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Washington Hilton October 8, 2015 Washington, DC SYLLABUS 1 1 NASPGHAN assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version. Table of Contents MODULE 1: NUTRITION OBESITY AND THE MICROBIOME 11 REDEFINING MALNUTRITION IN THE 21ST CENTURY 21 MANAGEMENT OF FOOD ALLERGIES AND FPIES 35 MODULE 2: ENDOSCOPY UPDATES ON CAUSTIC INGESTIONS 46 UPDATES ON FOREIGN BODY INGESTIONS 56 THE PROBLEMATIC POLYP 64 MODULE 3: GI POTPOURRI CLOSTRIDIUM DIFFICILE: DIFFICULT BUT NOT IMPOSSIBLE 75 GLUTEN SENSITIVITY: SURELY A SENSITIVE, BUT PERHAPS NOT A GLUTEN, SUBJECT 86 MEDICAL MANAGEMENT OF REFRACTORY ABDOMINAL PAIN 97 NAUSEA: UPDATES THAT WON’T MAKE YOU SICK 114 MODULE 4: LIVER/PANCREAS NEW HORIZONS IN HEPATITIS C 128 RENAL COMPLICATIONS OF CHRONIC LIVER DISEASE 139 AN UPDATE ON WILSON’S DISEASE 147 BLAME THE GENES? FAMILIAL AND AUTOIMMUNE PANCREATITIS IN CHILDREN 157 MODULE 5: INTESTINAL INFLAMMATION GETTING TO THE BOTTOM OF PERIANAL CROHN’S DISEASE 168 “IT’S ALL ABOUT THAT POUCH, 'BOUT THAT POUCH, NO COLON”: 179 EVALUATION AND MANAGEMENT OF COMPLICATIONS POST ILEAL POUCH ANAL ANASTOMOSIS COMMUNICATING THE BENEFITS AND RISKS OF IBD THERAPY TO PATIENTS AND FAMILIES 192 FACULTY NASPGHAN POSTGRADUATE COURSE Course Directors: Melanie Greifer MD Assistant Professor of Pediatrics New York University School of Medicine Division of Pediatric Gastroenterology and Nutrition NYU Langone Medical Center New York, NY Jennifer Strople MD, MS Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Clinical Director, Inflammatory Bowel Disease Program Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, IL Faculty: Carlo Di Lorenzo MD Chief, Division of Pediatric Gastroenterology, Hepatology and Nutrition Nationwide Children's Hospital Professor of Clinical Pediatrics The Ohio State University College of Medicine Columbus, OH Stacy A. Kahn MD Assistant Professor of Pediatrics and Medicine Pediatric Gastroenterology, Hepatology, & Nutrition Director, Transitional IBD Clinic The University of Chicago Medicine Chicago, IL Praveen Goday MBBS Professor Medical College of Wisconsin Division Pediatric GI, Hepatology & Nutrition Milwaukee, WI Robert E. Kramer MD, FASGE Co-Medical Director DHI/ Director of Endoscopy Associate Professor of Pediatrics Digestive Health Institute Children’s Hospital Colorado/ University of Colorado Denver, CO Stefano Guandalini MD Professor and Chief Section of Pediatric Gastroenterology University of Chicago Founder and Medical Director, Celiac Disease Center Chicago, IL Daniel H. Leung MD Assistant Professor of Pediatrics Baylor College of Medicine Division of Gastroenterology, Hepatology, and Nutrition Texas Children's Liver Center Medical Director, Viral Hepatitis Clinic Houston, TX Simon Horslen MB, ChB, FRCPCH Director - Hepatobiliary Program Medical Director - Liver & Intestine Transplantation Seattle Children's Hospital Professor - Department of Pediatrics University of Washington School of Medicine Seattle, WA Petar Mamula MD The Children's Hospital of Philadelphia Division of GI & Nutrition Philadelphia, PA Mark McOmber MD Phoenix Children's Hospital Pediatric GI & Nutrition Phoenix, AZ 4 Adrian Miranda MD Associate Professor of Pediatrics Section of Pediatric Gastroenterology, Hepatology and Nutrition Children’s Hospital of Wisconsin Medical College of Wisconsin Milwaukee, WI Maria Oliva-Hemker MD Stermer Family Professor of Pediatric Inflammatory Bowel Disease Director, Division of Pediatric Gastroenterology and Nutrition Johns Hopkins University School of Medicine Baltimore, MD Jean P Molleston MD Indiana University/Riley Hospital for Children Indianapolis, IN Joel R. Rosh MD Director, Pediatric Gastroenterology Vice Chairman, Clinical Development and Research Affairs Goryeb Children's Hospital/Atlantic Health, Morristown, NJ Véronique Morinville MD Director, Training Program Division of Pediatric Gastroenterology and Nutrition Montreal Children's Hospital Assistant Professor of Pediatrics McGill University Montreal, QC, Canada Hugh A. Sampson MD Kurt Hirschhorn Professor of Pediatrics Dean for Translational Biomedical Sciences Director, Conduits (Mount Sinai’s CTSA Program) Director, Jaffe Food Allergy Institute Department of Pediatrics Icahn School of Medicine at Mount Sinai New York, NY Marialena Mouzaki MD, MSc Hospital for Sick Children University of Toronto Division of GI, Hepatology and Nutrition Toronto, ON Corey A. Siegel MD, MS Associate Professor of Medicine, Geisel School of Medicine at Dartmouth Director, IBD Center, Dartmouth-Hitchcock Medical Center Lebanon, NH 5 Continuing Medical Education NASPGHAN CME Mission Statement The education mission of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition is to: 1) Advance understanding of normal development, physiology and pathophysiology of diseases of the gastrointestinal tract, liver and nutrition in children 2) Improve professional competence, quality of care, and patient outcomes by disseminating knowledge through scientific meetings, professional and public education. Our activities, education, and interventions will strive to use Adult Learning Methods (ALM) designed to improve competence, practice performance, and patient outcomes in measurable ways. These educational activities will be targeted to board certified or board eligible pediatric gastroenterologists, physicians with an expertise in pediatric gastroenterology, hepatology and nutrition, subspecialty fellows in pediatric gastroenterology, and nurses specializing in pediatric gastroenterology, hepatology and nutrition. Physicians The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Statement NASPGHAN designates this educational activity for a maximum of 8.25 AMA PRA Category 1 Credit(s)TM Physicians should only claim credit commensurate with the extent of their participation in the activity. 6 Thursday, October 8, 2015 Postgraduate Course - “Updates for the Practitioner” Course Directors: Melanie Greifer MD and Jennifer Strople MD 7:55AM – 8:00AM Welcome and Introduction Melanie Greifer MD 8:00AM - 9:15AM MODULE 1: NUTRITION Moderators: Melanie Greifer MD and Elizabeth Yu MD Obesity and the microbiome Marialena Mouzaki MD, The Hospital for Sick Children Learning objectives: 1. Understand the microbiota in obesity 2. Learn how dietary composition and caloric intake regulate the microbiota 3. Know the effect of the microbiota on the complications of obesity such as metabolic syndrome Redefining malnutrition in the 21st century Praveen Goday, MBBS, Children’s Hospital of Wisconsin Learning objectives: 1. Discuss the new definitions for malnutrition 2. Identify patient populations with malnutrition that are likely to be seen by the pediatric gastroenterologist 3. Discuss the management of different sub-populations with malnutrition Management of food allergies and FPIES Hugh Sampson MD, Icahn School of Medicine at Mount Sinai Learning objectives: 1. Discuss factors that may account for the rise in food allergies 2. Recognize various forms of food allergies including FPIES and other gastrointestinal food allergic disorders 3. Diagnose and manage various forms of food allergies 9:00AM – 9:15AM Rapid-Fire Q&A 9:15AM - 10:30AM MODULE 2: ENDOSCOPY Moderators: Melanie Greifer MD and Diana Riera MD Updates on caustic ingestions Mark McOmber MD, Phoenix Children’s Hospital Learning objectives: 1. Know the timing and preparation of intervention 2. Learn the immediate post procedure management including reintroduction of feeds, NG tubes etc. 3. Understand the follow up and long term issues of ingestion including treatment of these issues 7 Updates on foreign body ingestions Robert Kramer MD, Children’s Hospital Colorado Learning