Jonathan Moses

Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab

OBJECTIVES:Hepatitis B virus (HBV) reactivation has been described in patients treated with infliximab for inflammatory bowel disease (IBD). This has resulted in a “black box” warning. Although universal vaccination against hepatitis B was implemented in the United States in 1991, up to 10% of vaccine recipients fail to respond with adequate anti-hepatitis B surface antibodies (anti-HBs) levels after a primary series of vaccinations. In addition, anti-HBs levels are expected to decline with time. The objectives of this study were to determine HBV immunity in children with IBD on infliximab therapy and to determine response to a booster dose of the HBV vaccine in patients who were found to be non-immune.METHODS:This was a prospective cross-sectional, single-center study that included 100 pediatric IBD patients on infliximab. Serologic specimens were tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and anti-HBs. Patients with an anti-HBs level ≥10 mIU/ml were considered to be immune. One booster dose was given to non-immune patients and a serum sample was collected after 4 weeks to assess the presence of anamnestic response (anti-HBs level ≥10 mIU/ml after booster).RESULTS:The mean age of the patients was 17.9 (±4.0) years. None of the patients were positive for HBsAg or anti-HBc. In all, 87 patients were vaccinated against HBV and 49/87 (56%) had immunity to HBV as defined by anti-HBs level ≥10 mIU/ml. The mean concentration of anti-HBs levels in immune patients was 295.6 (±350.6) mIU/ml. Older age, lower albumin levels, and the presence of pancolitis were associated with the absence of protective antibodies; however, infliximab dose, frequency, duration, and the concurrent use of immunomodulators were not significantly different between immune and non-immune patients. Thirty-four patients received booster immunization and 26/34 (76%) had an anamnestic response. Interestingly, non-responders were given infliximab with higher frequency (every 5.9±1.2 weeks vs. every 7.1±1.8 weeks, P=0.01). Overall, 75/87 (86%) of previously immunized patients were considered immune against HBV infection.CONCLUSIONS:In pediatric IBD patients seen at a large, urban tertiary care facility in the United States, a significant minority (13%) have not been vaccinated against HBV. Nearly one-half of all patients (and 44% of previously vaccinated patients) did not have protective anti-HBs levels. Moreover, of those previously vaccinated, a significant minority (14%) appear at risk for HBV because protective anti-HBs levels were absent and could not be elicited through booster immunization. Given the high risk for severe HBV infection in this group, efforts should be made to screen for HBV immunity at the time of IBD diagnosis. Booster immunization should be considered in patients without protective antibodies.

Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children

Objective Nonalcoholic fatty liver disease (NAFLD) is one of the most common complications of childhood obesity. Our objective was to investigate the association of breath volatile organic compounds with the diagnosis of NAFLD in children. Methods Patients were screened with an ultrasound of the abdomen to evaluate for NAFLD. Exhaled breath was collected and analyzed per protocol using selective ion flow tube mass spectrometry (SIFT-MS). Results Sixty patients were included in the study (37 with NAFLD and 23 with normal liver). All children were overweight or obese. The mean age was 14.1±2.8 years and 50% were female. A comparison of the SIFT-MS results of patients with NAFLD with those with normal liver on ultrasound revealed differences in concentration of more than 15 compounds. A panel of four volatile organic compounds can identify the presence of NAFLD with good accuracy (area under the receiver operating characteristic curve of 0.913 in the training set and 0.763 in the validation set). Breath isoprene, acetone, trimethylamine, acetaldehyde, and pentane were significantly higher in the NAFLD group compared with normal liver group (14.7 ppb vs. 8.9 for isoprene; 71.7 vs. 36.9 for acetone; 5.0 vs. 3.2 for trimethylamine; 35.1 vs. 26.0 for acetaldehyde; and 13.3 vs. 8.8 for pentane, P<0.05 for all). Conclusion Exhaled breath analysis is a promising noninvasive method to detect fatty liver in children. Isoprene, acetone, trimethylamine, acetaldehyde, and pentane are novel biomarkers that may help to gain insight into pathophysiological processes leading to the development of NAFLD.

A single-center experience with methotrexate after thiopurine therapy in pediatric Crohn disease.

