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.

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.

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.

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)

Total parenteral nutrition-related cholestasis in infants.

An epidemiological study was conducted to estimate the proportion of infants on total parenteral nutrition (TPN) who developed cholestasis and to identify risk factors associated with the development of this disease. Data were abstracted from medical records of 624 infants less than or equal to 30 days of age who were treated with TPN. A case of TPN-related cholestasis was defined as an infant whose serum level of direct bilirubin was greater than or equal to 1.5 mg/dl subsequent to initiation of TPN. Risk factors were assessed using multiple logistic regression analysis. Forty-six of 624 infants in the cohort (7.4%) were classified as having TPN-related cholestasis. The multivariable analysis indicated that cholestasis was associated with intracranial hemorrhage, patent ductus arteriosus, sepsis and gastrointestinal conditions that require surgery. Two distinct processes appear to have occurred: in infants who experienced patent ductus arteriosus or intracranial hemorrhage (conditions associated with hypoxia) where TPN may be the necessary trigger for the development of cholestasis, and in infants with gastrointestinal conditions requiring surgery or sepsis, where cholestasis may develop with or without parenteral infusions.

Splanchnic bed vascular malformations and the development of portal hypertension.

The vascular lesions, angiomas, and arteriovenous malformations are known to be associated with a number of complications. These lesions, when present in the liver, may precipitate heart failure in infants. Recent reports suggest that although the prognosis is good for the majority of infants who survive the neonatal period, the lesions are capable of causing portal hypertension later in life. We have encountered three patients whose vascular lesions were in continuity with the portal circulation who subsequently went on to develop portal hypertension. One patient had angiomas of the liver, one splenic and colonic angiomas, and the third had diffuse arteriovenous malformations of the intestine. Data are presented and literature is reviewed, which suggest that any vascular lesion that is capable of substantially increasing portal blood flow may lead to the development of portal hypertension. The treatment of such lesions should be aggressive. If surgical management is not possible, alternative treatments such as embolization should be attempted early in order to increase the chance for successful therapy.

Immunodeficiency secondary to structural intestinal defects. Malrotation of the small bowel and cavernous hemangioma of the jejunum.

Two patients with gastrointestinal tract abnormalities were discovered to have significant defects in both humoral and cellular immunity. Patient 1, a 4-year-old girl with suspected food allergy, failure to thrive, and chronic diarrhea, exhibited a decreased serum IgG immunoglobulin level, decreased numbers of peripheral blood T lymphocytes (erythrocyte rosettes), decreased numbers of T-lymphocyte subpopulations (T3+, T4+), decreased responses of lymphocytes to common mitogens, and absent in vivo responses to delayed hypersensitivity skin test antigens. Patient 2, a 3-year-old girl with chronic anemia, presented with immunological abnormalities similar to those of patient 1. On investigation, both patients were found to have significant structural abnormalities of the gastrointestinal tract. Patient 1 had a malrotation of the small bowel, while patient 2 had a cavernous hemangioma of the mid-jejunum. Following surgical correction of the gastrointestinal abnormalities, there was improvement in all immunologic values. By ten to 18 months after surgery, both patients demonstrated normal immunological function. Thus, anatomic lesions of the gastrointestinal tract that mimic more common childhood disorders, such as food allergy and anemia, may produce serious states of secondary immunodeficiency.

Guide to early diagnosis of biliary obstruction in infancy. Review of 143 cases.

Presenting characteristics, long-term outcome, and techniques used in the diagnosis of 143 infants with suspected biliary obstruction are reviewed. Sixty-nine patients had surgically confirmed extrahepatic disease and 74 had intrahepatic disorders. A disproportionate number of infants with intrahepatic disease were boys (p = 0.013), low birthweight (p = 0.001), or had siblings with liver disease (p = 0.017). An initial total bilirubin of 20 mg/dl or greater was rare except in the intrahepatic disease category of neonatal hepatitis of known cause (p = 0.006). The initial percutaneous liver biopsy correctly predicted the ultimate diagnosis in 94 percent of all 143 patients. A methodological outline to diagnosis is presented, emphasizing early recognition of symptoms and careful follow-up with hepatobiliary imaging, liver biopsy, and surgical exploration, if required, until definitive diagnosis is made. This approach has aided us in reducing the age of diagnosis of biliary atresia from 12.8 +/- SD 7.3 weeks during the period 1971 through 1979 to 6.8 +/- SD 2.6 weeks from 1980 to 1982 (p = 0.0015). Eighteen-month survival has improved from 25 to 60 percent.

