Oral tacrolimus treatment of severe colitis in children.

OBJECTIVE: To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis. STUDY DESIGN: Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted. RESULTS: Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy. CONCLUSION: Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.

A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease.

BACKGROUND & AIMS: Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD). We report the results of a prospective, placebo-controlled, multicenter trial evaluating the combination of 6-MP and prednisone as therapy for children with newly diagnosed moderate-to-severe CD. METHODS: Fifty-five children (age, 13+/-2 years) were randomized to treatment with 6-MP (1.5 mg x kg(-1) x day(-1)) or placebo within 8 weeks of initial diagnosis. Both groups also received prednisone (40 mg/day). Prednisone dosage adjustments were based on a defined schedule determined by the change in a subject's disease activity score, and steroid administration was discontinued as remission was achieved. Study treatment with 6-MP or placebo continued for 18 months. RESULTS: Groups were comparable for age, sex, and site and activity of disease. In the 6-MP group, the duration of steroid use was shorter (P<0.001) and the cumulative steroid dose lower at 6, 12, and 18 months (P<0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P = 0.007). Growth was comparable in both groups. No clinically significant adverse events occurred, although mild leukopenia and increases in aminotransferase activity were noted in the 6-MP group. CONCLUSIONS: Addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. 6-MP should be part of the initial treatment regimen for children with newly diagnosed moderate-to-severe CD.

Prevalence and pathogenesis of pancreatic acinar tissue at the gastroesophageal junction in children and young adults.

BACKGROUND: Pancreatic acinar tissue (PAT) at the gastroesophageal junction (GEJ) has been reported in 3% of adults with Barrett esophagus (BE) and in 24% of healthy subjects. The pathogenesis of this ectopic tissue is controversial. Both an acquired metaplastic process in the setting of BE and a congenital abnormality have been suggested in adults. OBJECTIVE: To clarify the origin of PAT at the GEJ. METHODS: We reviewed material obtained from the GEJ in 69 children and young adults. Each specimen was evaluated by 3 levels stained with hematoxylin-eosin for the presence of PAT, BE, esophagitis, and gastritis. Selected cases were also examined with immunohistochemical stains for lipase, trypsin, and amylase. RESULTS: In 16% of the study population, PAT was present at the GEJ and was not associated with BE. The prevalence of esophagitis and/or gastritis did not vary significantly between patients with and without PAT. CONCLUSIONS: Our data suggest that PAT at the GEJ develops independently of inflammation and is, therefore, likely to be congenital.

Ontogeny of renal dysplasia in Ivemark syndrome: light and immunohistochemical characterization.

Ivemark syndrome is a rare sporadic or autosomal recessive disorder characterized by pancreatic fibrosis, renal dysplasia and hepatic dysgenesis. There have been no data describing the renal changes during embryologic development in this syndrome. In this report, we document the pathological findings of the kidney in three subjects with Ivemark syndrome: 6 months, 21 weeks and 16 weeks, respectively. Kidneys of subjects and age-matched controls were examined by light microscopy and immunohistochemically for cytokeratin, AE1/AE3 and epithelial membrane antigen. Renal dysplasia in Ivemark syndrome becomes apparent at 16 weeks of gestation and progresses thereafter in severity. It is characterized by disturbance in glomerular differentiation, delay in tubular differentiation and abnormal expression of epithelial markers in glomeruli and tubules. Cytokeratin and epithelial membrane antigen expression of cysts is similar to that of the collecting ducts.

Endoscopic screening for dysplasia and mucosal aneuploidy in adolescents and young adults with childhood onset colitis.