Background and Aim: Thiopurines are a common, effective means of maintaining remission in pediatric Crohn disease (CD). Methotrexate (MTX) may be considered for those intolerant of or unresponsive to thiopurines. The purpose of this study was to examine the effectiveness of MTX as maintenance therapy in patients previously treated with thiopurines. Patients and Methods: All of the patients at Nationwide Childrens Hospital from 1998 to 2007 with an International Classification of Diseases code indicative of CD were identified. Patients with a diagnosis of CD, a history of prior thiopurine use, no current infliximab therapy, and at least 6 months of follow-up after MTX initiation were included. The primary outcome was defined as steroid-/infliximab-free remission determined by the physician global assessment at 6 and 12 months. Secondary outcomes included subsequent treatment with infliximab and/or corticosteroids, rate of discontinuation of MTX, and adverse events (AEs). Results: Twenty-seven patients (17 boys, 63%) with a mean age at diagnosis of 12.3 ± 0.7 years and mean disease duration of 1.49 ± 0.3 years were identified. Indications for MTX included nonresponse to thiopurines, AE, and poor adherence to thiopurines. At 6 and 12 months, 13 of 27 patients (48.1%) and 9 of 27 patients (33.3%), respectively, were in steroid-/infliximab-free remission. A total of 10 patients (37.0%) required infliximab therapy during the 12-month period and 5 patients discontinued MTX. Nausea was the most commonly reported AE. Transient transaminase elevation occurred in 4 patients and transient leukopenia in 2 patients. Conclusions: MTX can be effective as maintenance therapy for patients with pediatric CD previously intolerant of or unresponsive to thiopurines; however, greater than one third of this cohort required escalation to antitumor necrosis factor therapy within 12 months following MTX initiation. MTX was well tolerated.

Approach to the Diagnosis and Treatment of Cyclic Vomiting Syndrome: A Large Single-Center Experience With 106 Patients

BACKGROUND Cyclic vomiting syndrome is characterized by repeated, stereotypical vomiting episodes. The diagnosis is made by exclusion of other organic diseases, which can lead to extensive testing. It has been suggested that these patients can have mitochondrial dysfunction. The aim of the study was to examine the evaluation of our cyclic vomiting patients and to determine whether they had associated, undiagnosed metabolic abnormalities. METHODS This retrospective study included 106 patients aged <21 years at diagnosis. Information regarding medical history, laboratory, and imaging studies were collected. Metabolic studies in plasma and urine were obtained when patients were well and when patients were in a vomiting cycle, including plasma amino acids, acylcarnitines, and urine organic acids. RESULTS The mean age at diagnosis was 8.9 ± 5.0 years. Neuroimaging revealed previously unknown intracranial abnormalities in <10% of patients, none of whom explained the vomiting signs. Abdominal ultrasounds revealed abnormalities in 15% of patients during an acute episode and 7% of patients when well. Sixty-one patients had an upper gastrointestinal series, all of which were normal. A total of 92% of patients had laboratory testing with 38% indicating abnormalities possibly suggesting mitochondrial dysfunction. CONCLUSIONS This large, single-center study further evaluated the need for more focused evaluation in patients with suspected cyclic vomiting syndrome. Thirty-eight percent of our patients had abnormalities in blood and/or urine suggesting mitochondrial dysfunction, which requires more detailed investigation in the future.

Response to hepatitis A vaccine in children with inflammatory bowel disease receiving infliximab

We read with great interest the recent article by Radzikowski et al on immunogenicity of the hepatitis A virus (HAV) vaccine in pediatric patients with inflammatory bowel disease (IBD). As outlined by the authors, there are few studies investigating the immune response to vaccinations in children with IBD. The authors specifically looked at immunogenicity of the HAV vaccine in pediatric IBD patients when compared to healthy controls. They vaccinated eligible patients with Havrix (GlakoSmithKline, Rixensart, Belgium), on a two-dose schedule of 0 and 6–12 months. They measured total anti-HAV antibodies prevaccination, at 4 and 12 weeks after the first dose, and 4 and 12 weeks after the second dose. Among the 66 IBD patients and 68 control patients, they found no significant difference in seroconversion after the second dose of the vaccine between the two groups (97% vs. 100%, P 1⁄4 0.2407). 6-Mercaptopurine (6-MP) or azathioprine (AZA) treatment with and without steroids did not affect seroconversion rates, but monotherapy with steroids reduced the rate of seroconversion at 4 weeks after the second dose. Their results were consistent with existing reports of HAV seroconversion in healthy patients and in patients with chronic liver disease. Of note, none of the patients in the study were on a biologic medication, such as infliximab. Herein we aimed to investigate the immunogenicity of the HAV vaccine in pediatric IBD patients receiving infliximab. We screened 100 patients for total anti-HAV antibodies and found that 14 patients (14%) had protective antibodies. We were able to enroll 12 patients who did not have anti-HAV antibodies to receive the full series of the vaccine. We used Havrix on a 0 and 6–12 months schedule, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units (ELU) per 0.5 mL for patients less than 19 years of age and 1440 ELU per 1 mL for patients 19 years of age and older, per the manufacturer’s recommendations. We checked the total anti-HAV prevaccination and 4 weeks after the second dose of the vaccine. The mean age at time of vaccination was 18.3 years (range 13–23 years) with a mean age at IBD diagnosis of 12.8 years. There were eight males and four females in the study. Overall, we found a seroconversion rate of 92% (11/12 patients) when the total anti-HAV was rechecked 4 weeks after the second dose. All of the patients were receiving infliximab at the time of vaccination and none of the patients were on concurrent steroids or 6-MP/AZA. Of note, two of the patients were on concurrent methotrexate, both of whom were responders to the HAV vaccine. In summary, we found a high rate of seroconversion to HAV vaccination in pediatric patients treated with infliximab for IBD. Taken together with the results of the study by Radzikowski et al, there is convincing evidence that pediatric IBD patients on a wide variety of medications for control of their disease are likely able to respond adequately to the HAV vaccine.

