Changes in trabecular bone density in incident pediatric Crohn's disease: a comparison of imaging methods.

UNLABELLED: This study of changes in dual energy x-ray absorptiometry (DXA) spine BMD following diagnosis and treatment for childhood Crohn's disease demonstrated that changes in conventional posteroanterior BMD results were confounded by impaired growth, and suggested that lateral spine measurements and strategies to estimate volumetric BMD were more sensitive to disease and treatment effects. INTRODUCTION: We previously reported significant increases in peripheral quantitative CT (pQCT) measures of trabecular volumetric bone mineral density (vBMD) following diagnosis and treatment of pediatric Crohn's disease (CD). The objective of this study was to compare pQCT trabecular vBMD and three DXA measures of spine BMD in this cohort: (1) conventional posteroanterior BMD (PA-BMD), (2) PA-BMD adjusted for height Z (PA-BMDHtZ), and (3) width-adjusted volumetric BMD (WA-BMD) estimated from PA and lateral scans. METHODS: Spine DXA [lumbar (L1-4) for posteroanterior and L3 for lateral] and tibia pQCT scans were obtained in 65 CD subjects (ages 7-18 years) at diagnosis and 12 months later. BMD results were converted to sex, race, and age-specific Z-scores based on reference data in >650 children (ages 5-21 years). Multivariable linear regression models identified factors associated with BMD Z-scores. RESULTS: At CD diagnosis, all BMD Z-scores were lower compared with the reference children (all p values <0.01). The pQCT vBMD Z-scores (-1.46 ± 1.30) were lower compared with DXA PA-BMD (-0.75 ± 0.98), PA-BMDHtZ (-0.53 ± 0.87), and WA-BMD (-0.61 ± 1.10) among CD participants. Only PA-BMD Z-scores were correlated with height Z-scores at baseline (R = 0.47, p < 0.0001). pQCT and WA-BMD Z-scores increased significantly over 12 months to -1.04 ± 1.26 and -0.20 ± 1.14, respectively. Changes in all four BMD Z-scores were positively associated with changes in height Z-scores (p < 0.05). Glucocorticoid doses were inversely associated with changes in WA-BMD (p < 0.01) only. CONCLUSIONS: Conventional and height Z-score-adjusted PA DXA methods did not demonstrate the significant increases in trabecular vBMD noted on pQCT and WA-BMD scans. WA-BMD captured glucocorticoid effects, potentially due to isolation of the vertebral body on the lateral projection. Future studies are needed to identify the BMD measure that provides greatest fracture discrimination in CD.

Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease.

Genome-wide association studies have implicated common variation at the 20q13 locus in inflammatory bowel disease, particularly for the pediatric Crohn's form. This locus harbors tumor necrosis factor receptor superfamily (TNFRSF6B), encoding a secreted protein, decoy receptor 3 (DcR3), which binds to and neutralizes pro-inflammatory cytokines of the tumor necrosis factor superfamily. We sought to further the evidence of DcR3's role in pediatric IBD by identifying missense mutations with functional significance within TNFRSF6B. We sequenced the exons of the gene in 528 Caucasian pediatric IBD cases and 549 Caucasian healthy controls to establish the frequency of such events in each population. Sequencing revealed that our IBD cohort harbored a greater number of missense variants, yielding an odds ratio of 3.9 (P-value=0.005). Using functional assays, we established that the frequency of mutants defective in secretion from cultured cells was greater in the Crohn's category than in the controls, yielding an odds ratio of 7.1 (P-value=0.004). These results suggest that rare defective variants in TNFRSF6B have a role in the pathogenesis of some cases of IBD and that interventions targeting this group of tumor necrosis factor-family members may benefit patients with IBD.

Paediatric parenting stress in inflammatory bowel disease: application of the Pediatric Inventory for Parents.