OBJECTIVES: In adults, the premalignant nature of ulcerative colitis (UC) has long been accepted. Currently there is increasing concern that Crohn's disease (CD) may be equally premalignant. As a consequence, most adults with long-standing UC and many with chronic CD are enrolled in ongoing endoscopic cancer surveillance programs. In contrast, the risk of colonic cancer in adolescents and young adults with either form of colitis is less well recognized, and the need for dysplasia and cancer screening in this population has not been systematically evaluated. We therefore report the prospective results of colonoscopic cancer screening in such a young population. METHODS: Thirty-five adolescents and young adults with long-standing colitis (18 UC, 17 CD; 21 +/- 3 yr old, 11 +/- 3 yr colitis duration) underwent colonoscopic cancer screening. All had multiple biopsies for flow cytometry and light microscopy. RESULTS: Seven subjects had aneuploidy (3/18 UC, 4/17 CD). Of these seven, only two had dysplasia [one high grade (UC), one low grade (CD)]. One additional subject had indefinite dysplasia with normal flow cytometry. The remaining 27 subjects had both normal flow cytometry and light microscopy. Five of the seven aneuploid subjects underwent surgery within 1 yr of screening. Four, including both subjects with dysplasia, had no evidence of colon cancer at surgery. However, a 24-yr-old female with a 14-yr history of UC and no evidence of dysplasia or cancer at screening had a Dukes C adenocarcinoma. CONCLUSIONS: Adolescents and young adults with childhood onset UC or CD are at risk for aneuploidy, dysplasia, and colon cancer. Aneuploidy can be evident 10 yr after the onset of colitis and in patients as young as 16 yr of age. Therefore, the risk for colon cancer in patients with childhood onset colitis must be based on the duration of the illness, not on their chronological age. Incorporation of flow cytometry into an endoscopic screening protocol appears to enhance the ability to identify individuals at highest risk for colon cancer.

Highly destructive perianal disease in children with Crohn's disease.

The perianal complications of Crohn's disease (CD) seen in children and adolescents include skin tags, anal fissures, fistulae, and abscesses. While these lesions are often chronic and variably responsive to medical therapy, only rarely are they severely destructive. In this report, we characterize the frequency, severity, and clinical course of a highly destructive form of perianal disease (HDPD) that we have noted in a number of children and adolescents with Crohn's disease. A database containing records from 350 children with inflammatory bowel disease was reviewed to identify all children with CD treated between 1970 and 1993. For each, the occurrence or absence of significant perianal pathology, including fistula, abscess, and HDPD, was determined. Pertinent clinical details were recorded for all patients. In addition, the clinical characteristics of those children with HDPD were compiled, and the courses of those with HDPD characterized. A search of the database identified 230 children and adolescents with CD followed for a total of 1,518 patient years. Sixty-seven of these patients (29% of the CD population) had significant perianal pathology. This included 6 with HDPD, 8 with complicated fistulae [rectourethroperineal (1), rectovaginal (1), rectolabial (2), and multiple communicating perineal (4)], and 53 with simple perianal fistulae or abscesses. All six with HDPD had deeply destructive perineal ulcerations, marked undermining of the perineal and perirectal tissues, and copious exudate, and often there was a deeply cleaved or fileted perineum on separating the buttocks. Two children with HDPD had fecal incontinence.

Atypical rectosigmoid histology in children with newly diagnosed ulcerative colitis.

BACKGROUND: In the untreated patient with inflammatory colitis, rectal sparing or patchy rectal inflammation is generally considered a sign of Crohn's disease (CD), rather than ulcerative colitis (UC). METHODS: The initial endoscopic rectosigmoid mucosal biopsies obtained at disease onset from 12 untreated children with UC who ultimately required surgery were blindly reviewed (randomly mixed with another 62 specimens obtained from children with CD or treated UC). Biopsies were classified as typical UC if there was diffuse, active inflammation and severe crypt destruction or distortion. Those with patchy, active inflammation and only mild crypt changes were classified as CD. Because all 12 subjects had ultimately been proven to have UC by examination of a subtotal colectomy specimen, for the purposes of this report biopsies read as either normal or CD were both considered evidence of atypical UC with rectal sparing. RESULTS: Five of 12 subjects (seven biopsies) had atypical histology. Mild, patchy inflammation was seen in six rectal or sigmoid biopsies, whereas one rectal biopsy was normal. The remaining seven subjects (10 biopsies) had diffuse inflammation. Two of five subjects with atypical biopsies had an endoscopically normal rectosigmoid, one had patchy inflammation, and the remaining two had diffuse endoscopic changes. All seven subjects with typical UC histology had diffuse endoscopic changes. Subjects with atypical findings could not be differentiated by age, duration, or types of symptoms at presentation, years of disease at colectomy, or indications for colectomy. CONCLUSIONS: Patchy or absent inflammation of the rectum and sigmoid can be present in untreated children with UC at disease onset. Because such children may be mistakenly diagnosed as having CD, these data must be considered when treatments or clinical research protocols are designed to include children with colitis.

The morphologic relationship of sinus and fistula formation to intestinal stenoses in children with Crohn's disease.