Metastatic osteosarcoma to the stomach and ascending colon in a pediatric patient causing gastrointestinal hemorrhage

Osteosarcoma metastasis to the gastrointestinal tract is a rare phenomenon (Horiuchi A, Watanabe Y, Yoshida M, et al.: Metastatic osteosarcoma in the jejunum with intussusception: report of a case. Surg Today 2007;37:440-2). Gastrointestinal metastases may cause intussusception, bowel obstruction, or hemorrhage (Horiuchi A, Watanabe Y, Yoshida M, et al.: Metastatic osteosarcoma in the jejunum with intussusception: report of a case. Surg Today 2007;37:440-2; Chondramohan K, Somanathan T, Kusamakumary P: Metastatic osteosarcoma causing intussusception. J Pediatr Surg 2003;38(E44):1-3; Hung GY, Chiou TJ, Hsieh YL, et al.: Intestinal metastasis causing intussusception in a patient treated for osteosarcoma with history of multiple metastases: a case report. Jpn J Clin Oncol 2001;31:165-167). We report a case of a 17 year old male with osteosarcoma metastatic to the stomach and ascending colon, causing significant chronic gastrointestinal hemorrhage. Surgical resection was performed due to persistent, symptomatic anemia. The patient is free of recurrent hemorrhage at 24months after metastectomy. Resection of gastrointestinal metastases of osteosarcoma offers good palliation of chronic hemorrhage related to these lesions.

Metabolic profiles and liver steatosis in children with liver transplantation for progressive familial intrahepatic cholestasis type 1

Aims: Severe liver steatosis is common complication post-transplantation in patient with progressive familial intrahepatic cholestasis type 1 (PFIC1). We aimed to evaluate metabolic profiles in children who received orthotopic liver transplantation (OLT) for PFIC1 and their correlation with the development of fatty liver disease (FLD). Methods: Patients transplanted for PFIC1 disease were identified and matched in a 1:2 ratio with patients transplanted for other indications. Liver biopsy was used to determine the presence of FLD. Lipid profiles were compared in the 2 groups. To investigate mechanistic pathways leading to the development of FLD, volatile organic compounds (VOCs) were analyzed on prospectively collected samples using a selective ion flow tube mass spectrometry. Results: Five children with PFIC1 disease and 10 children with other indications for liver transplantation were included. Liver biopsies demonstrated that all children with PFIC1 had moderate-to-severe steatosis. The PFIC1 group had significantly lower HDL (20.9±6.0 Ana Catalina Arce-Clachar1, Jonathan Moses1, Gursimran Kochlar1, Peggy George1, Vera Hupertz1, Kadakkal Radhakrishnan1, Raed Dweik1, Naim Alkhouri1 Affiliations: 1MD, Department of Pediatric Gastroenterology, Cleveland Clinic Children’s Hospital. Corresponding Author: Naim Alkhouri, MD, Department of Pediatric Gastroenterology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. USA; Tel: 216-444-9000; Fax: 216-444-2974; Email: alkhoun@ccf. org Received: 18 December 2014 Accepted: 29 January 2015 Published: 08 April 2015 mg/dL versus 51.3±17.1 mg/dL, respectively, p < 0.001) and total cholesterol levels (72±8.0 versus 156±103, p < 0.001) post transplantation compared to the other group. VOCs, including acetaldehyde, ammonia and pentane were elevated in the PFIC1 group, while isoprene was lower. Conclusion: Fatty liver disease was a consistent finding in the patients with PFIC1 post OLT. Lipid levels were uniformly low in PFIC1 patients. Metabolomic analysis suggested that pathways in oxidative stress, gut bacteria production and cholesterol synthesis were different in children with PFIC1.