objectives: 1. Know the timing and preparation of interventions dependent on ingestion 2. Review management of glass and sharps 3. Know the most current updates on magnets/batteries and detergent pod ingestions The problematic polyp Petar Mamula MD, Children’s Hospital of Philadelphia Learning objectives: 1. Review prerequisites for successful polypectomy 2. Discuss techniques for difficult polyps 3. Review polypectomy complications 10:15AM – 10:30AM Rapid-Fire Q&A 10:30AM – 10:50AM BREAK 10:50AM – 12:25PM MODULE 3: GI POTPOURRI Moderators: Chris Liacouras MD and Jennifer Strople MD Clostridium Difficile: Difficult but not impossible Stacy Kahn MD, University of Chicago Comer Children’s Hospital Learning objectives: 1. Learn appropriate identification and testing for C. Difficile 2. Know the updates on medical management 3. Understand fecal transplantation and the ethics involved in its use Gluten sensitivity: surely a sensitive, but perhaps not a gluten, subject Stefano Guandalini MD, University of Chicago Comer Children’s Hospital Learning objectives: 1. Define non-celiac gluten sensitivity 2. Understand the current uncertainties around gluten sensitivity 3. Know how to approach patients with suspected non-celiac gluten sensitivity Medical management of refractory abdominal pain Adrian Miranda MD, Children’s Hospital of Wisconsin Learning objectives: 1. Understand the mechanisms of refractory abdominal pain 2. Identifying the patient with refractory abdominal pain 3. Know the available and current treatment options Nausea: Updates that won’t make you sick Carlo Di Lorenzo MD, Nationwide Children’s Hospital Learning objectives: 1. Understand the differential diagnosis of children presenting with nausea as the predominant symptom 2. Become familiar with the medical interventions with the potential of improving functional nausea 3. Become familiar with the non-medical interventions with the potential of improving functional nausea 12:10PM – 12:25PM Rapid-Fire Q&A 12:25PM – 1:50PM LEARNING LUNCHES 8 1. Blurred lines: Where gastroenterology and allergy intersect Moderator: Chris Liacouras Hugh Sampson and Tiffani Hays 2. The child swallowed what? Management of caustic and foreign body ingestions Moderator: Deepali Tewari Robert Kramer and Mark McOmber 3. C. difficile meets its match: Approach to the complicated patient Moderator: Sunpreet Kaur Stacy Kahn and George Russell 4. Gluten sensitivity, more than a fad: A case based discussion Moderator: Kelly Thomsen Stefano Guandalini, Hilary Jericho and Pamela A. Cureton 5. Practical approach to treating the patient with persistent pain and nausea Moderator: John Stutts Adrian Miranda and Katja Kovacic 6. Challenging liver disease cases Moderator: Ritu Walia Jean Molleston and Simon Horslen 7. Viral hepatitis: When do you treat? Moderator: Vicky Ng Daniel Leung and Jessica Wen 8. Perplexing cases in pancreatitis Moderator: Deborah Neigut Veronique Morinville and Soma Kumar 9. Management of pouch and perianal complications Moderator: Dinesh Pashankar Maria Oliva-Hemker and Joel Rosh 1:50PM – 3:25PM MODULE 4: LIVER/PANCREAS Moderators: Melanie Greifer MD and Deborah Neigut MD New horizons in hepatitis C Daniel Leung MD, Texas Children’s Hospital Learning objectives: 1. Understand the epidemiology, burden of disease, and natural history of HCV 2. Appreciate the rapidity and timeline of HCV drug development 3. Become familiar with clinical indications to treat and soon to be available all-oral treatment regimens Renal complications of chronic liver disease Jean Molleston MD, Riley Children’s Hospital Learning objectives: 1. Define prevalence of renal complications in chronic liver disease 2. Review mechanisms of ascites and the role of the kidneys and diuretic use 3. Understand the role of electrolyte monitoring and fluid balance in cirrhosis 4. Review definition of hepatorenal syndrome and treatment recommendations, including use of terlipressin 9 cxAn update on Wilson’s Disease Simon Horslen MD, Seattle Children’s Hospital Learning objectives: 1. Review the clinical presentations in pediatric population and typical diagnostic evaluation 2. Understand genetics and patterns of inheritance to focus who should be screened 3. Understand treatment strategies and side effects of current and future therapies Blame the genes? Familial and autoimmune pancreatitis in children Veronique Morinville MD, Montreal Children's Hospital Learning objectives: 1. Understand when to consider familial and autoimmune etiologies in a child presenting with pancreatitis 2. Review the different genetic factors that may be involved in familial-type pancreatitis 3. Recognize factors implicated in autoimmune pancreatitis types 1 and 2 and what therapies may be attempted 3:10PM – 3:25PM Rapid-Fire Q&A 3:25PM – 3:45PM BREAK 3:45PM – 5:00PM MODULE 5: INFLAMMATORY BOWEL DISEASE Moderators: Judith Kelsen MD and Jennifer Strople MD Getting to the bottom of perianal Crohn’s disease Maria Oliva-Hemker MD, Johns Hopkins University Medical Center Learning objectives: 1. Review the classification systems for fistulizing disease 2. Understand the approach to initial diagnosis and assessment 3. Review surgical and medical therapy and role for each “It’s all about that pouch, 'bout that pouch, no colon”: Evaluation and management of complications post ileal pouch anal anastomosis Joel Rosh MD, Goryeb Children’s Hospital Learning objectives: 1. Review the data for evaluation, treatment and prevention of pouchitis 2. Understand other complications of IPAA 3. Review cancer screening /surveillance recommendations Communicating the benefits and risks of IBD therapy to patients and families Corey Siegel MD, Dartmouth-Hitchcock Medical Center Learning objectives: 1. Review the risks of immunomodulators and biologics 2. Discuss decision making between anti-TNF monotherapy or combination therapy 3. Learn about tools that can be used to better communicate the benefits and risks of IBD therapy 4:45PM – 5:00PM Rapid-Fire Q&A 10 Obesity and intestinal microbiome Marialena Mouzaki, MD MSc Hospital for Sick Children University of Toronto Disclosures Nothing to disclose Learning Objectives Understand the microbiota in obesity Learn how dietary composition and caloric intake regulate the microbiota Know the effects of the microbiota on the complications of obesity, such as metabolic syndrome 11 Microbiota in obesity Conventionally raised Germ-free Weight gain ob/ob mice Germ-free obesity Backhed et al. Proc Natl Acad Sci USA 2004; Turnbaugh et al. Nature 2006 Microbiota in obesity TWINS Germ-free Lean Germ-free Obese Ridaura et al. Science 2013; Vrieze et al Gastroenterol 2012; Wendelsdorf NIH Research Matters 2013 How can the microbiota contribute to obesity? LL: FIAF DNL: SREBP, ChREBP FAO: AMPK Gene expression Bile acids SCFA Appetite Prebiotics & Probiotics increased GLP-1, PYY CHO fermentation SCFA arcuate nucleus Obesity Energy expenditure Energy extraction Example: Bacteria produce H2 which is then used by Archea Acetate + H2 CH4+ CO2 12 Intestinal microbiota composition in obesity Study n - population Ley et al. 2006 Turnbaugh et al. 2009 17 14 (vs. 140) Results • Firmicutes/Bacteroidetes • bacterial diversity • Bacteroidetes Verdam et al. 2013 28 • bacterial diversity • Firmicutes/Bacteroidetes Duncan et al. 2008 37 • No difference in Bacteroidetes or Firmicutes Jumpertz et al. 2011 21 • No difference in Bacteroidetes or Firmicutes Schwiertz et al. 2010 101 • Firmicutes/Bacteroidetes Karlsson et al. 2012 40 • No difference in Bacteroidetes or Firmicutes Intestinal microbiota composition in obesity Bottom line and considerations: Results vary; decreased bacterial diversity is consistent Differences in methodology IM quantification