Riad M. Rahhal

Initial clinical experience with allopurinol‐thiopurine combination therapy in pediatric inflammatory bowel disease

Background: Thiopurines are a mainstay of immunomodulator therapy in inflammatory bowel disease (IBD). Despite their efficacy, some patients may have a poor response due to inability to achieve adequate levels of the active metabolite, 6‐thioguanine (6‐TGN). Others experience hepatotoxicity, which correlates with excessive 6‐methylmercaptopurine (6‐MMP) levels. Two adult studies have demonstrated successful manipulation of thiopurine metabolism with allopurinol, a xanthine oxidase inhibitor, to achieve more optimal thiopurine levels. The aim was to retrospectively characterize the utility of allopurinol to optimize thiopurine metabolite levels in pediatric IBD patients. Methods: Thirteen patients received allopurinol daily (100 mg in patients ≥30 kg and 50 mg <30 kg), and their thiopurine dose was simultaneously reduced to 25%–50% of the previous maintenance dose. Metabolite levels and other screening labs were checked 2–4 weeks later. Results: The mean azathioprine dose was decreased from 148.1 to 59.6 mg daily (60% of the mean original dose). The mean 6‐TGN level increased from 173 to 303 pmol/8 × 108 red blood cell count (RBC) (P = 0.03), and the mean 6‐MMP level decreased from 7888 to 2315 pmol/8 × 108 RBC (P < 0.001). Elevated transaminase levels improved or resolved in all patients. Two patients experienced reversible neutropenia. At the conclusion of the study 9 patients (69%) remained on combination therapy with a mean duration of follow‐up of 162.8 ± 119.2 days. Conclusions: Combination therapy successfully shunted thiopurine metabolites to a more favorable pattern. Reversible neutropenia was the most common side effect (2 patients). Long‐term prospective studies are needed in this patient population.

Re: Azathioprine monotherapy for maintenance of remission in pediatric patients with autoimmune hepatitis.

ABSTRACT Autoimmune hepatitis (AIH) is a chronic disorder characterized by unresolving liver inflammation and has a fluctuating clinical course. Standard therapy has been corticosteroids given daily, alone or in combination with azathioprine (AZA). The potential for significant side effects from prolonged corticosteroid use remains high. To date, no pediatric literature describes long-term AZA monotherapy after induction of remission with corticosteroids. We conducted a retrospective chart review from 1990 to 2002, which revealed 8 patients with AIH. Three patients were excluded because of other diseases requiring continued or intermittent use of corticosteroids. The time to complete biochemical remission on corticosteroids and AZA was 230 days (range, 74-288 days). Azathioprine was introduced early following the diagnosis (range, 1-35 days). All 5 patients were successfully weaned off corticosteroids after a median of 378 days and were maintained on AZA monotherapy for a median of 37 months (range, 28-82 months). One patient had a disease exacerbation on AZA monotherapy 75 months after the discontinuation of corticosteroids. She responded quickly to a corticosteroid burst and has been on AZA monotherapy for 7months. One patient relapsed after self-discontinuing all medications. Long-term remission of AIH was possible in our case series with the early introduction and maintenance treatment with AZA as monotherapy.

Effects of 70% ethanol locks on rates of central line infection, thrombosis, breakage, and replacement in pediatric intestinal failure.

