Carmen Cuffari

Guidelines for immunizations in patients with inflammatory bowel disease

During the past 2 decades, medical therapy for Crohns disease (CD) and ulcerative colitis (UC) has grown to incorporate a variety of immunesuppressing agents. At the same time, basic insights into the aberrant mucosal immune response underlying inflammatory bowel disease (IBD) have expanded dramatically. The interplay of host susceptibility to infection and the safety and efficacy of immunization for vaccine-preventable diseases has been explored in other immune-mediated disease states but only rarely in IBD. The purpose of this review is to formulate best-practice recommendations for immunization in children and adults with IBD by considering the effects of the IBD disease state and its treatments on both the safety and efficacy of immunization. To do so, we first considered the routine recommendations for immunization of children, adults and distinct populations at increased risk for vaccine-preventable disease. Because it was rarely possible to examine direct data on safety and efficacy of immunization in IBD populations, we relied to a large extent upon extrapolation from similar populations and from knowledge of basic mechanisms. The literature suggests that efficacy of immunization may be diminished in some patients whose immune status is compromised by immune suppression. However, except for live agent vaccines, most immunizations may be safely administered to patients with IBD even when immune compromised. Conversely, protection against vaccine-preventable illness may be of even greater benefit to those at risk for morbid or lethal complications of infections because of an immune compromised state. We conclude that for most patients with IBD, recommendations for immunization do not deviate from recommended schedules for the general population.

Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease.

BACKGROUND & AIMS Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). METHODS A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohns disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. RESULTS The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (</=12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P < 0.001). Patients with TPMT activity </=12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 +/- 29 pmol/8 x 10(8) red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%. CONCLUSIONS Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: Potential contributors to IBD‐associated diarrhea

Background: One of the most common symptoms among patients with inflammatory bowel disease (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study was designed to test the hypothesis that intestinal Na+‐related transporters/channels and their regulatory proteins may be downregulated as a potential contributor to IBD‐associated diarrhea. Methods: SDS‐PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na+/H+‐exchangers 1–3 (NHE1–3), epithelial Na+ channel (ENaC), Na+/K+‐ATPase, the intracellular Cl− channel 5 (ClC‐5), and NHE3 regulatory factors (NHERF1,2) in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of dextran sodium sulfate (DSS)‐ and TNBS‐induced acute murine IBD models. Results: NHE1,3 (but not NHE2), &bgr;‐ENaC, Na+/K+‐ATPase‐&agr;, ClC‐5, and NHERF1 were all downregulated in sigmoid mucosal biopsies from most cases of active UC and/or CD compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in ≈50% of sigmoid biopsies from inactive UC or CD. Importantly, similar downregulation of NHE1,3, &bgr;‐ENaC, and NHERF1,2 was also observed in the mouse colon (but not ileum) of DSS‐ and TNBS‐induced colitis. Conclusions: IBD‐associated diarrhea may be due to a coordinated downregulation of multiple Na+ transporter and related regulatory proteins, including NHE1,3, Na+/K+‐ATPase, and ENaC, as well as NHERF1,2, and ClC‐5, all of which are involved directly or indirectly in intestinal Na+ absorption.

Infliximab efficacy in pediatric ulcerative colitis

Background: The effects of infliximab, a tumor necrosis factor‐alpha (TNF‐&agr;) antibody, have been well established in adult patients with inflammatory and fistulizing Crohns disease. This study evaluates short‐ and long‐term efficacy of infliximab in children with ulcerative colitis. Methods: All pediatric patients with ulcerative colitis who received infliximab between July 2001 and November 2003 at the Johns Hopkins Childrens Center were identified. Short‐ and long‐term outcomes and adverse reactions were evaluated. Results: Twelve pediatric patients with ulcerative colitis received infliximab for treatment of fulminant colitis (3 patients), acute exacerbation of colitis (3), steroid‐dependent colitis (5), and steroid‐refractory colitis (1). Nine patients had a complete short‐term response, and 3 had partial improvement. The mean per patient dose of corticosteroid after the first infliximab infusion decreased from 45 mg/day at the first infusion to 22.2 mg/day at 4 weeks (P = 0.02) and 7.8 mg/day at 8 weeks (P = 0.008). Eight patients were classified as long‐term responders with a median follow‐up time of 10.4 months. Of the 4 long‐term nonresponders, 3 underwent colectomy, and the fourth has ongoing chronic symptoms. Three of 4 long‐term nonresponders were steroid‐refractory compared with 1 of 8 long‐term responders. Patients receiving 6‐mercaptopurine had a better response to infliximab. Conclusion: Infliximab should be considered in the treatment of children with symptoms of acute moderate to severe ulcerative colitis.

