Kathleen Campbell, MD; John Bucuvalas, MD; Jorge Bezerra, MD; Mike Leonis, MD, PhD
Pediatric Liver Transplant Program
The Pediatric Liver Transplant Program continues its’ mission of advancing the care of liver transplant recipients by improving the health care delivery system, providing unparalleled clinical care, and addressing gaps in knowledge through patient-based and basic laboratory research. The program remains one of the largest pediatric liver transplant programs in the country, with excellent clinical outcomes at or above the national average. Clinical highlights in fiscal year 2011 included the incorporation of advanced practice nurses into the inpatient care delivery team, a successful site survey from the United Network for Organ Sharing (the primary regulatory agency for solid organ transplantation in the United States), and a growing niche area in transplantation for hepatic tumors, fostered in collaboration with the Oncology division. In Fall 2010 the Liver Transplant program was chosen, in combination with the Biliary Atresia Program, as one of the first “High Impact Conditions” defined by hospital leadership as a focus area for achievement of “Best In Class” status by 2015, highlighting the strong accomplishments and solid performance of the program over time. Members of the Liver Transplant Program continue to be leaders in national quality improvement efforts and multi-center clinical and translational studies. These include: the Pediatric Acute Liver Failure Study Group (PALF), Medication adherence in children who had a liver transplant (MALT), Functional outcomes in liver transplant recipients (FOG), Immunosuppression withdrawal for sable pediatric liver transplant recipients (iWITH), Studies in Pediatric Liver Transplantation (SPLIT) clinical registry, SPLIT Quality Improvement Initiative sponsored by the Cincinnati Children's Center for Education and Research on Therapeutics, Calcineurin Inhibitor Minimization and Foxp3+ T-regs post-transplant.
Stavra Xanthakos, MD; Rohit Kohli, MD
Cincinnati Children's Steatohepatitis Center
The Cincinnati Steatohepatitis Center (CCSC) is a multidisciplinary clinic initiated in November 2007 to care for the unique needs of pediatric patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NAFLD, the hepatic consequence of obesity and metabolic syndrome, affects about 10% of children and ranges from fatty liver alone (NAFLD) to fatty liver with varying degrees of liver inflammation and fibrosis (NASH). NASH is estimated to progress to cirrhosis and liver failure in an estimated 25% of adult individuals; we have shown that fibrosis can progress even in childhood.
The CCSC evaluates patients for alternate causes of elevated liver enzymes and screens for closely related comorbidities including insulin resistance, hypertension, dyslipidemia, type 2 diabetes mellitus, polycystic ovarian syndrome and obstructive sleep apnea. For therapy, enrollment into intensive weight management programs such as Healthworks! is encouraged, but the clinic also provides individualized dietary consultation and recommendations for families who cannot participate in more intensive programs and follows progress in meeting nutritional and activity goals.
The CCSC faculty include: Stavra Xanthakos MD, MS (medical director), Rohit Kohli MBBS, MS (co-director) and William Balistreri, MD. Access has been increased this year by incorporating a nurse practitioner into our program as well. Research programs in the CCSC have also significantly expanded since its inception and aim to improve our understanding and treatment options for this disease. Researchers in the CCSC are currently studying the outcome of NASH after bariatric surgery in adolescents (K23DK080888, PI: Xanthakos) and animal models of bariatric surgery and NASH (K08 DK084310, PI: Kohli). The CCSC is a major participating pediatric site in the NIH-funded NASH Clinical Research Network (U01 DK08505, Center PI: Xanthakos), a multi-center study investigating the natural history and determinants of NASH in adults and children and will be offering a clinical therapeutic trial anticipated to begin in early 2012.
The CCSC has published clinical and pre-clinical papers in the area of steatohepatitis research over the last year in the following journals: Hepatology; Journal of Pediatric Gastroenterology and Nutrition, and the American Journal of Physiology, and Journal of Hepatology. The CCSC continues to give talks to local community pediatric care providers and practices. The CCSC presented its outcomes data at the annual meeting of the North American Society for Pediatric Gastroenterology at its annual meeting last year.
Phil Putnam, MD; James Franciosi, MD
Cincinnati Center for Eosinophilic Disorders (CCED)
The CCED is a high volume, multidisciplinary tertiary referral care center specializing in Eosinophilic Gastrointestinal Disorders (EGID) in both the pediatric and adult populations. The core clinical group is made up of members from the Divisions of Gastroenterology, Nutrition and Hepatology, Allergy and Immunology, Social Work and Nutrition. The CCED extensively utilizes a number of ancillary services within the hospital during the process of treating these patients. Families are seen for a week long baseline visit and then subsequent, one day follow visits on a regular basis (at least once yearly).
In 2010, the CCED physician’s and staff managed cared for 515 distinct patients that included: 190 new patient cases from 44 states (including Ohio) and one country outside of the U.S. (Peru), over 722 endoscopic procedures on patients with an EGID diagnosis (24% of the total GI endoscopies at Cincinnati Children's), and 607 GI clinic visits.
