Cincinnati Center for Eosinophilic Disorders (CCED)
Research at the Cincinnati Center for Eosinophilic Disorders (CCED) includes basic, clinical and translational studies. Phil Putnam, MD, has led projects including epidemiology, quality of life research, descriptive research databanks, specimen databanks, translational studies and clinical trials. In the past year, the CCED team participated in the publication of more than 10 manuscripts on aspects of eosinophilic disorders, including a major revision of the Consensus Recommendations for Diagnosis of Eosinophilic Esophagitis in children and adults. Marc Rothenberg, MD, PhD, continues basic science research to understand the genetic and immunologic bases for eosinophilic gastrointestinal disorders. 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) was launched in 2010 and has begun enrolling patients. The CCED is leading a multi-center registry collaboration with eight pediatric and adult hospitals with plans for further expansion. This year, Vincent Mukkada, MD, joined the CCED. He has recently published manuscripts on microRNA profiling of esophageal biopsies in EoE and the use of novel immunohistochemical biomarkers in pediatric EoE. In the coming year, the CCED will join a multicenter trial on the use of a new viscous budesonide product in EoE as well as initiate new trials on the use of losartan in EoE as well as novel dietary management strategies.
Cincinnati Children's Steatohepatitis Center
The Cincinnati Steatohepatitis Center (CCSC), led by Drs. Xanthakos and Kohli, is a multidisciplinary program 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 CCSC has evaluated over 200 children and collaborates clinically with 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. Research highlights from the CCSC in fiscal year 2013 include publications of the effects of innovative animal models of bariatric surgery on NASH and bile acid physiology, including sleeve gastrectomy. The pre-clinical research program has further been supported by grants from Ethicon Endosurgery Inc. and Cincinnati Diabetes and Obesity Center. In clinical research, the CCSC is a leading 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 NASH CRN clinical trial investigating cysteamine versus placebo for the treatment of pediatric NASH (CyNCH) is ongoing and anticipated to finish enrollment by December 2013. In the past year, the CCSC has published clinical and pre-clinical papers in the area of steatohepatitis research in the following journals: Endocrinology, Obesity, Journal of Pediatric Gastroenterology, Hepatology and Nutrition, Clinical Liver Disease, Journal of Clinical Endocrinology and Metabolism, and the Indian Journal of Pediatrics.
Diarrhea and Malnutrition
Our goal is to 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. Drs. Moore, Cole and Saeed have established and are evolving collaborations with colleagues in Brazil, Ghana, Nigeria and Pakistan focused on micronutrient deficiencies (zinc and iron), undernutrition, diarrheal diseases, and tropical/environmental enteropathy.
Sean Moore’s 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 (supported by the NIH and NASPGHAN Foundation), 2) human biomarkers and murine models of environmental enteropathy (supported by The Bill & Melinda Gates Foundation), and 3) intestinal epithelial cell signaling networks linking cell cycle, metabolism, DNA damage response, and circadian rhythms (supported by the 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.
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. Vincent Mukkada recently joined Scott Pentiuk, MD, as the second pediatric gastroenterologist on the team. The IFT continues to grow with over 1200 patient visits over the last year. The team has also had extensive outpatient treatment programs including 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.
Intestinal Rehabilitation Program
The Intestinal Rehabilitation Program continues in its mission to provide the best possible care through innovation for patients to experience optimal outcome. We continue to experience considerable growth, and our program is one of the largest intestinal rehabilitation programs nationally, with active basic scientific, translational and clinical research. Drs. Kocoshis and Cole managed patients from 26 states and three countries in the past year. The multidisciplinary model to standardize care and facilitate research among the three disciplines (gastroenterology, neonatology and surgery) providing care to infants and children with intestinal failure continues to be successful. Currently the rate of survival without significant liver disease (as measured by cholestasis) of our patients with intestinal failure is among the highest nationally due to this initiative and rapid translation of research into clinical care. Specific initiatives, including active event analysis with the home healthcare services, have contributed to the significant reduction in the incidence of outpatient acquired central line bloodstream infections and we now have one of the lowest rates nationally.
Ongoing translational and clinical trials research initiatives 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. An NIH/Emmaus Inc. funded multicenter clinical trial evaluating the safety and efficacy of enteral glutamine in the infants with short bowel syndrome continues to enroll participants. We also continue to enroll patients with persistent intestinal failure associated liver disease in an efficacy and safety trial using fish-oil derived lipid (Omegaven®) to prevent chronic liver disease and liver failure in this population.
Intestinal Transplantation Program
Under the leadership of Dr. Samuel Kocoshis, the Intestinal Transplant Program continues to implement quality improvement initiatives. The program, as the first within our medical center to utilize medical passports for patients, continues to use them with great success. The medical passport gives a snapshot of each patient’s medical history from pretransplant medical issues, the technical details of the transplant itself, to the unique postoperative problems faced by each patient. 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 continue to commend us for providing such a comprehensive view of our patients. The medical passport focuses not only upon medical complications but also upon psychosocial issues that impact adversely upon outcomes.
Our program remains an active participant in hospital-wide QAPI initiatives. Our “dashboard” continues to show good outcomes in complying with regulatory procedures and in patient survival. Hence we are developing metrics for nutritional parameters such as BMI, 25-OH vitamin D levels, and other nutritional markers. We maintain a 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. Moreover, among the 11 most recent patients transplanted between 2009 and 2012, we continue to 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 2013.