Objectives: Parenteral nutrition is essential for the growth and nutrition of patients with intestinal failure (IF). Catheter-related bloodstream infections (CRBSI) are a major complication of parenteral nutrition use. Few retrospective studies have shown that 70% ethanol lock (ETL) therapy for central lines can reduce the infection rate. Studies assessing line breakage, thrombosis, and replacement with the use of ETL are lacking in the pediatric literature. Methods: The present study is a retrospective chart review, with a primary outcome of CRBSI rate per 1000 catheter days, and secondary outcomes of line thrombosis, line breakage requiring repair, and line replacement rates with use of ETL compared with heparin locks. Rates were compared using the Wilcoxon signed-rank test for paired nonparametric data. Results: Seven patients satisfied the inclusion criteria that included having a single-lumen silicone central line exposed to both heparin and ETL therapy during the study period. There was a statistically significant decrease in overall and Gram-negative CRBSI rates per 1000 catheter days with a use of ETL therapy (10.3–1.4 per 1000 catheter days for overall CRBSIs, P = 0.02; 6.7–0 per 1000 catheter days for Gram-negative CRBSI, P = 0.03). There was an increasing trend in line thrombosis and repair rates with ETL therapy. Logistic regression analysis evaluating the impact of line luminal size on line repair rate showed a reduced risk of line repair when using larger-diameter central lines. Conclusions: ETL therapy is an effective method for decreasing CRBSI in patients with IF; however, it may have a negative impact on line integrity. Patients should be carefully selected when deciding on ETL therapy use for central line care. Studies are needed on the effect of different ethanol concentrations on infection rate and line integrity to optimize the outcome in this high-risk population.

Role of Thiopurine Metabolite Testing and Thiopurine Methyltransferase Determination in Pediatric IBD

Thiopurines have been used in inflammatory bowel disease (IBD) for >30 years, and measurements of both thiopurine methyltransferase (TPMT) and thiopurine (TP) metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), have been readily available. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Committee on Inflammatory Bowel Disease thought it appropriate to review the present indications for use of TPMT and TP metabolite testing. Substantial evidence demonstrates that TP therapy is useful for both Crohn disease and ulcerative colitis. Review of the existing data yielded the following recommendations. TPMT testing is recommended before initiation of TPs to identify individuals who are homozygote recessive or have extremely low TPMT activity, with the latter having more reliability than the former. Individuals who are homozygous recessive or have extremely low TPMT activity should avoid the use of TPs because of concerns for significant leukopenia. TMPT testing does not predict all cases of leukopenia and has no value to predict hypersensitivity adverse effects such as pancreatitis. Any potential value to reduce the risk of malignancy has not been studied. All individuals taking TPs should have routine monitoring with complete blood cell count and white blood cell count differential to evaluate for leukopenia regardless of TPMT testing results. Metabolite testing can be used to determine adherence with TP therapy. Metabolite testing can be used to guide dose increases or modifications in patients with active disease. Consideration would include either increasing the dose, changing therapy or for those with elevated transaminases or an elevated 6-MMP, using adjunctive allopurinol to help raise 6-thioguanine metabolites and suppress formation of 6-MMP. Routine and repetitive metabolite testing has little or no role in patients who are doing well and taking an acceptable dose of a TP.

Ulcerative colitis complicated by ischemic colitis and Budd Chiari syndrome.

Hypercoagulability and intravascular thrombosis are well recognized but uncommon complications of inflammatory bowel disease (IBD) (1–3). Both arterial and venous thromboses have been described as early as the 1930s by Bargen and Barker (4). Intravascular thrombosis can affect various organ systems including the pelvic plexuses, lungs, central nervous system, spleen and kidneys, leading to congestion, ischemia or infarction (2–5). A few case reports on hepatic venous involvement with subsequent Budd Chiari syndrome (BCS) are found in the literature, mainly describing adult patients with ulcerative colitis (UC) (5–8). Bowel ischemia secondary to vascular thrombosis in pediatric patients with IBD has never been described before. Response of hepatic venous thrombosis to anticoagulation and colectomy has not been studied either.

Gastrojejunal feeding tube use by gastroenterologists in a pediatric academic center.