Research through the CCED involves basic, clinical and translational studies. Patients are offered enrollment in diverse research studies including epidemiology, quality of life research, descriptive research databanks, specimen databanks (collections of endoscopy tissue, blood, and DNA), translational studies, and clinical trials. In 2010, members of the CCED team published over 15 papers on eosinophilic disorders in major medical journals including the journal Nature Genetics. Dr. Franciosi has further characterized the epidemiology of eosinophilic esophagitis as a chronic, under-recognized inflammatory condition in children. The CCED team has also determined that EGID conditions have a significant negative impact on quality of life. Dr. Rothenberg’s laboratory has identified a gene possibly involved in susceptibility to eosinophilic esophagitis at the 5q22 locus.
As a continuation of our $1.5 million NIH stimulus research grant awarded in 2009, the first national Registry for Eosinophilic Gastrointestinal Disorders (www.regid.org) has been launched in 2010 and will begin enrolling patients in 2011. The CCED is leading a multi- center registry collaboration with eight pediatric and adult hospitals with plans for further expansion.
Jorge Bezerra, MD; Mitchell Cohen, MD; Cynthia Wetzel, PhD
Digestive Health Center (DHC)
The DHC is one of 17 Silvio O. Conte Digestive Diseases Research Core Centers in the nation supported by the National Institutes of Diabetes & Digestive & Kidney Diseases. The DHC, located within the Division of Gastroenterology, Hepatology, and Nutrition at Cincinnati Children's Hospital Medical Center is the only Core Center dedicated to research on pediatric digestive diseases. The DHC cores provide services to increase the tempo of scientific discoveries in digestive disease research and to attract new investigators to the field. The overall goal of the DHC, is to promote research that will yield insights into the fundamental processes and pathogenic mechanisms of digestive disease in children and generate innovative treatment to restore digestive health. Specifically, the long term goals are to improve child health through better diagnosis, treatments and outcomes for our 4 key focus areas and diseases: 1) Chronic Liver Disease (biliary atresia, chronic cholestasis, and liver transplantation); 2) Inflammatory and Diarrheal Diseases (inflammatory bowel disease, eosinophilic gastrointestinal disorders, and infectious diarrhea) 3) Obesity and the Digestive System (including liver and metabolic complications of obesity), and 4) Development and Digestive Diseases (molecular basis of organogenesis, adult stem cell/homeostasis, and intestinal organoids from stem cells). The focus areas are linked by four highly innovative Biomedical Research Cores: Gene and Protein Expression, Bioinformatics, and Integrative Morphology; a Biostatistical Service is also available through a collaborative effort with the Center for Clinical and Translational Science and Training Program). In addition, the DHC provides 3-6 pilot and feasibility awards each year to investigators starting research projects with the potential for extramural funding. The DHC director is Dr. Jorge Bezerra, the associate Directors are Drs. Mitchell Cohen, Aaron Zorn, and Marshall (Chip) Montrose, and the Project Manager is Dr. Cynthia Wetzel. The DHC has 56 investigators and 29 associate members from 17 different divisions within the Department of Pediatrics and a total of 8 departments within the University of Cincinnati, College of Medicine.
Scott Pentiuk, MD
Interdisciplinary Feeding Team (IFT)
This multi-disciplinary team provides comprehensive evaluation of children with swallowing/feeding disorders. It includes members from gastroenterology, otolaryngology, human genetics, speech therapy, occupational therapy, social work, and nutrition. Dr. Scott Pentiuk MD is the pediatric gastroenterologist on the team. The IFT continues to grow at nearly 10% per year with over 1200 patient visits over the last year. The team has also expanded its outpatient treatment programs with the development of co-treatment sessions and Parent-Child Interaction Training for families. Current IFT research projects include the use and development of a pureed by G-tube diet, quality of life assessment of feeding therapies, methods to evaluate children with swallowing dysfunction, and the creation of a prospective database in order to track the effectiveness of therapies and patient outcomes.
Jorge Bezerra, MD; Alex Miethke, MD
Chronic Liver Disease Program
The Bezerra laboratory investigates regulatory mechanisms of liver and biliary injury. One major research focus is pre-clinical and translational research on biliary atresia, the most common cause of chronic liver disease in children. He has used large-scale expression arrays and bioinformatics to develop transcriptional maps for human and murine biliary atresia. These maps generated hypotheses regarding pathogenic mechanisms of disease. Testing these hypotheses in the laboratory, he began dissecting the cellular and molecular basis of neonatal injury and obstruction of extrahepatic bile ducts using unique in vitro and experimental models of disease. Experiments identified key regulatory functions for hepatic dendritic cells and CD8+ and NK lymphocytes in recognition and induction of apoptosis of the bile duct epithelium. Ongoing experiments are identifying co-stimulatory signals controlling cell survival during early postnatal development and small molecules regulating biliary diseases. In translational studies, he is also applying state-of-the-art approaches to identify the molecular determinants of treatment response in multi-center studies of children with biliary atresia and syndromes of intrahepatic cholestasis.