Storage, timing of sample collection, etc. Bahl et al. FEMS Microbiol Lett 2012; Thaiss et al. Cell 2014 Intestinal microbiota composition in obesity Low bacterial richness High bacterial richness Obesity Synthesis of organic acids Pre-DM2, DM2 Dyslipidemia Inflammation Synthesis of SCFA Methane production Carisili et al. Curr Opin Clin Nutr Metab Care 2014 13 Effect of diet on intestinal microbiota 10 adults, ages 21-33, BMI range 19-32 Placed on either diet x 5 days Observed x4 days pre and 6 days post Plant-based diet Animal-based diet Similar intakes No weight change Weight loss by day 3 Bilophila wadsworthia, Alistipes putredinis, Bacteroides Prevotella genus* David et al. Nature 2014 Effect of diet on bacterial metabolism & gene expression Fecal SCFA correlate with diet Diet alters microbial gene expression • Acetate, butyrate • Gluconeogenesis, glycolysis • Isovalerate, isobutyrate • B6 metabolism, aromatic hydrocarbon degradation David et al. Nature 2014 Effect of diet on fecal bile acids Increased fecal deoxycholic acid with animal diet Product of bacterial metabolism Can inhibit growth of certain Firmicutes and Bacteroidetes In animals, linked to HCC Increased expression of sulfite reductase with animal diet H2S can cause intestinal inflammation Link to B. wadsworthia and bile acids David et al. Nature 2014; Devkota et al. Nature 2012 14 Diet and intestinal microbiota Effect of calorie intake on microbiota Lean and obese on 2,400 and 3,400 kcal diets Hypercaloric diet: Bacteroidetes Effect of fiber on microbiota Fiber supplementation Firmicutes/Bacteroidetes Jumpertz et al. AJCN 2011; Holscher et al. AJCN 2015 It makes sense Evolutionary role of changing IM with changes in diet Figure from: livingwithulcerativecolitis.wordpress.com Intestinal microbiota and complications of obesity Diabetes NAFLD Intestinal microbiota Dyslipidemia/ Atherosclerosis Hypertension 15 Intestinal microbiota & diabetes High fat diet bacterial translocation and endotoxemia, prior to the development of diabetes NOD-1 activation inflammation insulin resistance NOD-2 activation insulin resistance in muscle Antibiotics following high fat diet lead to improved insulin sensitivity Caricilli et al. Nutrients 2013; Amar et al. EMBO Mol Med 2011; Zhao et al. Am J Physiol Endocrinol Metab 2011; Tamrakar et al. Endocrinol 2010; Carvalho et al. Diabetologia 2012 Intestinal microbiota and insulin sensitivity: human studies • Systemic insulin resistance • Improved insulin sensitivity • Habitual intake correlates with fasting glucose levels • Consumption leads to insulin resistance Mehta et al. Diabetes 2010; Vrieze et al. Gastroenterol 2014; Suez et al. Nature 2014 Intestinal microbiota and insulin sensitivity: human studies • Systemic insulin resistance • Improved insulin sensitivity • Habitual intake correlates with fasting glucose levels • Consumption leads to insulin resistance Mehta et al. Diabetes 2010; Vrieze et al. Gastroenterol 2014; Suez et al. Nature 2014 16 Intestinal microbiota and insulin sensitivity: human studies • Systemic insulin resistance • Improved insulin sensitivity • Consumption leads to insulin resistance • Fecal transplantation: humans to germ-free mice insulin resistance Mehta et al. Diabetes 2010; Vrieze et al. Gastroenterol 2014; Suez et al. Nature 2014 Intestinal microbiota and hypertension Genes Diet Low-grade inflammation associated with hypertension Probiotics improved BP Minocycline improved BP Environment Common determinants of outcome Singh et al. Immunol Res 2014; Khalesi et al. Hypertension 2014; Shi et al. Hypertension 2010 Dysbiosis is linked to hypertension Spontaneously HTN rat* Rat with HTN 2ndary to chronic AT-II infusion* Human volunteers (adults)* Diversity & richness Firmicutes/Bacteroi detes - Acetate & butyrate-producing bacteria No change - * Compared to controls Yang et al. Hypertension 201 17 SCFA participate in blood pressure regulation Olf78 renin BP Gpr41 vasodilation BP Vessels of small resistance Kidney Colon Pluznick et al. Proc Natl Acad Sci USA 2013 Intestinal microbiota and dyslipidemia Fatty acid oxidation, de novo lipogenesis & FIAF inhibition Bile acids: bile salt hydroxylase activity improved lipid profiles, possibly due to FXR activation Other molecules Mooradian et al. Nat Clin Pract Endocrinol Metab 2009; Org et al.Atherosclerosis 2015 Intestinal microbiota and atherosclerosis Org et al.Atherosclerosis 20 18 Intestinal microbiota and NAFLD Mouzaki, Bandsma. Curr Drug Targets 20 Take home messages Dysbiosis and altered microbial metabolism contribute to the development of obesity Dietary modifications lead to rapid and predictable changes in the intestinal microbiota composition Products of microbial metabolism interfere with host gene expression and contribute to the development of metabolic syndrome Future directions Understand further the interplay between environment, diet and intestinal microbiota Identify microbial patterns that predict future risk of obesity, to allow disease prevention Use the critical impact of the intestinal microbiota (SCFA and bile acids) on nutrient metabolism to develop treatments for obesity and its complications 19 Thank you 20 Redefining Malnutrition in the 21st Century Praveen S. Goday, MD Professor Pediatric Gastroenterology and Nutrition Medical College of Wisconsin Director of Clinical Nutrition Children’s Hospital of Wisconsin Milwaukee, WI Disclosures slide Dr. Praveen Goday serves an expert reviewer for Best Doctors, Inc. and a consultant for Fresenius Kabi. Any real or apparent conflicts of interest related to the content of this presentation have been resolved. Learning objectives • Discuss the new definitions for malnutrition • Identify patient populations with malnutrition that are likely to be seen by the pediatric gastroenterologist • Discuss the management of different sub-populations with malnutrition 21 • Are children in US hospitals malnourished? • Do we care that they are malnourished? • How do we diagnose malnutrition? • Where are pediatric gastroenterologists going to see malnutrition? • What can we do about malnutrition? Are children in US hospitals malnourished? Malnutrition in hospitalized US children 25% 21.0% 20% 15% 14.0% 11.0% 10% 8.0% 7.1% 6.1% 5% 0% UK 1990 UK 1995 USA 1997 France 2001 France 2005 Germany 2008 Clin Nutr 2008; 27:72–76; Arch Pediatr 2005; 12:1226–1231. Arch Pediatr 2001; 8:1203–1208; Arch Pediatr Adolesc Med 1995; 149:1118–1122. Clin Nutr 1997; 16:13–18; J Hum Nutr Diet 1990; 3:93–100. 22 50% 45% 40% 25% obesity 35% 30% 25% 20% 17.4% mild malnutrition 15% 10% 5.8% moderate malnutrition 1.3% severe malnutrition 5% 0% 1 Malnutrition Arch Pediatr Adolesc Med 1995; 149:1118–1122 Do we care that they are malnourished? Subjective global nutrition assessment (SGNA) Preoperative nutritional status in 175 children undergoing surgery Divided into - well nourished - moderately malnourished - severely malnourished Malnourished children - ↑ rates of infection - Longer post-op length of stay (8.2 vs 5.3 d) (P = 0.002) Secker. Am J Clin Nutr. 2007 Apr;85(4):1083‐9. 