We have embarked upon several research initiatives. We are working with the Behavioral Science Department, and have written an observational paper on the contributions that an adherence program can make within a transplantation program. We have also written an IRB protocol in collaboration with the Behavioral Science Department for a prospective study correlating clinical and psychosocial outcomes and regimen adherence of patients and their families following small bowel or multivisceral transplant. We have initiated a translational project in collaboration with Dr. Pierre Russo of the Pathology Department at Children’s Hospital of Philadelphia. It is a cross sectional study regarding the prevalence and significance of anti-enterocyte antibodies in small bowel transplantation. We hypothesize that anti-enterocyte antibodies may function as sensitive and specific biomarkers for antibody mediated rejection in intestinal transplantation. A third project is an emerging collaboration with Dr. Sander Vinks of the Clinical Pharmacology department to study intestinal metabolism of sirolimus and to study the ontogeny of that metabolism within the small intestine. A final protocol upon which we are about to embark is a collaborative study with Dr. Koji Hashimoto of the Cleveland Clinic. This study explores the role of helper T cells in acute cellular rejection of intestinal allografts. We will provide peripheral blood from patients undergoing intestinal transplant for flow cytometric analysis of T cell subpopulations. The hypothesis is that acute cellular rejection is most likely to occur when helper T cell populations are reconstituted following administration of antithymocyte globulin to intestinal transplant recipients.
The Liver Disease Program
The Liver Disease Program, led by Dr. Jorge Bezerra, provides comprehensive care for children with liver diseases. Staffed by seven 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 state-of-the-art gene sequencing techniques to diagnose mutations known to cause clinical phenotypes, and discover mutations in new genes relevant to liver diseases. In addition to the consultation with expert hepatologists and clinical nurse specialists, the outpatient program includes 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 improvement in child care, the Clinical and Research Staff lead patient- and laboratory studies in liver diseases. In patient studies, the staff conduct multi-center studies sponsored by the National Institutes of Health and the American Liver Foundation to advance knowledge on mechanisms of pediatric liver disease, to develop new diagnostic tests, and to perform clinical trials to explore new strategies to recover liver function and increase the short- and long-term outcomes of children with acute and chronic liver diseases. Ongoing projects include: 1) the development of the LiverChip, a new high-throughput blood test that screens for mutations in 13 genes that cause genetic liver diseases, 2) mitochondrial and immunologic diseases as causes of liver failure, 3) an ongoing trial to determine the efficacy of corticosteroids in children with biliary atresia, 4) studies to dissect the causes and develop new treatments for biliary atresia, 5) studies to discover biomarkers and new therapies for fatty liver disease, 6) identification of biomarkers of fibrosis, and 6) the development of new therapies for bile acid disorders.
In the laboratory, Research Staff use innovative models using transgenic technologies in rodents and zebrafish to study fundamental mechanisms of liver development and pathogenic basis of liver injury, repair, autoimmunity, cholestasis, steatohepatitis and tumor formation. Together, 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 and Transplant Hepatology.
Our mission is to provide comprehensive multidisciplinary management of pancreatic disorders that strives to improve patient outcomes through focused expertise, standardization of care and clinical research. The program is led by Joseph Palermo MD PhD, Tom Lin MD, and Maisam Abu-El-Haija MD. With its inception this year, this program has already completed a survey of Cincinnati Children’s providers to better understand the variation in management of acute pancreatitis, assembled a multidisciplinary care team to evaluate and treat complex pancreatic disorders and established a REDCap database for patient registry. In addition, the program participates in the INSPPIRE consortium for pediatric pancreatitis and are one the few children’s hospitals able to offer pediatric patients with chronic pancreatitis the option of total pancreatectomy with islet autotransplantation (TPIAT).
Pediatric Acute Liver Failure Study Group
The Pediatric Acute Liver Failure (PALF) Study Group is a NIH U01-funded consortium of 12 children’s hospitals (11 U.S. and one Canadian) whose focus is to study infants and children who develop acute liver failure. Patients with acute liver failure are gravely ill and often require liver transplantation in order to rescue the patient; despite this high morbidity and mortality, very little is known about the etiology of disease initiation or progression, or risk factors that will predict prognosis. Current goals of the PALF Study Group are to comprehensively study these patients’ biochemical and clinical management profiles and using this information, to develop models of PALF using statistical modeling techniques augmented with mechanistic models of complex biological systems to inform us of factors impacting prognosis or decision-making regarding liver transplantation.
The Pediatric Liver Care Center at Cincinnati Children’s has participated in the PALF Study Group since 2005. This past year, Cincinnati Children’s has enrolled nine patients into the study, which is the second highest enrollment of the 12 centers (total PALF Study Group enrollment for 2013 was 70 patients). Dr. Leonis is the Cincinnati Children’s site PI for this study, and has recently published an article on behalf of the PALF Study Group on chronic acetaminophen exposure in patients with PALF that was published in Pediatrics.
Pediatric Liver Transplantation
The Pediatric Liver Transplant Program, led by Kathleen Campbell, MD (medical director) 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. In addition to providing care for the most common pediatric liver disorders leading to transplantation, we are able to leverage institutional strengths in other Divisions to provide care, and the best outcomes available, to a number of patients with rare diseases and extremely complex needs, including those with advanced liver tumors and patients with primary immune defects. 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), the Studies in Pediatric Liver Transplantation (SPLIT) quality improvement community and clinical registry, the Clinical Trials in Organ Transplantation in Children (CTOT-C) project, and Impact of Everolimus on Renal Function in Pediatric Liver Transplantation.