Research At The Children’s Hospital: From Bench to Bedside
from Practice Update, Summer 2006
Bosentan Shows Long-Term Promise For Children With Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH), high blood pressure in the lungs, is a progressive, frequently fatal disease in children. PAH infants often present with low cardiac output, poor appetite, failure to thrive, lethargy and irritability. Older children can present with exertional dyspnoea and chest pain. Although PAH is relatively rare, prognosis has improved substantially for children diagnosed with PAH, in large part, because of new drug therapies and earlier diagnosis. Novel therapies have been FDA studied and approved in adults, but there is limited knowledge about use of these therapies in children. Bosentan, an oral dual endothelin receptor antagonist, improves hemodynamics, exercise tolerance and survival, but its long-term effect in children is unknown.
The Children’s Hospital, a national leader in pediatric PAH research, is currently investigating the long-term outcome of children with PAH receiving bosentan as single therapy or in addition to intravenous prostanoid therapy. Data for hemodynamics, New York Heart Association (NYHA) functional class and safety were collected for 86 children with PAH in a two-year retrospective study. Kaplan-Meyers survival estimates at one and two years were excellent at 98 percent and 91 percent, respectively. Bosentan therapy, as part of an overall treatment strategy, resulted in high survival rates, sustained clinical and hemodynamic improvement and probable delay in the worsening of PAH.
For more information about bosentan therapy and ongoing research into pediatric PAH contact Dunbar Ivy, MD, Principle Investigator, at The Children's Hospital at 720-777-1234.
Rosenzweig, EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barts RJ. Effects of long-term bosentan in children with pulmonary arterial hypertension. Journal of the American College of Cardiology. 46 697-704 2005.
Are Guidelines For the Introduction of Cereals In the Infant Diet Appropriate For Children at Risk For Celiac Disease?
Celiac disease (CD) is characterized by chronic inflammation in the small intestine induced by gluten present in wheat, rye or barley. Celiac disease is under diagnosed in the U.S. Symptoms are extremely varied and can often mimic other bowel disorders. Infants, toddlers and children can exhibit growth failure, vomiting, bloated abdomen and behavioral changes. Many can have no initial symptoms. A recent study at The Children’s Hospital and the University of Colorado at Denver and Health Science Center suggests that as many as one in every 105 children in the Denver area may have CD.
A prospective study through The Children’s Hospital Pediatric Clinical Translational Research Center (formerly the Pediatric General Clinical Research Center ) investigated whether there is an association between when cereals are introduced in the infant diet and the subsequent development of celiac disease autoimmunity (CDA) in children with a genetic predisposition for celiac disease. This study was conducted from 1994-2004 with 1,560 children at increased risk for celiac disease or type 1 diabetes. Children were tested for transglutaminase autoantibody in the blood, which marks the autoimmunity of Celiac Disease. Fifty-one of the 1,560 children developed CDA. After adjusting for the presence of celiac disease susceptibility gene alleles, children exposed to foods containing wheat, barley or rye in the first three months of life had a five-fold increased risk of CDA compared with children exposed to gluten-containing foods at four to six months. Children not exposed to gluten until after six months had a marginally increased risk of CDA compared with those exposed at four to six months.
Findings suggest that the current pediatric recommendation of introducing cereals at four to six months of age is appropriate, and that there is not a benefit in delaying the introduction of gluten-containing foods in children at increased risk for celiac disease.
For more information, contact Edward J. Hoffenberg, MD, Principle Investigator at The Children's Hospital at 720-777-1234.
Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, Emery LM, Sokol RJ, Erlich HA, Eisenbarth GS, Rewers M. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. Journal of the American Medical Association. 293 2343-51 2005.
Should Pediatricians Monitor Children Diagnosed Before 18 Months of Age With Polycystic Kidney Disease More Closely Than Kids Diagnosed Later?
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening inherited kidney disease. Kidney cysts developed over time eventually lead to kidney enlargement and a decrease in kidney function. ADPKD accounts for 4.4 percent of end-stage kidney disease in the United States . ADPKD can be diagnosed as early as fetal life and symptoms, such as enlarged kidneys and high blood pressure, can be present at birth. This study examined the natural outcome in children diagnosed with ADPKD in utero or within the first 18 months of life and compared findings to children who were diagnosed with ADPKD between 18 months and 18 years of age.
Since 1985, 895 subjects with ADPKD from 419 families participated in ADPKD studies conducted at The Children’s Hospital and the University of Colorado at Denver and Health Sciences Center . Forty-six subjects from 40 families were diagnosed with ADPKD within the first 18 months of life.