23 How do we diagnose malnutrition? JPEN 2013;37:460‐81. Recommendations • Use z scores to express individual anthropometric variables in relation to the population reference standard • Use a decline in z score for individual anthropometric measurement as the indication of faltering growth 24 When only one anthropometric data point is available Malnutrition Mild Moderate Severe -1 to 1.9 - 2 to -2.9 ≤-3 Length/height-for-age z score - - ≤-3 Mid–upper arm circumference z score -1 to 1.9 - 2 to -2.9 ≤-3 Weight-for-height or BMI for age z score Nutr Clin Pract.2015;30:147‐161 When more anthropometric data points are available Malnutrition Weight gain velocity (<2 y) Mild Moderate Severe <75% of expected <50% of expected <25% of expected Nutr Clin Pract.2015;30:147‐161 When more anthropometric data points are available Malnutrition Weight gain velocity (<2 y) Weight loss (2–20 y) Mild Moderate Severe <75% of expected 5% <50% of expected 7.5% <25% of expected 10% Nutr Clin Pract.2015;30:147‐161 25 When more anthropometric data points are available Malnutrition Weight gain velocity (<2 y) Weight loss (2–20 y) Decline in weight‐ for‐length/ BMI z score Mild Moderate Severe <75% of expected 5% <50% of expected 7.5% <25% of expected 10% ↓1 z score ↓2 z scores ↓ 3 z scores Nutr Clin Pract.2015;30:147‐161 When more anthropometric data points are available Malnutrition Mild Moderate Severe <75% of expected 5% <50% of expected 7.5% <25% of expected 10% Decline in weight‐ for‐length/ BMI z score ↓1 z score ↓2 z scores ↓ 3 z scores Inadequate nutrient intake 51‐75% estimated needs 26–50% estimated needs ≤25% estimated needs Weight gain velocity (<2 y) Weight loss (2–20 y) Nutr Clin Pract.2015;30:147‐161 Subjective global assessment (SGA) • Standard method for assessing nutritional status in adults • SGA status is associated with medical outcomes √ History › Weight change › Oral intake › GI symptoms › Functional status › Metabolic demands √ Physical exam › Fat stores › Muscle stores › Edema / ascites Detsky. JPEN J Parenter Enteral Nutr. 1987;11:8‐13 26 Subjective global nutrition assessment (SGNA) • Should become the standard method for assessing nutritional status in children • History • Physical exam › Appropriateness of height › Fat stores for age › Muscle stores › Appropriateness of weight › Edema / ascites for height › › › › › Changes in body weight Oral intake GI symptoms Functional status Metabolic demands Am J Clin Nutr. 2007 Apr;85(4):1083‐9. How to Perform Subjective Global Nutritional Assessment in Children. Secker DJ and Jeejeebhoy KN. Journal of the Academy of Nutrition and Dietetics 2012. 112: 424–431. GI symptoms • Severe if symptoms have been present for 2 weeks or longer • Symptoms for 3 days or fewer, can be disregarded 27 Functional status • Has a lack of nutrition affected the child’s physical function and altered her daily activities? √ Compare to the child pre-illness Metabolic demands Moderate metabolic stress • Routine surgery • Laparoscopic surgery • Exploratory surgery • Fracture • Infection √ Bronchiolitis √ Gastroenteritis) • Decubitus ulcer Metabolic demands Severe metabolic stress • Major organ surgery √ stomach, liver, pancreas, lung • Major bowel resection • Multiorgan failure • Severe pancreatitis • Severe sepsis • Severe inflammation • Chronic illness with acute deterioration • Current treatment for malignancy 28 Albumin and prealbumin • These proteins are negative acute phase reactants √ They are, in most instances, not indicative of malnutrition Where are pediatric gastroenterologists going to see malnutrition? Causes of malnutrition Non-illness related Starvation - Anorexia nervosa OR Illness related Acute (<3 months) - Trauma, burns Chronic (> 3 months) - CF, short gut syndrome Malabsorption Nutrient loss Hypermetabolism +/Inflammation Altered utilization of nutrients 29 Malnutrition in Pediatric Gastroenterology 25 43% 43% 20 Of the malnourished • 50% were admitted with a nutrition‐related diagnosis • Only 40% received nutrition intervention 15 10 7% 5 0 Normal Moderate Malnutrition Severe Malnutrition Malnutrition in the hospitalized Peds GI patient Consult service • Cardiac patients • Renal patients • Oncology/BMT • PICU • Neurology patients • Cystic fibrosis GI service • Chronic liver disease • Short bowel syndrome • Crohn disease Any patient that has been in the hospital for more than 4-5 days What can we do about malnutrition? 30 Identify it! Treatment of malnutrition Non-illness related Starvation - Anorexia nervosa Feed! OR Illness related Acute (<3 months) - Trauma, burns Chronic (> 3 months) - CF, short gut syndrome Malabsorption Nutrient loss Reverse nutrient loss & malabsorption Hypermetabolism +/Inflammation Altered utilization of nutrients Treat inflammation In the outpatient setting… • High-calorie beverages • Cyproheptadine • Enteral nutrition • Parenteral nutrition 31 In the inpatient setting… • Enteral nutrition • Parenteral nutrition Billing and coding for malnutrition Coding and Billing Reimbursement = Primary Diagnosis + Comorbidity • CPT Codes: √ 263.1 = Mild malnutrition √ 263 = Moderate malnutrition √ 262 = Severe malnutrition 32 Billable hospital charges $7,000 $6,142 $6,000 $5,304 +47% $5,000 $2,000 Malnutrition $3,000 $4,161 Malnutrition $4,000 +38% $3,950 $1,000 $0 Asthma Tonsillitis Conclusions • Malnutrition has a high prevalence and affects outcomes • Seek out, identify and treat malnutrition • You will be justified in billing the comorbidity of malnutrition if you identify and treat it! 33 34 Management of Food Allergy & FPIES NASPGHAN 2015 October 8, 2015 Hugh A Sampson, MD Dean for Translational Biomedical Sciences Professor of Pediatrics Department of Pediatrics/Allergy & Immunology Director, Jaffe Food Allergy Institute Faculty Disclosures • FINANCIAL INTERESTS I have disclosed below information about all organizations and commercial interests, other than my employer, which may create or be perceived as a conflict of interest. Name of Organization Allertein Therapeutics, LLC Regeneron Therapeutics Food Allergy Research & Education Danone Research Nature of Relationship Consultant, Minority Stockholder Consultant Medical Advisory Board Scientific Advisory Board • RESEARCH INTERESTS I have disclosed below information about all organizations which support research projects for which I serve as an investigator. Name of Organization Nature of Relationship National Institutes of Health Grantee Food Allergy Research & Education Grantee ThermoFisher Scientific Grantee • Patents – EMP-123 (recombinant protein vaccine) & FAHF-2 (herbal product) Learning Objectives Discuss factors that may account for the rise in food allergies Recognize various forms of food allergies including FPIES and other gastrointestinal food allergic disorders Diagnose and manage various forms of food allergies including FPIES 35 Prevalence of Food and Skin Allergies in the Pediatric Population [1 – 17 years] in the US “2nd Wave” of Allergy Epidemic ~17%% 12.5% 7.4% 5.1% 3.4% NCHS Data Brief #121; May 2013 Jackson KD et al Factors Thought to Promote Allergy Maternal vitamin intake, e.g. folate Genetic factors/family Older parental age history of allergy Prenatal Maternal smoking Maternal consumption of allergenic foods during pregnancy Caesarean section delivery Failure to initiate breastfeeding Infant dietary factors e.g. Later introduction of allergenic foods Immunizations Perinatal Postnatal Lack of vitamin D (sunlight) fetal epigenetic modification through maternal exposure to these factors Factors associated with the ‘hygiene hypothesis’ e.g. Smaller family size Direct infant exposure Exposure to tobacco smoke + other environmental pollutants Modified from Allen K & Koplin J. Epidemiology of Food Allergy. In Burks, James, Eigenmann et al. (Eds), Food Allergy 1e.2011. Randomized Trial of Early Peanut Consumption in High-risk Infants (LEAP) • 712 infant: 4 – 11 mos with egg allergy &/or severe atopic dermatitis - Prick skin tests (PSTs) to peanut: - 542 had neg PSTs - 98 had PSTs of 1 – 4 mm - 76 (~10%) had + PSTs > 4mm (were excluded) • One-half were randomly assigned to consume 2 gm peanut 3x’s/wk to age 5 yrs & one-half strictly avoided all peanut Du Toit G et al. NEJM 2015 36 Randomized Trial of Early Peanut Consumption in High-risk Infants (LEAP) • One PST negative infant & 6 PST pos infants reacted to peanut on initial challenge & did not consume peanut - 4/7 still reacted at 5 yrs of age • Adherence: median consumption at 2 yrs: - 0 gm in avoidance group - 7.7 gm in consumption group • Safety: no difference in severe adverse events Du Toit G et al. NEJM 2015 LEAP Trial Outcome 85% relative reduction ! 