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. Our program remains one of the largest pediatric liver transplant programs in the country, with clinical outcomes at or above the national average. Programmatic highlights in fiscal year 2012 include a successful review of the program by the Centers for Medicare/Medicaid Services, addition of a hospital-wide solid organ transplant administrator and creation of an Integrated Solid Organ Transplant Program with John Bucuvalas, MD as the medical director. Clinically, the Cincinnati Children's Hospital Medical Center Pediatric Liver Transplant Program has maintained its’ overall transplant volume and has continued to build expertise in transplantation for primary hepatic tumors. Since 2007, we have performed more pediatric liver transplants for primary hepatic tumors than any other program in the United States. Members of the Liver Transplant Program continue to act as leaders in national quality improvement efforts and multicenter clinical and translational research studies. These include: the Pediatric Acute Liver Failure Study Group (PALF), Medication Adherence in Children who had a Liver Transplant (MALT), Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH), and the Studies in Pediatric Liver Transplantation (SPLIT) quality improvement community and clinical registry. In addition, the program participated in a multicenter application to the Clinical Trials in Organ Transplantation in Children (CTOT-C) project, a cooperative research program sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), with co-funding from the National Heart, Lung and Blood Institute (NHLBI).
Conrad Cole, MD, Adam Mezoff, MD, Samuel Kocoshis, MD
Intestinal Rehabilitation Program
The Intestinal Rehabilitation Program continues to experience considerable growth and is positioned for a national leadership role in conducting basic scientific, translational and clinical research. We managed patients from 24 states and 3 countries in the past year. 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 have been successfully 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 and we now have one of the lowest rates nationally.
Translational and clinical trials research initiatives were also implemented. These 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. A NIH/Emmaus Inc. funded multicenter clinical trial evaluating the safety and efficacy of enteral glutamine in the infants with short bowel syndrome was initiated. We continue participation in the 15-center Pediatric Intestinal Failure Consortium and the data describing factors impacting outcomes in pediatric intestinal failure was recently published.
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.
Samuel Kocoshis, MD
Intestinal Transplantation Program
Implementation of numerous quality improvement initiatives has translated into unprecedented clinical success for the intestinal transplantation program. The program was the first within our medical center to utilize medical passports for patients. The medical passport gives a snapshot view of each of our patient’s medical history from prior to transplant to the technical aspects of each transplant to the unique details of each post transplant history. Individual drug reactions, organ dysfunction of other organ systems, and clinical quirks of each patient are highlighted in a cogent story which provides caregivers with insights to our patients that they would never have otherwise acquired. These insights facilitate the care of our patients wherever they travel or whenever they are seen by either other divisions or by emergency physicians. Numerous physicians and other healthcare providers have commended us for providing such a comprehensive view of our patients that enhance communication greatly. In addition all clinical protocols were reviewed and updated according to new information obtained from the transplantation literature. Furthermore, our program has been an active participant in hospital wide QAPI initiatives. Our “dashboard” has shown striking improvement in all outcome measures, due in large part to our meticulous adherence to protocols. Yet another initiative was our close association with the “adherence” program from the behavioral science department. A psychologist sees all of our patients as inpatients and outpatients in order to analyze and correct barriers to adherence. Our initiatives were rewarded when the all of the institution’s transplant programs were reviewed by CMS and the intestinal transplantation program was found to have absolutely no deficiencies. Moreover, among the 10 most recent patients transplanted between 2009 and 2011, we have 100% one-year survival, making us the most successful program in North America in terms of patient survival for the three year period between 2009 and 2012.
Our stunningly good results have placed us on the radar screen of a number of referring institutions nationally, and we have seen new referrals in the past 12 months from Michigan, Oklahoma, Texas, Tennessee, Wisconsin and Alabama. Our transplantation “waiting list” now numbers 4 patients, and we believe that a goal of performing 5-10 small bowel transplants per year is realistic.
Clinical and translational research is slowly evolving. Even though only one peer reviewed article emanated from our program during the past academic year, it is the “definitive” article on graft versus host disease in intestinal transplantation. We have learned from our experience and changed our immunosuppressive protocol and surgical technique to minimize the risk for graft versus host disease.
We are actively pursuing several research initiatives at present. We are working with the Behavioral Science Department, writing an observational paper on the contributions that an adherence program can make within a transplantation program. A second paper will be analysis of risk factors for poor psychosocial outcomes. A translational project that we are initiating is a cross sectional study regarding the prevalence and significance of anti-enterocyte antibodies in small bowel transplantation. If our hypotheses are correct, anti-enterocyte antibodies may function as sensitive and specific biomarkers for antibody mediated rejection in transplant patients. Yet another project is in its earliest stages. We are seeking funding to retrospectively stain biopsy specimens for FOXP3 within T lymphocytes , speculating that excessive absence or reduction of FOX P3 expression on intestinal lymphocytes predisposes to acute cellular rejection.
Jorge Bezerra, MD, Alex Miethke, MD, Joseph Palermo, MD, Ph.D.