Sinus and fistula (SF) formation in adults with Crohn's disease has been ascribed to increased intraluminal pressure from stenotic lesions or to inflammation. We retrospectively evaluated 55 surgically resected specimens from 30 children with Crohn's disease for stenotic lesions, sinuses, fistulas, and inflammation. Eighteen of 30 children had one operation, and there were 12 multiple surgeries. Thirty-one of 55 specimens (56%) contained stenoses. SF formation was seen in 16 of 31 specimens with stenosis; it developed proximal to the stenosis in seven patients, distal in five, and both proximal and distal in four. SF formation was also noted in 12/24 specimens without stenosis. In 93% of the cases, the SF was associated with moderate to severe inflammation. Although 56% of the patients had stenoses, SF frequently developed independent of stenosis. All SF were associated with inflammation. Therefore, inflammation rather than increased intraluminal pressure appears to be the primary factor in SF formation in children with Crohn's disease.

Growth failure in pediatric inflammatory bowel disease.

To assess whether children with inflammatory bowel disease (IBD) develop permanent impairment of linear growth, we analyzed records from 48 young adults who had IBD during childhood or early adolescence (Tanner I-III; 11.8 +/- 2.4 years old at diagnosis). All were fully grown (Tanner V; 21.1 +/- 3.0 years) at last examination. Adult heights were predicted from data obtained at or shortly after the diagnosis of IBD by three methods: height for age percentile, the Bailey-Pinneau (BP), and Roche-Wainer-Thissen (RWT) methods. Predicted adult heights were then compared with the actual ultimate height of each subject. Permanent growth failure occurred in 19-35% of subjects, depending upon the method used to assess growth. Overall, 31% (15 of 48) of the subjects had deficits of adult height identified by two or more methods, including 14 of 38 (37%) of those with Crohn's disease but only one of 10 with ulcerative colitis. Age at diagnosis of IBD, age at last examination, age at cessation of linear growth, and site of IBD did not differ between impaired and normal growth groups. Duration of corticosteroid use was longer (p < 0.05) in growth-impaired subjects. In addition, although 60% of all subjects had periods of poor growth that put them in height-for-age percentiles two or more major growth channels below previous percentiles, only 19% remained at these levels upon achieving their final adult heights. Permanent impairment of linear growth leading to clinically meaningful deficits of ultimate adult height is common in patients with IBD in childhood or early adolescence. New therapeutic approaches are needed to address this problem.

Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum.

We report the results of a survey of the membership of the North American Society for Pediatric Gastroenterology and Nutrition designed to determine pediatric gastroenterologists' attitudes toward the use of immunosuppressive therapy for inflammatory bowel disease (IBD), and to assess how these medications are actually being used in the treatment of children with IBD. One hundred five physicians (27% of surveys) responded. Eighty-eight (84%) had prescribed 6-mercaptopurine and/or azathioprine for IBD, and 66 believed that they were effective. Only 12 had used cyclosporine and four methotrexate. All physicians who had used immunosuppressives in IBD had prescribed them for patients with Crohn's disease, but only 50% had prescribed them for ulcerative colitis. The predominant indications for use included intractable symptoms despite traditional medical therapy (92%) and for corticosteroid-sparing effects (86%). Potential toxicities of greatest concern included marrow and immune suppression and malignancy. The vast majority of responders were not certain what to recommend with respect to the use of immunosuppressive agents prior to and during pregnancy. A clinical database was compiled from 165 retrospective case reports submitted by 45 physicians (33 medical facilities). At the start of immunosuppressive therapy, patients were 15.3 +/- 4.0 yr of age, and 52% were Tanner IV-V. Eighty-one percent had Crohn's disease, 8% ulcerative colitis, and 11% indeterminant colitis. One hundred twenty-two were treated with 6-mercaptopurine, and 43 with azathioprine. Five also received cyclosporine concomitantly. Overall, 68% of patients treated with an immunosuppressive improved. Complications requiring discontinuation of immunosuppressive therapy occurred in 6% of patients. It appears that immunosuppressives are commonly used to treat children with IBD despite a paucity of data regarding their safety and efficacy in this age group. Controlled, prospective trials are warranted to better define the role of immunosuppressive therapy in pediatric IBD.

Hepatic pathology in pediatric acquired immunodeficiency syndrome.

