is documented.

Accuracy and reproducibility of 12-h esophageal pH monitoring

Seventy-five consecutive 24-h intraesophageal pH recordings performed according to the methods of Jolley et al. were evaluated. Total scores and the mean duration of sleep reflux (ZMD) were calculated for the first and the last 12 h, respectively, and compared to each other, as well as to the full 24-h recording. The accuracy of the first and last 12 h in predicting whether the 24-h study was abnormal was 85% and 87%, respectively. The accuracy in predicting whether the ZMD for the 24-h study was abnormal was 73% and 83%, respectively, with an overall 39% false-negative rate. The 12-h study reproducibility was 72% for the total score and 56% for the ZMD. Since the original standards were determined from 18- to 24-h recordings, the test was restandardized based on 12-h recordings from patients with normal 24-h studies. Restandardization did not improve the accuracy or reproducibility. The high false-negative rate for the ZMD and the poor reproducibility cast serious doubt on the utility of 12-h pH recordings, especially in patients with respiratory symptoms.

Grasp biopsy, suction biopsy, and clinical history in the evaluation of esophagitis in infants 0-6 months of age

Fifty-three infants 0–6 months of age with abnormal 24-h intraesophageal pH monitoring were evaluated by esophageal suction biopsies and endoscopic grasp biopsies. Histologic esophagitis was present in 30% of the infants. Of the infants with esophagitis, 88% were accurately identified by suction biopsy, and 75% were accurately identified by endoscopic grasp biopsy. Suction biopsy alone was not significantly different from combined grasp and suction biopsy, while differences between grasp biopsy and combined biopsy approached significance (p = 0.051). Twelve clinical symptoms and 21 intraesophageal pH monitoring parameters were evaluated for their ability to predict esophagitis, and none were found to be useful. We conclude that endoscopic esophageal biopsy, while more costly, offers no advantage over suction biopsy for the detection of esophagitis in young infants.

Bilirubinuria: An early indicator of gallbladder hydrops associated with Kawasaki disease.

We report four cases of gallbladder hydrops associated with Kawasaki disease diagnosed over a 7.5 year period. Despite varying clinical presentations, all four of these patients had the common finding of bilirubinuria prior to clinical symptoms or at the time of admission. Review of 40 other cases of Kawasaki disease without evidence of hydrops over this time period revealed that urinalysis had been performed in each and bilirubinuria was present in only one case. Bilirubinuria appears to be an early indicator of hydrops in these patients.

Safety of infliximab treatment in pediatric patients with inflammatory bowel disease

Background: Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy. Methods: A retrospective review of all infliximab infusions administered to IBD patients at a tertiary children’s hospital was undertaken. Data was obtained from an infliximab infusion database maintained in the section of Pediatric Gastroenterology, pharmacy records and patient charts. Results: 594 infusions were administered to 111 IBD patients (88 CD and 23 UC; 55 male and 56 female; ages 4 to 20 years; mean age, 13.4 years). The number of infusions ranged from 1 to 24 with a mean of 5.4/patient. Infusion reactions occurred in 8.1% of patients (seven early and two delayed) and in 1.5% of all infusions. Reactions occurred more frequently in female patients (14% versus 2%; P = 0.03). All reactions were mild and responded rapidly to treatment. Four patients had infections deemed unusual, including three cutaneous tinea infections and one case of shingles. Conclusion: Infliximab is safe in pediatric IBD patients with a low incidence of generally mild reactions that respond rapidly to intervention. Infusion reactions are more common in female patients. Our patients had no serious infectious complications, although cutaneous tinea infection may represent a newly reported associated complication.