The Chronic Liver Disease Program
The Chronic Liver Disease Program provides comprehensive care for children with liver diseases. Staffed by 9 pediatric hepatologists, the Program serves a national and international referral population via a comprehensive evaluation of all medical and surgical aspects of liver disease and the 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. In addition to the consultation with expert hepatologists and clinical nurse specialists, the clinic facilitates the timely consultation with surgeons, pathologists, radiologists, and nutritionists with expertise in pediatric liver disease. This coordinated approach enables 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, improve post-transplant course, and optimizes outcomes.
Recognizing that research is critical to improved care, the Clinic Staff leads multi-center studies sponsored by the National Institutes of Health to advance knowledge on mechanisms of pediatric liver disease and to develop new 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) studies to dissect the causes and develop new treatments for biliary atresia, 4) investigations of the role of immune dysregulation in the etiology of acute liver failure, 5) studies to discover biomarkers and new therapies for fatty liver disease, and 6) the development of new 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.
Sean Moore, MD, Conrad Cole, MD, Mitchell Cohen, MD
Diarrhea and Malnutrition
Our goal is advance the quality of care for children with diarrhea and malnutrition by creating new knowledge through robust research and clinical collaborations between Cincinnati Children's Hospital Medical Center and international partners. We have established and evolving collaborations with colleagues in Brazil, Ghana, Nigeria and Pakistan focused on micronutrient deficiencies (zinc and iron), undernutrition, diarrheal diseases, and tropical/environmental enteropathy.
The Moore laboratory is broadly interested in understanding and reversing the “vicious cycle” of malnutrition and enteric infections in developing countries. Current areas of focus are: 1) laboratory and clinical studies of glutamine supplementation in enteroids, murine models of weanling malnutrition, and underweight children in Northeast Brazil (NIH, NASPGHAN Foundation), 2) murine models of environmental enteropathy and rotavirus immunization (Bill & Melinda Gates Foundation Grand Challenges Exploration), and 3) intestinal epithelial cell signaling networks linking cell cycle, metabolism, DNA damage response, and circadian rhythms (DARPA Biochronicity Program).
In a related program, Dr. Cohen completed phase I studies on a new candidate vaccine with potential efficacy against enterotoxigenic E. coli and cholera, two important causes of diarrhea in developing countries.
Stavra Xanthakos, MD, Rohit Kohli, MD
Cincinnati Children's Steatohepatitis Center
The Cincinnati Steatohepatitis Center (CCSC) is a multidisciplinary clinic that provides care to a growing population 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 and has become the third leading cause for liver transplantation in adults. NAFLD and NASH often begin in childhood and progressive severe fibrosis can occur in early adolescence. Early identification and intervention is critical to minimize progression to end-stage liver disease.
Since its inception in 2007, the program has evaluated over 190 children. The CCSC screens 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. Accordingly, our program collaborates with faculty from other obesity-related programs at Cincinnati Children's, including the Center for Better Health and Nutrition, Sleep, Hypertension and Lipid, and Diabetes Clinics, and the Surgical Weight Loss Program for Teens. First line treatment for NAFLD and NASH involves achieving a healthier weight. The CCSC provides individualized dietary consultation and activity recommendations, utilizing a patient centered approach to assess readiness for change and goal-setting. Families are also encouraged to participate in more intensive medical and surgical weight loss programs at Cincinnati Children's, as appropriate. Progress in meeting goals is tracked and quality outcomes measure change in BMI and serum aminotransferase levels over time.
Research programs in the CCSC aim to improve our understanding of pathogenesis and expand treatment options for this disease. Researchers in the CCSC are studying innovative animal models of bariatric surgery and NASH, including sleeve gastrectomy. The pre-clinical research program has further been supported by grants from Ethicon Endo-Surgery Inc. and the University of Cincinnati’s CCTST T1 grant programs. In clinical research, the CCSC is a major participating pediatric site in the NIDDK-funded NASH Clinical Research Network (NASH CRN), a multi-center study investigating the natural history and determinants of NASH in adults and children. A new NASH CRN clinical trial investigating cysteamine versus placebo for the treatment of pediatric NASH (CyNCH) is now open for enrollment at our site.
The CCSC has published clinical and pre-clinical papers in the area of steatohepatitis research over the last year in the following journals: The Journal of Pediatrics; PLoS One; Indian Journal of Pediatrics; Journal of Pediatric Gastroenterology, Hepatology and Nutrition and Journal of Hepatology. CCSC faculty were invited to present at national scientific meetings, including the annual meeting of the American Gastroenterology Association last year.
Lee (Ted) Denson, MD, Shehzad Saeed, MD
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, and prospective cohort studies to develop personalized models of disease behavior and response to therapy. Investigators have received funding from
the National Institutes of Health (NIH) to conduct 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 are one three centers conducting 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. Locally, we have recently achieved the milestone of an 80% remission rate across our IBD patient population. The ICN 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.