70% relative reduction ! Du Toit G et al. NEJM 2015 Prevalence of Food Allergy by Age in the United States 13 % Prevalence 11 9 7 5 3 1 1 2 3 4 5 6 7 8 Years of Age Affects ~12 million Americans Sicherer SH & Sampson HA. Annu Rev Med. 2009; 60:261-278. 9 10 20+ <3 yrs Overall Milk 2.5 0.3% Egg 1.5% 0.2% Peanut 1.4% 0.8% Fish 0.1% 0.4% Shellfish 0.1% 2.0% 37 Cutaneous Allergies IgE-Mediated Urticaria Angioedema Non-IgE-Mediated Atopic Dermatitis Dermatitis Herpetiformis Contact Dermatitis Atopic Dermatitis & Food Allergy 4 month old breast fed infant with an eczematous rash - cleared with exclusion of egg from mother’s diet With permission Atopic Dermatitis & Food Allergy Mother ingested eggs 4 hours before breast-feeding ~30 minutes later, the baby is irritable and has developed facial rash With permission 38 Atopic Dermatitis & Food Allergy Erythematous rash on extensor surfaces With permission Gastrointestinal Allergies IgE-Mediated Oral Allergy Acute GI Hypersensitivity Non-IgE-Mediated EoE AEG Enterocolitis Enteropathy - Celiac Disease Proctocolitis Eosinophilic Esophagitis (EoE) • Onset - infancy to adulthood • Symptoms - Young children: reflux esophagitis, vomiting, food refusal, abdominal pain, irritability sleep disturbance & FTT - Adolescents: chest pain, dysphagia, globus & impaction • Foods implicated - milk, wheat, soy, egg, beef, corn - often involves multiple foods • Diagnosis - failure to respond to PPIs - endoscopy and biopsy of esophagus 39 EoE: Endoscopic Diagnosis Normal Furrows Rings Plaques Plaques & Furrows Pre-Diet Esophageal Biopsy Kelly et al. Gastroenterology 1995 Post-Diet Esophageal Biopsy Kelly et al. Gastroenterology 1995 40 Diagnosis of Acute FPIES Major criterion: Minor criteria: 1. Repetitive vomiting 1- 4 hours after eating the suspect food 1. A second episode of repetitive vomiting after eating the same suspect food 2. Repetitive vomiting episode 1 - 4 hours after eating a different food 3. Extreme lethargy with suspected reaction 4. Marked pallor with suspected reaction 5. Emergency room visit with suspected reaction 6. Need for intravenous fluid support with any suspected reaction 7. Diarrhea in 24 hours (usually 5-10 hours) The diagnosis of FPIES based on the major criterion plus at least 3 minor criteria. Diagnosis of Chronic FPIES • Severe presentation*: when the offending food is ingested on a regular basis, [e.g., infant formula] intermittent but progressive vomiting & diarrhea, + blood in stool, + dehydration & metabolic acidosis • Milder presentation*: lower doses of the problem food (e.g. solid foods or food allergens in breast milk) lead to intermittent vomiting, and/or diarrhea, usually with poor weight gain/ FTT, but without dehydration or metabolic acidosis • *Symptoms resolve within days following elimination of the offending food(s) and acute recurrence (1 – 4 hours) of symptoms when the food is reintroduced Respiratory Allergies IgE-Mediated Allergic Rhinitis Laryngeal edema Anaphylaxis Non-IgE-Mediated Asthma Heiner’s Syndrome 41 Diagnosing Food Allergy • NIAID Guideline 11: Expert Panel recommends using oral food challenges for diagnosing food allergy. • The double-blind placebo-controlled oral food challenge (DBPCFC) is the “gold standard” • Single-blind & open food challenge may be considered diagnostic in clinical settings when - food challenges elicit no symptoms (i.e. neg challenge) - there are objective symptoms (i.e. pos challenge) that correlate with medical history & are supported by laboratory tests • Skin tests and in vitro IgE measurements alone can never be considered diagnostic NIAID Expert Panel. J Allergy Clin Immunol. 2010; Predictive Value of PSTs Comparison of PST results & the outcome of 120 oral milk challenges ‐ 37% positive Wheal > 95% PPV Milk > 8 mm Egg > 7 mm Peanut > 8 mm Sporik R et al. Clin Exp Allergy, 2000 Probability Predictive Value of Food-specific IgE 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Egg white Allergen Decision Pt (kUA/L) Egg (< 2 yrs of age)+ Milk (< 1yr of age)++ Peanut Logit model using log(kUA /L) 0.35 0.7 1.2 3.5 7.0 17.5 50 100 IgE Antibody Concentration (kUA/L) UniCAPTM Sampson HA JACI 2001 7 2 15 5 14 Soy 30 Wheat 26 Tree nuts+++ 15 + Boyano MT, et al. Clin Exp Allergy 2001 ++ Garcia-Ara C, et al. JACI 2001 +++ Clark AT, Ewan P. Clin Exp Allergy 2003 Maloney J et al. JACI 2008 42 FPIES Oral Food Challenge Challenge: 0.06 – 0.6 gm/kg (up to 3 gm) in 3 doses over 30 mins Major Criterion Minor Criteria Vomiting in the 1-4 hour period after ingestion of the suspect food and the absence of classic IgE-mediated allergic skin or respiratory symptoms 1. Lethargy 2. Pallor 3. Diarrhea in 5-10 hours after food ingestion 4. Hypotension 5. Hypothermia 6. Increased PMN’s > 1500 above the baseline count Treatment: IV saline bolus (20ml/kg); ondansetron (0.1-0.15 mg/kg IV or IM) Natural Course of Food Allergy Percent with clinical food allergy 100 80 60 40 20 0 Birth 2 4 6 8 Years • Following standard of care: strict food allergen avoidance Effect of Baking (heat-denaturation) on Sequential & Conformational Epitopes of Food Proteins M I M I L K 1 M I L L K K M I Heat & Processing K L 2 ~80% of young children with milk (egg) allergy “outgrow” their food allergy; react primarily to conformational epitopes 43 Development of Tolerance Milk: Treated vs. Controls Egg: Treated vs. Controls ~15 x’s more likely to tolerate egg at 6 years 16 x’s more likely to develop full tolerance at 5 yrs compared to control; p < 0.0001 N = 57 N = 60 Kim et al. JACI 2011; 128:125-131 Leonard S et al. JACI 2012; 130:473-80 Managing Food Allergy & Foodinduced Anaphylaxis • Appropriate diagnosis of specific food allergy • Education - strict avoidance of food allergen - learn to read food labels & recognize high risk situations - early signs of an allergic / anaphylactic reaction • Provide emergency treatment plans in writing - FARE website: www.foodallergy.org • Provide self-Injectable epinephrine & liquid antihistamine • Instructions to go to a medical facility Managing FPIES • Strict elimination of the culprit food(s) - milk, soy, rice, oat, other grains, fish & shellfish • Plans for dietary advancement - infants should be challenged every 1 – 2 years • Treatment of symptoms at presentation or re-exposure - IV fluids (10-20ml/kg); IV or IM ondansetron; - International Association for Food Protein Enterocolitis website, http://fpies.org/docs/Emergency_Plan.pdf • Plan for supervised OFCs to address FPIES resolution - in milk-FPIES diagnosed by 6 mos, 50% outgrown by 1 year and 90% by 3 years of age - 50% of children with “solid food” FPIES react to more than one food; reactivity may persist longer 44 Immunotherapeutic Strategies in Human Trials • Allergen-specific Immunotherapy - Heat-denatured protein - Oral immunotherapy (OIT) + omalizumab - Sublingual immunotherapy (SLIT) - Epicutaneous immunotherapy (EPIT) - Engineered recombinant protein - Nanoparticles with CpG • Allergen non-specific immunotherapy - Chinese Herbal medications - Anti-IgE immunotherapy Conclusions • Food allergy has increased dramatically over the past 15 years and now affects ~4% of the US population • Although the oral food challenge remains the “gold standard” for diagnosis, laboratory tests are becoming more sensitive and specific • Several therapeutic strategies are under investigation, but OIT provides the most protection • Omalizumab dramatically reduces adverse reactions to