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.

Quality of life in inflammatory bowel disease: background and definitions.

Defining and measuring quality of life is a relatively new dimension of health care for many clinicians. The traditional method of evaluating clinical status and response to treatment has been to look at disease-specific symptoms, global assessments (e.g., impressions of the good, better, or worse condition of a patient), days missed at school, and a variety of disease activity scores. These impressions and techniques may or may not reflect how patients are functioning day to day and how they feel about the illness. To address these issues, health-related quality of life questionnaires have been developed to measure the functional effect of an illness and its treatment on a patient, as perceived by the patient. There are four broad domains that are considered part of a health-related quality-of-life questionnaire: 1) physical and occupational function, 2) psychologic state, 3) social interaction, and 4) somatic sensation. In the case of children, the perception of parents or caretakers may be added to complete the picture. Significant social and psychiatric problems have been described in children with IBD, including absenteeism from school, depression, suicide, and major disruption of family patterns. To understand fully the impact of inflammatory bowel disease and its treatment on patient and family function requires one or more quality-of-life instruments that are sensitive to the full range of symptoms, growth and development, and response (including side effects) to many new therapies.

Treatment of obstructive jaundice in erythroblastosis fetalis with ursodeoxycholic acid (UDCA): a case report.

OBJECTIVE: To report a significant improvement of direct hyperbilirubinemia values, in an infant with cholestasis secondary to erythroblastosis fetalis, after treatment with ursodeoxycholic acid (UDCA). STUDY DESIGN: Case report. RESULTS: A full term infant, with total and direct bilirubin values of 26 mg/dl (445 micromol/l) and 24.5 mg/dl (419 micromol/l), respectively, on the third day of life, had total and direct bilirubin values of 8.2 mg/dl (140 micromol/l) and 6.9 mg/dl (118 micromol/l), respectively, after 2 days of treatment with UDCA. Because the natural course of this cholestasis takes several weeks to resolve, the observed improvement is highly suggestive of a direct effect of UDCA on the disease course. CONCLUSION: This treatment may add a new therapeutic option to the limited measures available for this condition, although further studies regarding safety and its mechanism of action are needed before it can be routinely recommended.

Balloon pulmonary valvuloplasty and stent implantation. For peripheral pulmonary artery stenosis in Alagille syndrome.

We report the case of a patient with Alagille syndrome and severe pulmonary valve and bilateral pulmonary artery branch stenosis. In this patient, transcatheter balloon pulmonary valvuloplasty combined with bilateral pulmonary artery angioplasty and stent placement provided excellent immediate results and long-term improvement.

Mechanisms of growth retardation, drug therapy, and nutritional support in pediatric inflammatory bowel disease: a workshop sponsored by the north american and European societies for pediatric gastroenterology and nutrition.

SUMMARY: : Growth retardation is common in children with inflammatory bowel disease (IBD). The most sensitive measure of impaired growth, growth velocity, is abnormal in 65% of children with Crohn's disease. With treatment, growth velocity may return to normal, but catch-up growth is often incomplete and ultimate height lower than predicted. In some patients delayed puberty may compensate for poor growth earlier in life, and there is good evidence that even after menarche, significant growth can occur. Surgery may have a favorable impact on growth in the short term, but final height often remains reduced. The mechanism for growth failure in IBD is thought to be related to both prolonged periods of suboptimal nutritional intake and persistent inflammation. Growth throughout childhood is dependent on growth hormone and insulin-like growth factors (IGF). At puberty, androgens and estrogens also play a significant role in normal growth. Both malnutrition and inflammatory bowel disease result in low levels of IGF-1. With recovery, levels return to normal. Although little work has been done to measure the effects of chronic maintenance drug therapy on growth, it is known that children taking alternate-day prednisone grow normally and can exhibit catch-up growth. Nutritional therapy with tube feeding of elemental diets also improves nutrition and decreases inflammation. Children with either small-bowel Crohn's or Crohn's ileocolitis respond to tube feedings of both elemental or semielemental diets.

Limy bile syndrome.

Limy bile syndrome (LBS) is a rare condition in which a radiopaque gallbladder and/or bile ducts are noted on plain roentgenograms. LBS is caused by calcium carbonate precipitation in the bile and is usually associated with distal biliary tract obstruction. The etiology of limy bile syndrome is unclear; however, it may be a long-term complication of total parenteral nutrition.

Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial.

The safety and efficacy of olsalazine sodium was compared to sulfasalazine over 3 months in a multicenter, randomized, double-blind study of 56 children with mild to moderate ulcerative colitis. Twenty-eight children received 30 mg/kg/day of olsalazine (maximum, 2 g/day) and 28 received 60 mg/kg/day of sulfasalazine (maximum, 4 g/day). Side effects were frequent in both groups. Eleven of 28 patients (39%) on olsalazine reported headache, nausea, vomiting, rash, pruritus, increased diarrhea, and/or fever. Thirteen of 28 on sulfasalazine (46%) reported similar side effects and/or neutropenia, and four patients had the drug stopped because of an adverse reaction. After 3 months, 11 of 28 (39%) on olsalazine were asymptomatic or clinically improved, compared to 22 of 28 (79%) on sulfasalazine (p = 0.006). In addition, 10 of 28 patients on olsalazine versus one on sulfasalazine required prednisone because of lack of response or worsening of colitis (p = 0.005). The dose of olsalazine used in this clinical trial was thought to be equivalent to a standard dose of sulfasalazine, but fewer patients on olsalazine improved and a greater number had progression of symptoms when compared to sulfasalazine. Although side effects were slightly less frequent for olsalazine, the number of patients was too small to detect a clinically significant difference.