In a retrospective study we assessed the hepatic changes in children with the acquired immunodeficiency syndrome by reviewing 12 biopsy specimens and 48 autopsy specimens from 54 children. Hepatopathology differed in biopsy and autopsy material. In biopsy specimens, chronic active hepatitis with predominantly T8 lymphocytes by tissue immunochemistry was common (five of 12 specimens). Fatty degeneration and hepatocellular necrosis were either absent, mild, or patchy. On the other hand, at autopsy, chronic active hepatitis was not observed. The most prominent changes were extensive fatty degeneration, nonspecific portal mononuclear infiltration, portal fibrosis, and confluent (ischemic) necrosis. Opportunistic infections such as Mycobacterium avium-intracellulare (MAI) were noted only at autopsy. In addition, three unusual morphologic characteristics were noted: nodular lymphoplasmacytic portal infiltrate, a pseudosarcomatous variant of Mycobacterium avium-intracellulare infection, and multinucleated giant cells (foreign both type and giant cell transformation of hepatocytes).

Immunology of inflammatory bowel disease: summary of the proceedings of the Subcommittee on Immunosuppressive Use in IBD.

As outlined, scanty data exist with regard to immunologic therapy in children with IBD despite the fact that the pediatric population affords a unique opportunity for clinical evaluation. Children are less affected by modifying conditions such as smoking, alcohol ingestion, and the long-term use of medications, and because of their specific needs for ponderal and linear growth, children might benefit most from immunological therapy that has been proven to be steroid sparing. Therefore, clinical trials to evaluate the efficacy of 6-MP and/or azathioprine in growing children with Crohn's disease would appear to provide a fruitful avenue for collaborative research. Efforts to organize a multicenter evaluation of these agents have been initiated. The studies are crucial in evaluating the efficacy and safety of immunosuppressive therapy in the pediatric population with IBD.

Neuronal intestinal dysplasia: quantitative diagnostic criteria and clinical management.

Neuronal intestinal dysplasia (NID) clinically resembles Hirschsprung's disease but is characterized by hyperplasia rather than aganglionosis of the intramural plexus. Surgical intervention is common. We report the 5-year follow-up of an infant with the mixed form of NID managed medically and a method by which NID can be quantified histologically. Hyperganglionosis was determined by counting the number of ganglia per high-power field and the number of ganglion cells per ganglia from at least two biopsy specimens. The patient's biopsies and biopsies from "normal" and "inflamed" patients were compared. Normals contained 0.68 +/- 0.28 (mean +/- SD) ganglia per high-power field and 2.16 +/- 0.31 ganglion cells per ganglion. The inflamed biopsies were similar, 0.69 +/- 0.38 ganglia per high-power field and 2.63 +/- 0.40 ganglion cells per ganglion. The patient's initial rectal biopsy revealed 7.6 ganglia per high-power field and 3.8 ganglion cells per ganglion. Management of the patient included saline colonic irrigations and hyperalimentation with gradual reinstitution of breast-feeding. Clinical improvement was associated with normalization of manometry and biopsy findings, a phenomenon not documented previously in the literature. Irrigations were stopped at age 9 months, and the child is now asymptomatic.

Long-term 6-mercaptopurine treatment in adolescents with Crohn's disease.

Although 6-mercaptopurine is often used to treat adolescents with intractable Crohn's disease, its long-term efficacy has not yet been studied in this population. This study shows data derived from 36 adolescents (mean age +/- SD, 16.5 +/- 3.3 years; 27 males, 9 females) treated at least 6 months with 6-mercaptopurine (1.5 mg.kg-1.day-1, maximum of 75 mg/day). Sites of Crohn's disease at the start of 6-mercaptopurine therapy included 17 ileocolic, 9 pancolic, 7 small bowel, and 3 partial colon. All had received corticosteroids, sulfasalazine, antibiotics, and nutritional support for 5.0 +/- 3.0 years before administering 6-mercaptopurine, but intractable symptoms persisted. Disease activity lessened during the first year of 6-mercaptopurine, reflected by a higher Lloyd-Still disease activity score (pre, 64 +/- 9 vs. 6-mercaptopurine, 72 +/- 11; P less than 0.0001). General activity, physical examination, nutrition, and laboratory subscores all improved (P less than 0.004). Lessened disease activity occurred despite concomitant decrease in duration of prednisone use (pre, 9.5 +/- 4.2 vs. 6-mercaptopurine, 6.6 +/- 4.9 months/year; P less than 0.001) and cumulative annual prednisone exposure (pre, 3672 +/- 2106 vs. 6-mercaptopurine, 1964 +/- 1460 mg; P less than 0.0007). The frequency of perianal fistulae and abscesses also decreased (P less than 0.01) during treatment. Annual rates of hospitalization decreased in 44% of subjects during 6-mercaptopurine treatment, while increasing in only 22%. Follow-up beyond 1 year of 6-mercaptopurine treatment showed continued remission in 23 of 30 subjects. No serious complications were seen. 6-mercaptopurine is an effective long-term therapy for adolescents with intractable Crohn's disease. While inducing remission, it also has a significant steroid-sparing effect which may be of particular benefit to this population.