OIT and markedly alters its safety profile • Several new therapeutic approaches in the “pipeline” that could induce more lasting effect 45 Dangerous Mimicry: Addressing Caustic Ingestions in Children Mark E. McOmber, M.D. Director of Endoscopy and Therapeutic Endoscopy Phoenix Children’s Hospital Phoenix, AZ Financial Disclosure I have no financial relationship with any commercial entity to disclose Objectives • Review the epidemiology and pathophysiology of caustic ingestions • Know the key features of the clinical assessment • Review the treatment options and long term management 46 Epidemiology Nearly 200,000 ingestions reported per year Most are accidental and the amounts small Most are young children from 1‐3 yrs old In adolescents the ingestions tend to be intentional, as a suicide attempt, and the quantities are larger • There are limited reports of ingestion injury as a result of child abuse • • • • Accidental Ingestions • Alkaline agents more common than acidic • Household cleaning products – Toilet bowl and oven cleaners • Cosmetic products – Hair relaxers • Dishwasher/Laundry agents • Pool products * Batteries/magnets are unique and were covered separately Mimicry‐ When Marketing and Safety are at Polar Opposites • Agents are often mistaken for more palatable items by young children – Colorful – Misleading container or wrapper may suggest a safer substance – Overly Accessible 47 Colorful A delicious candy? ‐ offered by a smooth talking person with a fancy accent Or poison? Misleading Wrappers and Containers Accessibility Mechanism of Injury • Alkaline agents (esp. pH >11.5), – injury through LIQUEFACTION necrosis – Deep penetration dependent on concentration and duration of exposure • Acidic agents (esp. pH <2), – injury through COAGULATION necrosis – more superficial because of the esophageal mucosa and the coagulum/eschar – Antral spasm can pool the acid in the stomach, resulting in outlet obstruction from injury and fibrosis Mechanism of Injury • Delayed damage beyond the necrosis over the first week – From inflammatory process – From vascular thrombosis • By the third week fibrogenesis and strictures become more likely Clinical Manifestations • Dysphagia is the MOST COMMON symptom – Related to dysmotility from inflammation, and later from fibrosis/stricture • • • • • Drooling (even in the absence of oral burn) Pain Vomiting Perforation Airway injury with stridor, hoarse voice, respiratory distress 49 Evaluation • History – Timing of exposure – Type and amount of exposure • pH can be measured or use of Material Safety Data Sheets or Poison Control Center (in U.S. 800.222.1222) • Exam – Mental status, vitals, respiratory and oral exams Evaluation • Imaging – CXR if respiratory symptoms • Retained foreign body, perforation, or pneumonia – Esophagram unreliable for early injury unless perforation is suspected by other imaging • If done, use only water‐soluble contrast – CT or MRI when perforation is suspected or concern of vascular involvement Initial Management • Supportive with IVF and limit further injury • Induction of vomiting is CONTRAINDICATED – Leads to further esophageal injury and risk of aspiration • Neutralizing agents, dilution, and charcoal are NOT recommended – Additional damage from heat injury – Increase risk of vomiting – Obscure findings on endoscopic evaluation 50 Initial Management • Asymptomatic (no oral burn, dysphagia, emesis, etc.) – Endoscopy unnecessary unless . . . • pH of substance is more caustic (>11.5 or <2) or the causticity is unknown • Symptomatic – Admit for supportive care – Prepare for endoscopy – Hold oral nutrition until initial evaluation is complete Initial Management • Endoscopy – Ideally within 24 hours of ingestion – Very early endoscopy (less than 6 hours after ingestion) may not show full extent of the injury – After 4 days, the risk of perforation increases • Contraindications – – – – Hemodynamic instability Evidence of perforation Respiratory distress Severe oropharyngeal injury with edema and necrosis Endoscopy • Staging – Grade 0 is normal mucosa – Grade 1 is superficial with edema or hyperemia – Grade 2a: friable, hemorrhage, erosions, blisters, shallow ulcerations, white membrane 2b • 2b‐ above plus circumferential OR focal but deep – Grade 3a: grade 2 PLUS focal necrosis that is brown‐black or grey discoloration 3a • 3b‐ extensive whereas 3a is only focal 51 Outcome by Stage • 1 or 2a‐ most have a good prognosis and do not develop stricture or outlet obstruction – Risk of stricture with 2a is 4.7% • 2b and 3‐ 32% to 75% develop strictures in 2b and 3 grade burns, respectively • 3b‐ mortality reported up to 65%; majority require esophagectomy/replacement surgeries Management 2a • Grade 1 or 2a‐ short observation and PO challenge • Grade 2b and 3 – Consider NG placement under endoscopic guidance 2b • Maintain lumen • Route for future feeding VS. 3a • Concern for infection, GER • Concern for long stricture Management of Grade 2b and 3 • Steroids? – Prevent strictures in animal models – Mixed results in human studies • *3 days of high dose methylprednisolone (1g/1.73m2) reduced the stricture occurrence without noted side effects in 83 children with grade 2b burns • Other studies suggest increased incidence of infection without a decrease in stricture incidence *Usta et al. Pediatrics 2014 52 Management of Grade 2b and 3 • Antibiotics? – Lack of evidence to support or guide use and patient selection – Suggested in cases where infection is suspected or at an increased risk • Perforation • Grade 3 esophageal injury • On corticosteroid therapy – 3rd generation cephalosporins, ampicillin/sulbactam, piperacillin/tazobactam, etc. Management of Grade 2b and 3 • Acid Blocker (PPI or H2RA)? – Decrease acid and pepsin exposure to the injury – No controlled trials for efficacy – No study to determine duration or dose Endoscopy • Endoscopic Ultrasound (EUS) – Miniprobe EUS • Safe but not all centers are trained in EUS • No difference in predicting early complications • May detect if muscle layer is intact which may predict less stricture formation or the response to dilation • More studies needed Kamijo et al. Am J Gastroenterol 2004 53 Strictures • Most common serious long‐term complication of caustic ingestions • 32‐75% chance of developing strictures in grade 2b and 3 injury • Develop as early as 3wks with 80% of strictures by 8 weeks post injury Strictures • Diagnostic imaging to evaluate for stricture is usually performed about 2‐3 weeks after the injury. • Dilation typically recommended starting 4‐6 weeks after injury – *Recent studies have shown less stricture when done sooner (5‐15 days) but these retrospective studies were small with milder injuries (2a,2b) *Boskovic et al. Eur J Gastroenterol Hepatol 2014; Temiz et al. World J Gastroenterol 2012 Endoscopic Dilation 54 Dilation • Historically, Savary and Tucker dilators‐ longitudinal shearing forces • Currently, endoscopic balloon dilation‐ applies radial pressure • Serial dilations are often required and typically are done every 1‐3 weeks until oral feeds are tolerated – Prospective studies are needed to evaluate frequency Long‐term Management • Risk of esophageal adenocarcinoma or squamous cell carcinoma is 1000x the occurrence rate of the general population. • Recommended to begin surveillance 15‐20 years after the injury and repeat every 1‐3 years thereafter. Summary • Accidental caustic ingestions are a major health risk for young children • Clinical symptoms can be misleading so endoscopy is the primary means of evaluation • Stricture is the main complication • Evidence based treatment protocols are still lacking and prospective studies are needed • Increased risk of esophageal cancer even years