Background and Objectives: Enteral feeding through gastrojejunal (GJ) tubes is an established method of nutrition for patients with feeding difficulty who do not tolerate intragastric feedings. The pediatric literature about the long-term outcome, safety, and complications of different GJ tubes and placement methods is lacking. Our study aims to provide information about indications, techniques, and long-term outcome of GJ tube use in children. Methods: Retrospective chart review for GJ tube placement procedures was used at our center for 10 years (1999–2009). Data collected included demographics, placement indications, underlying diagnosis, tube type, placement methods, complications, tube survival, and patient outcome. Results: Thirty-three patients using GJ tubes were identified, with a total of 160 successful procedures documented (overall success rate of 97.6%). At initial placement, the mean age was 6 years (range 0.6–21.6) and the mean weight was 19.4 kg (range 6.6–72.2). Patients had a mean of 4.9 tubes placed per patient (range 1–20) during a follow-up of 26.8 months (range 0.4–115.3). The most common indications for replacement included accidental dislodgement, tube obstruction, coiling back into the stomach, and broken tube component. At the end of the study, 39% continued using GJ tubes, 30% were transitioned back to gastrostomy or oral feeds, and 15% underwent a surgical intervention. Conclusions: Long-term GJ tube use is possible and safe in children. Various feeding tubes and placement methods can be used by pediatric gastroenterologists to provide long-term jejunal feeds in children.

Simultaneous herpetic and candidal esophagitis in an immunocompetent teenager

Infection is an uncommon cause of esophagitis in children. Common pathogens causing esophagitis include Candida spp. and Herpes simplex virus (HSV). Infectious esophagitis is generally seen in immunocompromised patients but has been rarely reported in healthy individuals. Esophagitis with evidence of both Candida spp. and HSV has not been reported previously in immunocompetent children. We report a case of a healthy teenager with both pathogens causing esophageal infection.

Incremental interactive mining of constrained association rules from biological annotation data with nominal features

Data arising from genomic and proteomic experiments is amassing at high speeds resulting in huge amounts of raw data; consequently, the need for analyzing such biological data --- the understanding of which is still lagging way behind --- has been prominently solicited in the post-genomic era we are currently witnessing. In this paper we attempt to analyze annotated genome data by applying a very central data-mining technique known as association rule mining with the aim of discovering rules capable of yielding deeper insights into this type of data. We propose a new technique capable of using domain knowledge in the form of queries in order to efficiently mine only the subset of the associations that are of interest to researcher in an incremental and interactive mode.

Sacrosidase Trial in Chronic Nonspecific Diarrhea in Children

Chronic nonspecific diarrhea in children, or toddlers diarrhea, is a frequently encountered entity in pediatric clinical practice. This disorder remains poorly understood. Suggested etiologies include malabsorption, dietary intake and motility abnormalities. We investigated the use of sacrosidase (a yeast sucrase supplement) in children with toddlers diar- rhea. The study outcome was clinical response to sacrosidase supplementation. Children, 1-6 years of age, with toddlers diarrhea were enrolled in an open prospective trial. Stooling patterns were obtained at baseline and while on supplementa- tion. Twelve patients were enrolled out of 40 patients who presented with chronic diarrhea. Eight patients did not respond to standard diet changes and were entered into the trial. With supplementation, 4 out of the 8 patients responded clinically with a decrease in mean daily stool frequency and an improvement in the mean daily stool consistency. Sacrosidase sup- plementation demonstrated a potential benefit in a subset of children with toddlers diarrhea. Response to sacrosidase may suggest excessive sucrose intake or unrecognized partial or complete sucrase deficiency in some children with toddlers diarrhea.

Difficulty Achieving Vitamin D Sufficiency With High-Dose Oral Repletion Therapy in Infants With Cholestasis.

Objectives: Oral high-dose repletion vitamin D therapy, also known as stoss therapy, can be effective in the treatment of nutritional vitamin D deficiency rickets in infants and young children without liver disease and in patients with cystic fibrosis. There is no literature about this approach in infants with new-onset cholestasis. Methods: This was a retrospective chart review of infants with cholestasis from March 2010 to March 2012 at a pediatric tertiary care center. Four cases satisfied the inclusion criteria, and were described in detail. Results: All of the patients received oral high-dose repletion therapy with ergocalciferol (vitamin D2) 300,000 IU daily for 2 to 3 days. Follow-up vitamin D levels approximately 4 weeks later showed failure to achieve sufficiency levels (>20 ng/dL) in any patient. Conclusions: Unlike infants without liver disease, use of oral high-dose repletion therapy may not be adequate as treatment of vitamin D deficiency in the setting of cholestasis.