Clinical response to short-term nasogastric feeding in infants with gastroesophageal reflux and growth failure.

When conventional treatment with upright positioning and thickened feedings fails to control vomiting associated with gastroesophageal reflux (GER) of infancy, malnutrition and growth failure may result. If this occurs, fundoplication is usually recommended. In this study, 12 infants with growth failure associated with GER were given a trial of short-term (11.1 +/- SE 1.6 days) continuous-drip nasogastric (NG) feedings prior to surgical referral. Five of 10 infants for whom long-term follow-up (3-12 months) was obtained showed immediate weight gain, cessation of vomiting, and long-term resolution of growth failure without the need for surgery. All infants who had a favorable long-term response showed evidence of catch-up growth during the first 7 days of NG feeding. Infants who did not begin catch-up growth during the first 7 days did not benefit from longer periods (up to 21 days) of NG feeding. Poor response to NG feedings was associated with the presence of other medical problems (p = 0.024), including chronic pulmonary disease, malabsorption, cerebral palsy, and laryngomalacia. Four infants who did require fundoplication still showed no improvement in growth 2-6 months after surgery. In infants with GER and growth failure without other complicating disorders, a 7-10-day course of NG feeding may improve nutrition and bring about a permanent resolution of vomiting.

Complications of gastroesophageal reflux in patients with cystic fibrosis.

Seven patients with cystic fibrosis who had complications of gastroesophageal reflux including abdominal pain, peptic esophagitis, upper gastrointestinal hemorrhage, and esophageal stricture are described. We believe that these are gastrointestinal complications of CF and that they may be responsible for significant morbidity. The mechanical influence of a depressed diaphragm caused by hyperinflation, along with increased abdominal pressure with chronic coughing, may contribute to GER in CF. Early detection and treatment are important not only to prevent esophageal complications but also to increase the quality of life by relief of pain and by avoiding the resultant decrease in appetite, which can contribute to malnutrition.

Childhood acute leukemia: a search for occult extramedullary disease prior to discontinuation of chemotherapy.

Between January 1978 and September 1979, 29 children with acute leukemia in complete continuous remission for three or more years were examined for evidence of occult extramedullary disease immediately prior to discontinuation of chemotherapy. Bilateral open wedge testicular biopsy demonstrated the presence of bilateral leukemic infiltrates in 2/13 boys. Gallium scans prior to biopsy had identified unilateral infiltration in an enlarged testis in one patient but failed to identify microscopic disease in the opposite testis or in the testes of the second patient. Percutaneous kidney and liver biopsies, pelvic ultrasonography, intravenous pyelogram, skeletal survey, cranial computed axial tomography scan, electroencephalography, and ophthalmologic examinations failed to demonstrate evidence of occult disease. Except for testicular biopsy, this study does not support extensive clinical or invasive procedures to identify extramedullary disease prior to discontinuation of chemotherapy.

Peroral small-bowel biopsies in infants and children using a directable biopsy instrument.

Fifty children, ages 1 month to 12 years, underwent peroral jejunal biopsy with a four-way directional suction biopsy instrument (Medi-Tech). Mucosal specimens were obtained in 88% of attempted biopsies in an average time of 4 min. Fluoroscopy time was minimal, and there were no complications.

Value of fiberoptic gastrointestinal endoscopy in infants and children.

Fiberoptic gastrointestinal endoscopy was performed on 52 patients between the ages of 2 months and 16 years. The procedures were safely and easily done with premedications consisting of meperidine, promethazine, and chlorpromazine, and atropine, with diazepam given at the time of the procedure. Fiberoptic endoscopy was particularly helpful in localizing the site of upper gastrointestinal hemorrhage, in retrieving foreign objects, and in removing colonic polyps. In contrast, endoscopy added little to the clinical history and roentgenographic studies in children with recurrent abdominal pain or vomiting, in whom we believe fiberoptic endoscopy is not indicated unless the symptoms or history appear inconsistent with the diagnosis of functional bowel disease.

Cholesterol ester storage disease: clinical, biochemical, and pathological studies.

Of three siblings affected with cholesterol ester storage disease, two died at ages 7 and 9 years, respectively, with hepatic scarring and portal hypertension. Lipid storage was documented in both patients, as were esophageal varices and aortic plaques in the older child. The third affected sibling, followed to 13 years of age, has hepatomegaly, hyperlipidemia, short stature, adrenal calcification, and acid lipase deficiency. Leukocyte extracts demonstrated deficiency of acid lipase in this patient. This autosomal recessive condition may be allelic with Wolman disease with a more malignant course in this family than in most reported cases.