BACKGROUND: The psychosocial functioning of caregivers of adolescents managing inflammatory bowel disease (IBD) has been understudied; yet, poor caregiver functioning can place youth at risk for compromised disease management. The current study addressed this limitation by examining a sample of caregivers of adolescents with IBD. Study aims included (1) documenting rates of paediatric parenting stress; (2) identifying associated sociodemographic predictors of parenting stress; and (3) comparing previously published rates of parenting stress to those within other paediatric chronic conditions, including cancer, type 1 diabetes, obesity, sickle cell disease, bladder exstrophy. METHODS: Caregivers of adolescents with an IBD diagnosis (M(age) = 15.4 ± 1.4, 44.4% female, 88.7% Caucasian) and receiving tertiary care within a gastroenterology clinic (n = 62) completed the Pediatric Inventory for Parents (PIP) as a measure of paediatric parenting stress with frequency and difficulty as PIP subscales. Paediatric gastroenterologists provided disease severity assessments. RESULTS: Adolescents with IBD were experiencing relatively mild disease activity. Bivariate correlations revealed that PIP-difficulty was positively associated with Crohn's disease severity (r = 0.38, P < 0.01). Caregiver age was negatively associated with the frequency of parenting stress total (r = -0.25, P = 0.05) and communication scores (r = -0.25, P < 0.05). The frequency and difficulty of parenting stressors within the IBD sample were similar to rates within type 1 diabetes, but were significantly lower than rates identified in other paediatric chronic conditions. CONCLUSIONS: Caregivers of adolescents with IBD seem to experience low rates of parenting stress when their adolescents are receiving outpatient care and during phases of IBD relative inactivity. The sociodemographic characteristics of IBD families (i.e. primarily Caucasian, well-educated and higher socio-economic status) likely encourage greater access to financial and psychosocial resources, which may aid in promoting more optimal stress management.

Success rate and duration of paediatric outpatient colonoscopy.

BACKGROUND: The paediatric colonoscopy completion rates have rarely been reported. AIMS: We sought to evaluate colonoscopy completion rate and compare the rates using colonoscope versus enteroscope. METHODS: We prospectively investigated 60 patients who underwent colonoscopy between July 1999 and June 2001. The following data were collected: demographics, type of endoscope used, extent of colonoscopy, indication for procedure, histology, adverse events and time to reach the caecum and the terminal ileum. RESULTS: Sixty colonoscopies were performed during the study period, 30 with an enteroscope and 30 with a colonoscope. The caecum was reached in 56/60 (93%) and the terminal ileum in 50/60 (83%). An average time of 12.61 min (S.D. 7.3) was necessary to advance the instrument from the anus to the caecum, and additional 3.67 min (S.D. 3.62) to terminal ileum. There was no difference in the success rate between enteroscope and colonoscope. Six patients (10%) had definitive diagnosis established because a full colonoscopy was performed. No serious adverse events occurred. CONCLUSION: Paediatric colonoscopy to the caecum can be completed safely and expeditiously in more than 90% of procedures. Various types of instruments do not appear to influence completion rate. Full colonoscopy contributes to the establishment of a definitive diagnosis.

Growth after intestinal resection for Crohn's disease in children, adolescents, and young adults.

OBJECTIVE: Growth before and after intestinal resection for Crohn's disease (CD) was examined in a group of children, adolescents, and young adults. METHODS: Retrospective chart review of patients who had intestinal resections as clinical management of complications of CD between 1985 and 1996. Pre- and postoperative measurements of weight and height were reviewed. Z-scores were computed for weight-forage (WAZ), height-for-age (HAZ), and weight-for-height (WHZ). Two tailed t tests were used to compare postoperative growth patterns. Significance was defined as p < 0.05. RESULTS: Twenty-five subjects (8 females, mean age 16.2+/-2.8 years with one operation, and 3 males, mean age 15.7 years with multiple operations) were identified. There were significant improvements in the postoperative growth patterns of subjects who had one operation: HAZ (-1.28+/-1.45 versus -0.98+/-1.37, p = 0.041), WAZ (-1.35+/-1.02 versus -0.74+/-0.93, p = 0.0006) and WHZ (-0.64+/-0.95 versus -0.23+/-0.81, p = 0.036). Furthermore, the magnitude of postoperative weight gain directly correlated with the age at CD diagnosis, R2 = 0.16, p = 0.046. Trends towards improved postoperative WAZ (-0.83 versus -0.49) and HAZ (-0.47 versus -0.27) were also observed in the three subjects who had multiple operations. CONCLUSION: The pattern of weight and height growth was improved after intestinal resection for CD. Nonetheless, close monitoring of postoperative growth is necessary especially in children diagnosed with CD at a young age.