Relationship of common laboratory parameters to the activity of Crohn's disease in children.

The Pediatric Crohn's Disease Activity Index (PCDAI) has been proposed as a simple instrument to aid in the classification of patients by disease severity. The PCDAI includes subjective patient reporting of symptoms, physical examination, nutritional parameters, and several common laboratory tests (hematocrit, erythrocyte sedimentation rate, albumin). In this report we examine the relationship of each of the laboratory parameters to the PCDAI, as well as to a modified Harvey-Bradshaw Index score and physician global assessment of disease activity. Data were gathered from the clinical and laboratory observations from 133 children and adolescents at 12 pediatric gastroenterology centers in North America. A statistically significant relationship (p less than 0.05) was noted between each of the laboratory tests and the PCDAI for patients with either disease limited to the small bowel or in those with colonic involvement. For patients with disease limited to the small bowel, a statistically significant (p less than 0.05) relationship was also noted between the three laboratory parameters and the modified Harvey-Bradshaw Index and global assessment. For patients with large-bowel involvement, the erythrocyte sedimentation rate was statistically related to the modified Harvey-Bradshaw Index and global assessment (p less than 0.01), as was hematocrit to global assessment (p less than 0.01). Although the laboratory parameters used in the PCDAI appear to generally reflect disease activity in most patients, no single laboratory test is adequate to reflect disease activity in all patients. Future work will need to identify additional laboratory measures to reflect the inflammatory process and serve as important adjuncts in the assessment of disease activity.

Development and validation of a pediatric Crohn's disease activity index.

Clinical and laboratory observations of 133 children and adolescents with Crohn's disease were used to validate an index of severity of illness previously developed by a group of senior pediatric gastroenterologists at a research forum in April 1990. This pediatric Crohn's disease activity index (PCDAI) included (a) subjective reporting of the degree of abdominal pain, stool pattern, and general well-being; (b) presence of extraintestinal manifestations, such as fever, arthritis, rash, and uveitis; (c) physical examination findings; (d) weight and height; and (e) hematocrit, erythrocyte sedimentation rate, and serum albumin. Independent evaluation of each patient by two physician-observers was performed at the time of a visit, and each physician completed a PCDAI index and a modified Harvey-Bradshaw index and made a "global assessment" of disease activity as none, mild, moderate, or severe. Excellent interobserver agreement was noted for the PCDAI, modified Harvey-Bradshaw index, and global assessment. There was a strong correlation between global assessment and both the PCDAI or modified Harvey-Bradshaw. Increasing PCDAI scores were noted with increasing disease severity, and significant differences in scores were noted between the severity groups. We propose that the PCDAI could be used in multicenter projects to facilitate patient stratification by disease severity and that longitudinal PCDAI scores might provide a numerical measure of response to therapeutic regimens.

Liver transplantation for cholesteryl ester storage disease.

This case describes a patient with cholesteryl ester storage disease who underwent liver transplantation for progressive cirrhosis, portal hypertension, ascites, and uncontrollable gastrointestinal bleeding. Four and one-half years posttransplant, her growth improved, cholesterol levels have returned to normal, and she is clinically well except for mild hypersplenism and an elevated blood urea nitrogen (BUN) and creatinine. Serum triglycerides remain elevated, but there have been no signs of progressive renal, intestinal, vascular, or pulmonary disease.

Hepatocellular transplantation in acute hepatic failure and targeting genetic markers to hepatic cells.

Orthotopic liver transplantation (OLT) represents the only therapeutic option for many patients with end-stage liver disease as well as many inborn genetic errors of hepatic metabolism. Despite dramatic progress in methods for OLT, the utilization of this procedure is limited by its considerable morbidity and mortality, by a chronic shortage of organs for transplant, and by difficulty arranging funding for many patients. Many children with fulminant hepatic failure do not receive OLT because this technology is unavailable or unaffordable. Hepatocellular transplantation (HCT), in which isolated, heterologous hepatocytes from a donor liver would be infused into the diseased organ in order to provide essential hepatic functions, could provide a much needed therapeutic alternative to OLT in the treatment of some causes of hepatic insufficiency. Experiments in animals have demonstrated that several genetic deficiencies of hepatic metabolism as well as experimental induced hepatic failure in animals can be reversed by HCT. Despite this experience, HCT has never been attempted in human subjects. This protocol represents the first proposed clinical trial of HCT. We are proposing a clinical trial in which HCT would be attempted as a therapeutic intervention in children with acute hepatic failure who have no other medical or surgical options. This proposal is intended to establish surgical methods for HCT and to evaluate the feasibility of this procedure for treating hepatic disease in humans. It is our expectation that HCT may provide short-term support for patients awaiting organ availability, a "bridge to recovery" allowing patients with fulminant hepatic failure to recover, or a long-term repopulation of the patient's liver with healthy donor cells. One of the major limitations of many animal studies in HCT is that, since the donor hepatocytes are often indistinguishable from those of the host, it has often been difficult to demonstrate a clear correlation between engraftment and the therapeutic effect. In order to verify engraftment independent of the therapeutic response, we propose to "mark" the donor hepatocytes by transducing these cells with a recombinant retroviral vector (LNL6) carrying a marker gene (NEO-R, neomycin phosphoribosyl transferase). The presence of this marker will enhance the ability to identify transplanted cells in the host using assays for the NEO-R gene or transcribed NEO-R mRNA. The LNL6 vector has been approved for human use and has been used as a marker gene for transplanted cells in human subjects without any reported adverse effects. We would like to emphasize that this is a proposal with therapeutic intent.(ABSTRACT TRUNCATED AT 400 WORDS)