The Chronic Liver Disease Program
Staffed by nine pediatric hepatologists, the Chronic Liver Disease Program serves a national and international referral population via a comprehensive evaluation of all medical and surgical aspects of liver disease and offers prompt initiation of conventional and innovative treatments. The evaluation includes a full spectrum of metabolic analysis, inflammatory processes and high-throughput gene sequencing to screen for genetic diseases. The clinic allows for timely consultation with surgeons, pathologists, radiologists and nutritionists with expertise in pediatric liver disease, thus enabling a thorough evaluation of the impact of the illness on the child’s well-being. For children with advanced stages of liver disease, an evaluation for liver transplantation and close follow-up in the pre-transplant clinic enable the implementation of the most comprehensive treatment protocol to minimize complications and improve post-transplant course.
Recognizing that research is critical to improved care, clinic staff members lead multicenter studies sponsored by the National Institutes of Health to advance knowledge on mechanisms of pediatric liver disease and to develop diagnostic and treatment modalities. Recent innovations include: 1) the development of a high-throughput gene chip to diagnose mutations in children with genetic liver diseases, 2) an ongoing trial to determine the efficacy of corticosteroids in children with biliary atresia, 3) a study to examine the role of immune dysregulation in the etiology of acute liver failure, 4) studies to discover biomarkers and therapies for fatty liver disease, and 5) the development of therapies for bile acid disorders. The clinical and research programs create an outstanding environment for the training of future leaders in the field via a fellowship training program in advanced hepatology.
Intestinal Rehabilitation Program
The Intestinal Rehabilitation Program has experienced considerable growth during the past year to position itself for a national leadership role in conducting basic scientific, translational and clinical research. The multidisciplinary initiative to standardize care and facilitate research among the three disciplines (gastroenterology, neonatology and surgery) providing care to infants and children with intestinal failure was implemented. Currently the rate of survival without significant liver disease (as measured by cholestasis) of our patients with intestinal failure is among the highest nationally. Major clinical initiatives include weekly multidisciplinary bedside rounds; development of a specific emergency department protocol for standardized evaluation and treatment of fevers among children with central venous catheters; and pre-clinic planning meetings, which are expected to improve the patient’s clinic experience. In addition, we have protocolized management of central venous catheters with suspected bacterial biofilms by initiating ethanol lock therapy and laboratory assessment of nutritional markers. These initiatives have significantly reduced the incidence of outpatient acquired central line bloodstream infections.
Translational and clinical trials research initiatives were also implemented. These include evaluating the relative value of biomarkers of infection (sTREMs [triggering receptors of myeloid cells] and LBP [lipoprotein binding protein]) for identifying acute bloodstream infections (BSI) and for predicting need for liver/bowel transplant and death among our population on total parenteral nutrition (TPN). Other studies include developing in vitro culture methods to grow and expand both normal and diseased intestinal tissue from patients with intestinal failure; validating the use of bomb calorimetry as a measure of enteral energy balance among intestinal failure patients; and feeding advancement trial in patients with gastroschisis to identify the method that optimally decreases the duration of TPN. We continue participation in the 15-center Pediatric Intestinal Failure Consortium and are in the process of analyzing data describing factors impacting outcomes in pediatric intestinal failure.
Inflammatory Bowel Disease
The number of patients receiving multidisciplinary care for IBD has continued to grow, with children from more than 25 states seen over the past year. State-of-the art services including diagnostic imaging modalities, which do not require radiation exposure, and targeted psychology interventions for nonadherence have been implemented. We have continued to contribute to international genome-wide association studies to identify susceptibility genes specifically for pediatric-onset disease. Investigators have received funding from the National Institutes of Health (NIH) to develop the first multicenter North American randomized controlled trial in newly diagnosed children with ulcerative colitis, the PROTECT study. Within this trial, we will develop a model to predict individual patient therapeutic responses and clinic outcomes that will incorporate clinical, genetic and immune biomarkers that we have developed. At Cincinnati Children’s, this trial will include collaborators in the Divisions of Pulmonary Biology and Biomedical Informatics. Under the leadership of Kevin Hommel, PhD, in the Adherence Center, we will be one of three centers to participate in the first randomized controlled trial of telehealth interventions to improve medication adherence in children with IBD.
It is anticipated that the knowledge gained from these studies will be rapidly translated to practice through our collaborations with Peter Margolis, MD, PhD, in clinical effectiveness, via his leadership of the ImproveCareNow (ICN) pediatric IBD quality improvement network. The IBD Center has continued to play a leading role in ICN, which has achieved a 20 percent improvement in patient remission rates with implementation of consensus patient care guidelines and practices. This network was the basis for an NIH award to Margolis in the Center for Health Care Quality to develop an innovative web-based social networking model to improve outcomes for children with IBD, termed C3N. As part of this collaborative network, patient-focused activities are being developed to improve patient outcomes and engage patients and their families to become more involved in the care of their IBD. A pilot trial of daily symptom assessment using innovative bioinformatics tools was undertaken with the patient participating in daily and weekly surveys of the symptoms and QOL measures.