Home nocturnal supplemental nasogastric feedings in growth-retarded adolescents with Crohn's disease.

We hypothesized that supplemental nutritional support delivered at home by nocturnal nasogastric feedings would result in accelerated growth in growth-retarded adolescents with Crohn's disease. Eight Tanner stage I adolescents with Crohn's disease, mean age 14 yr 5 mo, had a mean weight gain of 0.38 kg and height gain of 1.4 cm for the year before initiation of nasogastric feedings. All had been either asymptomatic or had only minimal symptoms in the year before the study, but were ingesting only 55%-80% of their daily required caloric intake. The subjects were taught to pass by themselves a nasogastric feeding tube, through which 1000-1500 ml of commercial, nonelemental isocaloric formula was infused during sleep to supplement their usual dietary intake. After 12 mo of nocturnal feedings, the subjects had a mean weight gain of 11.75 kg and a mean height gain of 6.98 cm. Six control subjects, matched for age and degree of growth and sexual retardation at the beginning of the study period, but who had refused the nasogastric feedings, had no change in weight and height during the same period of observation. We conclude that home nocturnal nasogastric feedings can achieve dramatic improvement in weight gain and linear growth in motivated adolescents with Crohn's disease and growth retardation.

Prognostic significance of epithelioid granulomas found in rectosigmoid biopsies at the initial presentation of pediatric Crohn's disease.

The prognostic significance of epithelioid granulomas in Crohn's disease (CD) remains controversial. We have determined the prognostic significance of epithelioid granulomas noted in endoscopic rectosigmoid biopsies obtained from untreated pediatric patients at initial presentation of CD. Data collected from 19 subjects with rectosigmoid granulomas and inflammation (Group 1) were compared to those obtained from another 37 subjects (Group 2) with CD of the rectosigmoid, but in whom no granulomas were present. Both groups had similar ages at disease onset [Group 1: 11.6 +/- 3.6; Group 2: 10.4 +/- 4.0 years (X +/- SD)]. At diagnosis, Group 1 had more extensive CD (small bowel and colon involvement, with Group 1 74% versus Group 2 30%; isolated rectosigmoid involvement, with Group 1 11% versus Group 2 35%; p less than 0.01). Perianal disease was also more common in Group 1 (58% versus 27% Group 2; p less than 0.05). However, CD activity scores and clinical laboratory findings were comparable. Duration of follow-up was identical (5.6 +/- 3.3 years) for both groups. By the end of the period of follow-up, 43% of Group 2 had developed small bowel involvement, but Group 1 continued to have more extensive CD (p less than 0.05). Perianal fistulae and abscesses and anal stenosis were more frequent in Group 1. Throughout this period, the need for oral and parenteral corticosteroids, 6-mercaptopurine, and nutritional support modalities were similar in the two groups. Although the number of subjects requiring hospitalization and the number of hospitalizations per patient were similar in both groups, Group 1 had more surgery (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloidosis in children with inflammatory bowel disease.

Reactive systemic or secondary amyloidosis occurs in 1-29% of adults with Crohn's disease, but only sporadic cases of amyloidosis have been recognized in children with inflammatory bowel disease. We therefore have studied operative specimens (ileal, ileocolonic, and colonic) from 46 children (30 with Crohn's disease and 16 with ulcerative colitis) to determine the frequency of amyloid deposits. Sections of bowel, skin, and lymph nodes (n = 940) were stained by Congo red and examined by light microscopy and by polarized light. Amyloid deposits were found in only one of 46 subjects, an 18-year-old girl who had had Crohn's disease for 6 years. Intestinal amyloid deposits, present 16 months before the clinical diagnosis of amyloidosis, were patchy and seen predominantly in the intestinal mucosa. We conclude that amyloidosis is rare in children requiring surgery for Crohn's disease and ulcerative colitis. Examination of Congo red-stained sections can detect even subclinical amyloidosis. The amyloid deposits in our patient, which were both patchy and consistently mucosal, suggest that multiple endoscopic biopsy samples, not necessarily containing submucosa, are sufficient for diagnosis.