Chronic diarrhea. A practical approach for the pediatrician.

Despite the high prevalence of chronic diarrhea there is no universal approach to its diagnosis and treatment. This article summarizes the pathophysiologic processes that result in chronic diarrhea and presents a diagnostic and therapeutic approach to this often distressing problem.

Topical diphenhydramine toxicity in a five year old with varicella.

The toxic effects of oral diphenhydramine are well documented and include central nervous system and anticholinergic symptomatology. We present a case of diphenhydramine intoxication from combined oral/percutaneous medication. Overzealous application of a commercially available topical diphenhydramine preparation resulted in hallucinations and other side effects in a five-year-old child with varicella.

Povidone iodine as a cause of factitious hematuria and abnormal urine coloration in the pediatric emergency department.

The observation of a cola-colored dipstick positive for "hematuria" was made in an 11-year-old black male who presented to the emergency department with a chief complaint of dysuria. Thorough questioning eventually revealed the source of these two abnormalities to be the addition of povidone iodine to the urine sample. The reported causes of abnormal urine coloration and of false positive dipstick hematuria are summarized.

Inflammatory bowel disease in pediatric and adolescent patients.

IBD is a chronic pediatric disease that needs to be treated by a team of experts consisting of pediatricians, pediatric gastroenterologists, psychologists, nutritionists, social workers, and nurses. A critical factor in successful management of this disease is the willingness of the patient to participate and cooperate with the team. Parents and patients must be educated and supported to treat these disorders effectively. Much further research is necessary to understand the specific causative and therapeutic issues unique to young patients with IBD.

Up-regulation of glutathione S-transferase activity in enterocytes of young children.

The relationship between age and busulfan apparent oral clearance (Cl/F) expressed relative to adjusted ideal body weight and body surface area (bsa) was evaluated in 135 children aged 0 to 16 years undergoing hematopoietic stem cell transplantation for various disorders. Busulfan plasma levels were measured by gas chromatography-mass spectrometry after the first daily dose of the 4-day dosing regimen. Cl/F expressed relative to adjusted ideal body weight (ml/min/kg) and bsa (ml/min/m(2)) was lower in 9- to 16-year-old (y.o.) compared with 0- to 4-y.o. children (49 and 30%; p<.001). We hypothesized that the greater busulfan Cl/F observed in young children was in part due to enhanced (first-pass intestinal) metabolism. Busulfan conjugation rate was compared in incubations with human small intestinal biopsy specimens from healthy young (1- to 3-y.o.) and older (9- to 17-y.o.) children. Villin content in biopsy specimens was determined by Western blot and busulfan conjugation rate was expressed relative to villin content to control for differences in epithelial cell content in pinch biopsies. Intestinal biopsy specimens from young children had a 77% higher busulfan conjugation rate (p =.037) compared with older children. We have previously shown that glutathione-S-transferase (GST) A1-1 is the major isoform involved in busulfan conjugation, and that this enzyme is expressed uniformly along the length of adult small intestine. Thus, the greater busulfan conjugation activity in intestinal biopsies of the young children was most likely due to enhanced GSTA1-1 expression. We conclude that age dependence in busulfan Cl/F appears to result at least in part from enhanced intestinal GSTA1-1 expression in young children.

Nutrition and inflammatory bowel disease.

This article reviews the nutritional aspects of inflammatory bowel disease (IBD) including the mechanisms and manifestations of malnutrition and the efficacy of nutritional therapies. Nutrient deficiencies in patients with IBD occur via several mechanisms and may complicate the course of the disease. Nutritional status is assessed by clinical examination and the use of nutritional indices such as the Subjective Global Assessment of nutritional status. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need parenteral nutrition.

Crohn's disease monocytes are primed for accentuated release of toxic oxygen metabolites.