Critical analysis of bariatric procedures in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex genetic disorder localized to chromosome 15 and is considered the most common genetic cause of the development of life-threatening obesity. Although some morbidities associated with PWS, including respiratory disturbance/hypoventilation, diabetes, and stroke, are commonly seen in obesity, others such as osteoporosis, growth hormone deficiency, and hypogonadism, and also altered pain threshold and inability to vomit, pose unique issues. Various bariatric procedures have been used to cause gastric stasis, decrease gastric volume, and induce malabsorption, with poor results in PWS patients in comparison with normal obese individuals.

Gadolinium‐enhanced magnetic resonance imaging. A useful radiological tool in diagnosing pediatric IBD

BackgroundRecent advances in gadolinium-enhanced magnetic resonance imaging (G-MRI) have been developed to enhance the resolution of the intestinal mucosa and facilitate the differentiation of ulcerative colitis (UC) from Crohn’s disease (CD). The objective of this study is to apply this technology in Pediatrics. MethodsA G-MRI was performed on 58 consecutive children with suspected IBD between 1999 and 2002 using intravenous gadolinium, fat suppression, and respiration-suspended sequences to enhance the resolution of the intestinal wall. The sensitivity and specificity in diagnosing either UC or CD was determined by comparing the G-MRI to the established histologic diagnosis. ResultsG-MRI confirmed the diagnosis of either CD (21) or UC (7) with a sensitivity and specificity of 96% and 92%, respectively. Among the 21 patients with CD, 14 showed proximal small bowel involvement by G-MRI. In total, 17 patients were diagnosed with indeterminate colitis (IC) based on histologic criteria alone, and among these patients, G-MRI had a significantly lower non-classification rate (P < 0.02). In comparison, endoscopy was less sensitive (57%), but more specific (100%) than either histology or G-MRI in diagnosing IBD. G-MRI also showed a strong concordance with computed tomography in diagnosing CD (P = 0.001). ConclusionG-MRI is a both a sensitive and specific radiologic tool in diagnosing pediatric IBD. In patients with CD, G-MRI may be useful in identifying proximal small bowel involvement. Longitudinal follow-up studies are needed in those patients diagnosed with IC to determine the predictive value of G-MRI testing.

Indeterminate colitis: A significant subgroup of pediatric IBD

Background: Indeterminate colitis (IC) is a subgroup of inflammatory bowel disease (IBD) that cannot be characterized as either ulcerative colitis (UC) or Crohns disease (CD). Our aims are to determine the prevalence of IC in our pediatric patient population and to describe its clinical presentation, natural history,and disease distribution. Methods: We performed a retrospective database analysis of all children diagnosed with IBD at the Johns Hopkins Childrens IBD Center between 1996 and 2001. Patient demographics, including age, sex, and age at disease onset, were tallied. Disease distribution was identified on the basis of a review of all endoscopic, colonoscopic, histopathological, and radiological records. All of the patients were followed up clinically to determine the extent of disease progression on the basis of the initial diagnosis of IC. Results: Among 250 children registered in the database, 127 (50.8%) had a diagnosis of CD, 49 (19.6%) had UC, and 74(29.6%) had IC. Patients with IC had a significantly younger mean ± SEM age (9.53 ± 4.8 years) at diagnosis compared with patients with CD (12.4 ± 3.8 years; P < 0.001) but not compared with patients with UC (7.41 ± 3.5 years). Among the patients with IC, 59 (79.7%) had a pancolitis at diagnosis, and the remaining 15had left‐sided disease that progressed to a pancolitis within a mean of 6 years. Twenty‐five patients (33.7%) with an initial diagnosis of IC were reclassified to either CD or UC after a median follow‐up of 1.9 years (range 0.6–4.5 years). Forty‐nine patients (66.2%) maintained their diagnosis of IC after a mean follow‐up of 7years (SEM 2.5 years). Conclusions: IC is a distinct pediatric subgroup of IBD with a prevalence that is higher than that observed in adults. Children with IC have an early age of disease onset and a disease that rapidly progresses to pancolitis. Longitudinal studies are needed to determine the clinical implications of this pediatric IBD subgroup.

Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy

Azathioprine and 6‐mercaptopurine have proven efficacy in the treatment of Crohn’s disease. Immunosuppression is mediated by their intracellular metabolism into active 6‐thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6‐thioguanine levels.

Outcome after percutaneous endoscopic gastrostomy in children and young adults.

Background and Objectives: Factors predicting outcome after percutaneous endoscopic gastrostomy (PEG) in large pediatric cohorts are not well defined. We hypothesized that definable preoperative clinical factors predict the need for further intervention to provide enteral access after PEG. Our aim was to identify factors associated with PEG outcome. Materials and Methods: A retrospective review of 760 (407 boys and 353 girls) patients was performed after PEG at the Johns Hopkins Childrens Center from 1994 to 2005. Logistic or multiple linear regression was used to analyze indication; diagnosis; age; prematurity; neurological impairment; weight-for-age z scores; modified barium swallow; postoperative complications; need for fundoplication (FP), gastrojejunal tube, or jejunostomy; and length of hospital stay. Results: The median age was 1 year (range 0–26 years). The most common indications given for PEG were failure to thrive (n = 373) and dysphagia (n = 27). Postoperative FP, gastrojejunal tube, or jejunostomy were performed in 66 (10%), 24 (4%), and 9 (1%) patients, respectively. Preoperative report indicated that dysphagia and direct aspiration on modified barium swallow was strongly associated with patients undergoing FP after PEG, 10.6% of patients (P = 0.008, odds ratio 2.4) and 11.2% of patients (P = 0.013, odds ratio 2.8), respectively. Younger preoperative age was also associated with the need for FP (P = 0.0006; median age of 5.8 vs 14 months). Patients with preoperative dysphagia had a longer median length of hospital stay: 8 versus 3 days (P < 0.00001). Patients with neurological impairment demonstrated greater weight gain than neurologically normal patients after PEG (P = 0.04). Minor postoperative complications (most commonly wound infection) were observed in 4% (27/747) of children before hospital discharge from PEG and in 20% of children (138/682) after discharge. There were only 2 major complications (gastric separation and gastrocolonic fistula.). There were no fatalities. Conclusions: Preoperative diagnosis, indication, prematurity, and neurological impairment did not influence postoperative complications.

Identification of Novel Serological Biomarkers for Inflammatory Bowel Disease Using Escherichia coli Proteome Chip

Specific antimicrobial antibodies present in the sera of patients with inflammatory bowel disease (IBD) have been proven to be valuable serological biomarkers for diagnosis/prognosis of the disease. Herein we describe the use of a whole Escherichia coli proteome microarray as a novel high throughput proteomics approach to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls (n = 39) and clinically well characterized patients with IBD (66 Crohn disease (CD) and 29 ulcerative colitis (UC)). Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Surprisingly significance analysis of microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Among those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and only 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm (k-top scoring pairs), we identified two sets of serum antibodies that were novel biomarkers for specifically distinguishing CD from healthy controls (accuracy, 86 ± 4%; p < 0.01) and CD from UC (accuracy, 80 ± 2%; p < 0.01), respectively. The Set 1 antibodies recognized three pairs of E. coli proteins: Era versus YbaN, YhgN versus FocA, and GabT versus YcdG, and the Set 2 antibodies recognized YidX versus FrvX. The specificity and sensitivity of Set 1 antibodies were 81 ± 5 and 89 ± 3%, respectively, whereas those of Set 2 antibodies were 84 ± 1 and 70 ± 6%, respectively. Serum antibodies identified for distinguishing healthy controls versus UC were only marginal because their accuracy, specificity, and sensitivity were 66 ± 5, 69 ± 5, and 61 ± 7%, respectively (p < 0.04). Taken together, we identified novel sets of serological biomarkers for diagnosis of CD versus healthy control and CD versus UC.