One hundred fifty-three subjects from 109 families were diagnosed after 18 months, but before 18 years of age.
Children with early-onset ADPKD had higher serum creatinine concentration, lower creatinine clearance, lower overnight urinary osmolality and a greater frequency of hypertension as compared to older children diagnosed with ADPKD.
Results suggest that children diagnosed with ADPKD very early in life (<18 months age) have more extensive kidney cystic disease and worse kidney function than children who are diagnosed later in life. Children with early-onset ADPKD should be closely monitored and interventional treatment strategies begun as soon as possible.
For more information about the patient care implications of ADPKD, contact Melissa Cadnapaphornchai, MD, Principal Investigator at The Children's Hospital at 720-777-1234.
Cadnapaphornchia MA, Fick-Brosnahan GM, Duley I, Johnson AM, Strain JD, DeGroff CG, Schrier RW. Design and baseline characteristics of participants in the study of anti-hypertensive therapy in children and adolescents with autosomal dominant polycystic kidney disease (ADPHD). Contemporary Clinical Trials. 2005 26: 211-22.
Research Confirms Non-Invasive Test For Vitamin A Status For Children With Cholestatic Liver Disease Effective
Malabsorption of fat-soluble vitamins, such as vitamin A, is a major complication of childhood cholestatic liver diseases or those diseases associated with poor bile flow. Vitamin A is necessary for normal vision, normal development and resistance to infection. Worldwide, vitamin A deficiency is the leading cause of blindness. Previous studies suggest that 35-69 percent of children with cholestatic liver disease may be vitamin A deficient. A standardized test is the Relative Dose Response (RDR) test in which a parenteral (IM or IV) dose of vitamin A is given and serum levels of vitamin A are monitored over time. An RDR test using a parenteral dose is invasive and often impractical to perform in children.
Researchers at Children’s postulated that an oral test could be developed to assess vitamin A status during cholestasis by co-administration of a water-soluable form of vitamin E with vitamin A; with the vitamin E promoting the absorption of oral vitamin A. The new test, the “modified oral-RDR,” accurately reflected vitamin A status in cholestatic children, negating the need for a parenteral (IV or IM) RDR and identifying 100 percent of the patients with vitamin A deficiency. Based on the results of this study, serum retinol can be used as the initial screen for vitamin A deficiency in children with chronic liver disease. If serum retinol is low serum retinal is low (<20 μg/dl), a modified oral-RDR can be performed to confirm vitamin A deficiency and the need for supplementation.
For more information about the modified oral-RDR test, contact Ronald J. Sokol, MD, Principal Investigator, at The Children's Hospital at 720-777-1234.
Feranchak AP, Gralla J, King R, Ramirez RO, Corkill M, Narkewicz MR, Sokol RJ. Comparison of indices of vitamin A status in children with chronic liver disease. Hepatology 42 782-92 2005.
Who’s On First? A guide To the Players
Research funding comes through many different sources including the National Institutes of Health (NIH), industry sources (pharmaceutical and therapy companies), private foundations and individual contributions. Grants are awarded to institutions such at the University of Colorado at Denver and Health Sciences Center (UCDHSC) and The Children’s Hospital. The following organizations collaborate to ensure the overall success of research conducted at, or in partnership with Children’s.
Pediatric Clinical Translational Research Center (PCTRC)
Formerly the General Clinical Research Center (GCRC), the PCTRC provides clinical research infrastructure to assist investigators who receive their primary funding from the National Institutes of Health (NIH), although investigators funded by other federal, state and local agencies, private foundations and industry are also eligible for support. The PCTRC funds hospital beds, specialized laboratory testing, ancillary costs related to research, and trained personnel to support the investigator.
The Children’s Hospital Research Institute (TCHRI)
TCHRI is an umbrella organization for all research at Children’s. The RI facilitates pre-and post-award management of grants and subcontracts with outside organizations.
Clinical Trials Organization (CTO)
Clinical Trials Organization generally administers and coordinates clinical trials evaluating state-of-the-art drugs and devices for treating childhood diseases.
Colorado Multiple Institution Review Board (COMIRB)
The board reviews all research involving human subjects to ensure compliance with federal and state research guidelines. COMIRB oversees research conducted by the University of Colorado Health Sciences Center, Colorado Prevention Center, Denver Health Medical Center , Denver Veterans Affairs Medical Center , The Children’s Hospital and the University of Colorado Hospital.