BACKGROUND: Inflammatory bowel disease occurs in regions of the intestine characterized by a bowel content high in bacteria. Intestinal bacteria synthesize cell wall products such as lipopolysaccharide; when normal monocytes or macrophages come in contact with these products, they can be primed to release a number of inflammatory mediators. Mediators such as toxic oxygen metabolites released as part of the respiratory burst may contribute to inflammatory tissue damage. The aim of this study was to determine if monocytes from patients with Crohn's disease are primed by lipopolysaccharide for a greater respiratory burst. METHODS: The generation of superoxide anion was measured by superoxide dismutase inhibitable reduction of ferricytochrome c. RESULTS: Freshly isolated monocytes from active untreated Crohn's disease patients (n = 8) showed enhanced stimulated release of superoxide anion when compared with normal monocytes (n = 15; 3.80 +/- 0.12 vs. 1.02 +/- 0.06 nmol/5 min; P < 0.001). We tested the hypothesis that the monocyte priming factor in Crohn's disease serum may be lipopolysaccharide by showing that Crohn's disease serum lost its ability to prime normal monocytes after lipopolysaccharide was removed (0.25 +/- 0.25 nmol/5 min, P < 0.001). CONCLUSIONS: These studies indicate that bacterial cell wall products may be important proinflammatory molecules involved in the initiation and/or perpetuation of Crohn's disease.

Failure of single-toxin assays to detect clostridium difficile infection in pediatric inflammatory bowel disease.

OBJECTIVES: The aims of this retrospective study were 1) to determine the ability of single-toxin assays for Clostridium difficile to detect infection among pediatric patients with inflammatory bowel disease (IBD) and 2) to determine the toxin assays routinely used by pediatric tertiary care hospitals in the United States. METHODS: Stool specimens from patients with IBD (submitted from January, 1996, to August, 1999) were evaluated for the presence of C. difficile toxin A and toxin B. Toxin profile (toxin A alone, toxin B alone, toxin A and B together) was compared in positive specimens. A phone interview was conducted with representatives from laboratories in 22 pediatric hospitals to investigate which toxin assays were routinely used. RESULTS: A total of 697 specimens were submitted from 284 IBD patients. In all, 81 IBD patients (28.5%) had at least one documented infection. Toxin A assay failed to identify 41.5% of C. difficile infections. Toxin B assay failed to detect 34.9% of C. difficile infections. Toxin profile changed in 55% of patients with multiple infections. Of the hospitals surveyed, 59% did not test for both toxins. CONCLUSIONS: Single-toxin assays for C. difficile fail to detect a significant percentage of infections. The toxins identified during one infection are not predictive of the toxins identified in subsequent infections. Despite this, many pediatric hospitals do not routinely use both toxin assays to diagnose C. difficile infection. When infection is suspected, assays for C. difficile toxin A and toxin B should be requested.

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.

Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis.

BACKGROUND: The effectiveness of 6-mercaptopurine combined with azathioprine in treating severe ulcerative colitis has been shown in several adult studies. Reported pediatric experiences are rare. The purpose of this study was to investigate the safety and the potential efficacy of 6-mercaptopurine and azathioprine in the treatment of active ulcerative colitis in a pediatric population. METHODS: The medical records of patients with active ulcerative colitis who were under observation at The Children's Hospital of Philadelphia and its satellite clinics from January 1984 through December 1997 were retrospectively reviewed. Patients were included who had received a diagnosis of ulcerative colitis, who met no criteria for Crohn's colitis, and who had received treatment with 6-mercaptopurine and azathioprine. They were then analyzed for the development of side effects, the indication to use 6-mercaptopurine and azathioprine, and the ability to discontinue corticosteroid use in those patients taking 5-acetylsalicylic acid products who were corticosteroid-dependent or whose disease was refractory to treatment. Excluded from the corticosteroid analyses were patients who underwent surgery for their disease and patients treated with 5-acetylsalicylic acid only. Statistical analysis was performed by the Kaplan-Meier survival curve and paired Student's t-test. RESULTS: In a review of 200 medical records of patients with active ulcerative colitis, 20 patients met the criteria. The patients' average age at the initiation of treatment with 6-mercaptopurine and azathioprine was 13.8 years. Sixteen patients (80%) were corticosteroid dependent and 3 (15%) had ulcerative colitis refractory to corticosteroid treatment. One patient had severe colitis treated with 5-acetylsalicylic acid only. Discontinuation of corticosteroid was accomplished in 12 (75%) of 16 patients. The median time to discontinuation of corticosteroid after initiation of 6-mercaptopurine and azathioprine therapy was 8.4 months. Eight patients (67%), observed from 3 months to 65 months, have continued without corticosteroid therapy. Side effects included pancreatitis and shingles that resulted in discontinuation of 5-acetylsalicylic acid, leukopenia corrected by withholding 6-mercaptopurine, and self-resolved hepatitis. CONCLUSIONS: The data support the safety of 6-mercaptopurine and azathioprine use in the treatment of pediatric patients with ulcerative colitis; side effects were minimal and reversible. Eighteen (90%) of 20 patients tolerated the therapy well. The results also show that 12 (75%) of 16 pediatric patients with ulcerative colitis will benefit from the use of 6-mercaptopurine and azathioprine after initial discontinuation of corticosteroid therapy. Although 6-mercaptopurine and azathioprine may not prevent further relapses, medical management of these flares may be less intense and may not require long-term corticosteroid use. Prospective clinical trials in pediatric patients are necessary to delineate further the role of 6-mercaptopurine and azathioprine in pediatric ulcerative colitis.

Pediatric Crohn's disease: risk factors for postoperative recurrence.

OBJECTIVE: Postoperative recurrence of Crohn's disease in adults has been extensively studied; however, the course of Crohn's disease after surgery in children has not been well defined. The aim of this study was to examine the postoperative course of pediatric Crohn's disease and the factors that may predict early postoperative recurrence. METHODS: We identified 100 resective surgeries in 79 children with Crohn's disease seen at the Children's Hospital of Philadelphia between 1978 and 1996. A retrospective, multivariable analysis of factors potentially influencing postoperative clinical recurrence was performed. Preoperative and postoperative height measurements were compared, and z scores were computed for height-for-age. Two-tailed t test was used for the analysis. RESULTS: Clinical recurrence rates were 17% at 1 yr, 38% at 3 yr, and 60% at 5 yr. Patients with colonic Crohn's disease had a significantly shorter postoperative recurrence-free interval (median 1.2 yr) than patients with ileocecal (median 4.4 yr) or diffuse disease (median 3.0 yr) (p = 0.01). On multivariable analysis, a high Pediatric Crohn's Disease Activity Index at the time of surgery (p = 0.01) and preoperative use of 6-mercaptopurine (6-MP) (p < 0.005) were also independently associated with higher postoperative recurrence rates. There was a significant improvement in z scores for height (p = 0.04) after surgery. CONCLUSIONS: In children undergoing resective surgery for Crohn's disease, high rates of postoperative Crohn's disease recurrence are associated with severe disease at the time of surgery, colonic Crohn's disease, and the preoperative use of 6-MP. Patients who require preoperative use of 6-MP are likely to suffer from a more aggressive disease and would benefit from postoperative 6-MP prophylaxis. Height growth was improved after intestinal resection for Crohn's disease.

Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children.

Numerous adult studies show a 30-65% response rate to azathioprine (AZA) or 6-mercaptopurine (6-MP) for significant perianal Crohn's disease. The aim of this study was to evaluate whether these drugs healed pediatric perianal Crohn's disease. Records of pediatric Crohn's patients were retrospectively reviewed for significant perianal disease treated with AZA or 6-MP for > or =6 months. The patient's perianal disease was reviewed and evaluated for fistulas, drainage, induration, and tenderness. In addition, the patients were given a score using the Irvine Perianal Disease Activity Index (PDAI). Patients were retrospectively scored upon initiation of treatment and after six months of therapy. Possible scores ranged from 0-20. Twenty patients met the study criteria. Five patients were considered treatment failures. One patient required a colostomy after 1.5 months of therapy, one developed pancreatitis, and three were noncompliant with therapy. Of the remaining 15 patients who were treated for > or =6 months, 67% had an improvement in drainage, 73% in tenderness, 60% in induration, and 40% in fistula closure. The mean Irvine PDAI was 7.67 +/- 2.19 initially and 4.40 +/- 1.72 after six months of therapy. The improvement was statistically significant (p < 0.001). AZA and 6-MP are effective treatments for healing significant perianal Crohn's disease in pediatrics.

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 Children's 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.