after injury 55 Updates on Foreign Body Ingestions Robert E. Kramer, MD, FASGE Director of Endoscopy Associate Professor of Pediatrics Children’s Hospital Colorado Financial Disclosure No relevant financial relationships to disclose Objectives •Outline the timing and preparation of interventions dependent on type of ingestion •Discuss changes in the management of button battery and magnet ingestions •Review the management of glass and other sharp ingestions •Summarize current state of knowledge regarding ingestion of detergent pods and superabsorbent materials 3 56 1 Crystalline Opportunity •“What we are drawn to in this imperfect science, what we in fact covet in our way, is the alterable moment‐the fragile but crystalline opportunity for one's know‐how, ability, or just gut instinct to change the course of another's life for the better.” ― Atul Gawande, Complications: A Surgeon's Notes on an Imperfect Science 4 Timing of Endoscopic Intervention Type Location Symptoms Timing Button Battery Esophagus YesorNo Emergent Gastric/SB Yes Emergent No Urgent(ifage<5andBB≥20mm) Elective(ifnotmovingonserialX‐ray) Magnets Esophagus Yes No Emergent(ifnotmanagingsecretions,otherwiseurgent) Urgent Gastric/SB Yes No Emergent Urgent Esophagus Yes No Emergent(ifnotmanagingsecretions,otherwiseurgent) Urgent Gastric/SB Yes No Emergent(ifsignsofperforationthenwithsurgery) Urgent Esophagus Yes No Emergent(ifnotmanagingsecretions,otherwiseurgent) Urgent Esophagus Gastric/SB Yes No Yes Emergent(ifnotmanagingsecretions,otherwiseurgent) Urgent Urgent LongObject Esophagus Gastric/SB No YesorNo YesorNo Elective Urgent Urgent Absorptive Object Esophagus Yes No YesorNo Emergent(ifnotmanagingsecretions,otherwiseurgent) Urgent Urgent Sharp Food Impaction Coin Gastric/SB Emergent (< 30 Min) Emergent (< 2 hours) Urgent (<8 Hours) Elective (<24 Hours) 5 Preparation • Optimal venue • Endoscopy unit, OR, IR, IC, Hybrid OR • Additional personnel • Pediatric surgery, ENT, Cardiac surgery, Interventional Cardiology • Fully stocked "Foreign Body" Tool Box • Ex‐vivo practice run to select best device • Additional tools • Foreign body hood • Overtube • Blakemore tube • Banding device 6 57 2 Tools of the Trade Raptor Forceps Polyp Snare Multi-Prong Forceps Roth Net Foreign Body Hood Coin Grasper Rubber-Tipped Forceps Wire Basket Endoscopy Caps Overtube 7 The Usual Suspects 60 50 40 30 20 1 10 mm 8 Button Batteries • Home Movie Demonstration 9 58 3 Button Batteries (BB)‐ New Aspects • Gastric/SB : Consider endoscopy in high risk group (Age ≦5, BB diameter ≧ 20 mm) • Purpose: assess for esophageal injury, removal of battery is secondary • To date only a single patient survived from aortoesophageal fistula (AEF) • Further need to refine multidisciplinary care • Consider immediate transfer to Interventional Cardiology/ Hybrid OR for high risk cases • Vigilant for sentinel bleed, warning sign of catastrophic hemorrhage • Ongoing injury, risk of AEF up to 3 weeks after removal • Maintain high index of suspicion for BB ingestion • Any child < 5 with even slight hematemesis (consider X‐ray?) 10 Magnet Ingestions • Controversial aspect: Beyond ligament of Treitz, asymptomatic • Spectrum: observation surgical removal • Take ownership, especially long distance patients • Balloon enteroscopy a good option • Highlights need for rapid endoscopic removal from proximal GI tract • Advise against metal buckles, etc • Though technically off the market, still millions in circulation 11 Neodymium Magnets 12 59 4 Glass Ingestions • Very challenging ingestions • Radiolucent and small • Judgment call depending on • Symptoms • Witnessed ingestion • Evidence of injury in oropharynx • Imaging studies may be helpful (CT, contrast study) • But may delay anesthesia • Rubber‐tipped forceps helpful for small shards • Use of FB hood or cap to protect mucosa • (overtube for older patients) 13 Other Sharps • Jackson’s Axiom‐ Leading points perforate, trailing points do not • One end heavier than the other (ie screw, nail) have the sharp end trailing • Literature suggests endoscopic removal of all sharps • 35% perforation rate, 26% mortality rate but data old1 • Toothpick: most worrisome sharp • Radiolucent, long, wood may harbor more bacteria • Reports of perforation and migration to liver, heart, kidneys • High risk of accidental ingestion • Review2 of 136 case reports by Steinbach et al in 2014 • 50% not aware of ingestion • Bowel perforation in 79% 1. MacManus J, Am J Surg 1941; 53:393-402. 2. Steinbach C, World J Surg 2014; 38(2):371-7. • Mortality 9.6% 14 Detergent Pods • Introduced to US market in 2010 • Water‐soluble membrane • Higher concentrations of surfactant caustic injury • Propylene glycol lactate, metabolic acidosis • Number of case reports • Esophageal injury described • Primarily respiratory injury • Management more similar to caustic rather than FB ingestion • Review from Poison Control in 2015 of 111 ingestions1 • Mean age 1.4 years • 66% managed at home • 9 pts admitted (8.1%) • 67% of admissions intubated • CNS depression 22% (ethoxylated alcohols) 1. Stromberg PE, Am J Emerg Med,2015;33(3): 349-51 15 60 5 Superabsorbent Objects • Polymers that can absorb up to 100x their weight in water • Found in a number of household objects • Diapers, feminine hygiene products • Used in many toys, under the name Water Balz, H2O Orbs • Radiolucent • May reach 30‐60x original volume • May be easily swallowed and cause obstruction as they expand • Large round shape, likely best removed with a net • Four reports in the literature with one documented death1 • Led to a recall by CPSC in 2012 • Reports of canine ingestion of feminine hygiene products in veterinary literature, but none in humans 16 1. Zamora IJ, Pediatrics 2012; 130(4):e1011-4. Water Balz 17 Coin Ingestions • Most common FBI in children • >250,000 ingestions, 20 deaths in 10 year period1 • Distal esophageal coins may clear in up to 60%2 • Coins > 23.5 mm (American, Canadian quarters) more likely to become impacted in children < 5 yo • Majority of ingestions are pennies • Post 1982 zinc 5% 97.5% • Causes corrosive injury in acid environment • Production of hydrogen gas and zinc chloride production (O’Hara S) • Newer pennies may appear less dense in center on X‐ray • Coin grasper may not be as effective as rat‐tooth or alligator jaw forceps • Get lateral film to differentiate from BB 1. Chen X, Int J Pediatr Otorhinolaryngol 2006;70:325-9. 2. Tander B, J Laroendosc Adv Surg Tech A 2009;19:241-3. 18 61 6 Summary •Management of FBI’s in children depends on the object, location, timing, age and symptoms •BBI and multiple magnet ingestion remain the most dangerous FBI in children and may require aggressive management even in asymptomatic patients •A multidisciplinary approach is often necessary in complicated FBI’s and requires good communication between GI, surgery, CV surgery, ED, Radiology, ENT •Detergent pods and superabsorbent objects pose an emerging threat for ingestion in children 19 APPENDIX 1‐ BUTTON BATTERY Witnessed or suspected BB Ingestion Gastric or Beyond Esophageal Active Bleeding or Clinically Unstable: Otherwise Stable: Immediate Endoscopic Removal <5 years of age AND BB >20 mm ≥5 years of age AND/OR BB < 20mm Consider assessment of any esophageal injury and endoscopic removal if possible, within 24‐48 hours May consider outpatient observation only Endoscopic removal in OR with Surgery/CV surgery present If evidence of any esophageal injury: Admission, NPO, IV anbx Consider CT Angiography to exclude aortic injury. Consider MRI of chest to determine proximity of injury to aorta No significant injury to surrounding tissue or proximity to aorta Repeat X‐ray in 48 hours for BB ≥20 mm, repeat at 10‐14 days for BB < 20 mm if failure to pass in stool If esophageal injury present: Admit, NPO, IV anbx and consider CT Angiography, MRI of chest Demonstation of injury close to aorta Continue NPO and Anbx and serial MRI q 5‐7 days until injury seen to recede from aorta Esophagram to exclude leak before advancing diet as tolerated Endoscopic removal if develops GI symptoms or not passed stomach by time of X‐ray at time described above If presence of hematemesis or UGI bleeding within 21 days of removal, assume aortoenteric fistula and emergently prepare for thoracotomy with CV surgery 20 Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037 APPENDIX 2‐ MAGNET INGESTION I i i lP InitialPresentation i ‐ObtainHistory ‐KnownMagnetingestion ‐UnexplainedGIsymptomswithrareearthmagnetsinenvironment ‐ObtainanabdominalX‐ray.Ifmagnetsarepresentonflatplateobtainlateralx‐ray ‐Determinesingleversusmultiplemagnetingestion Determinesingleversusmultiplemagnetingestion MultipleMagnet (orsinglemagnet&metallicobject) SingleMagnet Allwithinthestomachoresophagus Withinthestomach oresophagus ‐Option1:Consult PediatricGIif available ‐Considerremovalif patientatincreased riskforfurther ingestion ‐Option2:Follow serialx‐raysas outpatientand educateparents* Beyondthestomach ‐ConsultpediatricGIif available. ‐Considerremovalif possible. ‐Followwithserialx‐ raysasoutpatient ‐Educateparents* ‐Confirmpassagewith serialx‐ray ‐Ifdelayed progressionmayuse PEG3350orother laxativetoaid passage Beyondthestomach ‐IfpediatricGIavailablenotifyforremovalespeciallyifless than12hours ‐Ifnotavailable,transfertoreferralcenter ‐ConsultpediatricGIandpediatric surgeonifavailable ‐Ifnotavailablesendtoreferralcenter ‐Ifgreaterthan12hoursuntiltimeofprocedure,then consultpediatricsurgerypriortoendoscopicremoval ‐Managementdependsonwhether symptomaticorasymptomatic Successfulremoval ‐Dischargehome withfollow‐up& education Unsuccessful removal ‐Refertosurgeryfor removal Symptomatic Asymptomatic ‐Refertopediatric ‐Ifnoobstructionor perforationonx‐raymay surgeryfor removebyenteroscopyor removal colonoscopyifavailableor followwithserialx‐ray SuccessfulEndoscopicRemoval ‐Maydoserialx‐rayinEDto ‐Dischargeafterfeedingtolerance,with checkforprogressionevery4‐6 appropriatefollow‐upandeducation hours Noprogressionon *ParentalEducation: ‐Removeanymagneticobjectsnearby ‐Avoidclotheswithmetallicbuttonsor beltswithbuckles ‐Ensurenoothermetalobjectsor magnetsareinthechildenvironment foraccidentalingestion serialx‐rays ‐Admitforfurthermonitoringandserialx‐raysor surgicalremoval ‐MayusePEG3350orotherlaxativetoaidinpassage andtohelpprepareforcolonoscopy ‐Continueserialx‐rayevery8‐12hours.Ifnosymptoms thenproceedwithsurgicalremovalorendoscopic removalwithsurgicalback‐up Progressionofmagnetsonserialx‐rays ‐Educateparentsonprecautions*and dischargewithclosefollow‐up ‐Confirmpassagewithserialx‐rays ‐Ifatanytimemagnetsdonotprogressor patientbecomessymptomatic,admitto hospitalforremovalofmagnets 21 Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037 62 7 APPENDIX 3‐ SHARP INGESTION Known or suspected ingestion of sharp object Radio‐opaque Radiolucent Small bowel (distal to ligament of Treitz) Gastric Symptomatic self‐ reported or witnessed ingestion: Esophageal: Urgent endoscopic removal Symptomatic Asymptomatic: Consider CT, ultrasound, MRI or esophagram for further assessment Urgent endoscopic evaluation and removal Asymptomatic Enteroscopy or surgical removal Consider endoscopic removal unless short object with heavier blunt end Follow clinically with serial X‐ray Evidence of FB: Endoscopic removal Enteroscopy or surgical removal considered if develops symptoms or > 3 days without passage No evidence of FB: Clinical observation, close follow‐up, reassess if develops symptoms 22 Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037 APPENDIX 4‐ FOOD IMPACTION Suspected EFI Consider FB series with water‐ soluble contrast to identify obstruction Not tolerating secretions: Tolerating secretions: Urgent endoscopic removal Endoscopic removal within 24 hours Obtain Proximal and distal esophageal biopsies and assess for stricture GI Follow‐up Stricture without eosinophilic inflammation Consider repeat endoscopy with possible dilation Eosinophilic inflammation with stricture Eosinophillic inflammation without stricture No eosinophilic inflammation and no stricture Consider repeat endsocopy after 4‐8 weeks of PPI therapy and/or EoE therapy Consider repeat endsocopy after 4‐8 weeks of PPI therapy Follow clinical status and consider PPI if nonspecific inflammation present 23 Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037 APPENDIX 5‐ COIN INGESTION Coin ingestion: PA and lateral films, ensure no button battery Esophageal Symptomatic (drooling, dysphagia, respiratory compromise): Urgent endoscopic removal Asymptomatic: Endoscopic removal within 24 hours Gastric Small bowel No endoscopy needed: Consider straining stools, laxatives, repeat x‐ray at 2 weeks Clinical observation: Enteroscopy/surgical removal if symptomatic Consider glucagon if distal esophageal coin or if endoscopy not readily available Endoscopic removal if not passed within 2‐4 weeks Repeat X‐ray immediately prior to removal to ensure coin still present 24 Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037 63 8 THE PROBLEMATIC POLYP Petar Mamula, MD The Children’s Hospital of Philadelphia • I have no financial relationships to disclose OBJECTIVES 1. Review prerequisites for successful polypectomy 2. Discuss techniques for difficult polyps 3. Review polypectomy complications 64 Polypectomy video clip DEFINITION • Greek polύpous‐ animal with mouth surrounded by tentacles like hydra • Difficult or problematic polyp‐ any polyp that poses difficulties in removing and can be further defined by its size, location, shape, or number DEFINITION • SIZE: 2‐3 cm large and >3 cm giant polyp • LOCATION: – involving 2 colon folds – >1/3 of luminal circumference – cecum/right colon, appendiceal orifice, IC valve, upper GI tract • SHAPE: Pedunculated‐ stalk and head Sessile‐ height > ½ base diameter Flat‐ height < ½ base diameter • NUMBER: >10 polyps 65 DEFINITION SMSA Classification Level 1 (4‐5) Level 2 (6‐9) Level 3 (10‐12) Level 4 (>12) NASPGHAN Training Guidelines‐ 10 procedures Gupta et al. Gut. A129. 2011. PREREQUISITES • PATIENT: anti‐coagulation/NSAIDS, preparation, laboratories • EQUIPMENT: generator, accessories, irrigation pump, CO2 insufflation • STAFF: experienced technician, collaborative anesthesiologist • ENDOSCOPIST: knowledge, experience ENDOSCOPIST Liu et al. JPGN. 2007. 66 EQUIPMENT‐ GENERATOR Ohm’s law: V = I x R Power (Watts): P = V x I Joule’s law: Q = I2 x R x t Current types: coagulation (slower increase in tissue temperature) and cut (cell burst) • Current density: (current/area)2 • Waveform (duty cycle) • • • • EQUIPMENT‐ GENERATOR Modern units with microprocessor keep voltage constant while power fluctuates depending on change in impedance EQUIPMENT‐ ACCESSORIES Monkemuller et al. Clinic Gastroenterol Hepatol. 2009. 67 POLYPECTOMY TECHNIQUE • Colonoscope position: 5‐6 o’clock • Place the snare proximal to distal and parallel to the colon wall • May require retroflexion, abdominal pressure, or patient repositioning • Once snare in place lift the polyp and “jiggle” during resection to avoid contact with the wall POLYPECTOMY TECHNIQUE POLYPECTOMY TECHNIQUE • Pedunculated – Large stalk (>1 cm) may contain large vessel‐ consider epinephrine injection or clip/loop placement – Large polyp may benefit from epinephrine head injection in order to shrink it (up to 80% in size) – Giant polyp could be resected piecemeal Tholoor et al. Ann Gastroenterol. 2013. 68 POLYPECTOMY TECHNIQUE • Video stalk clip placement POLYPECTOMY TECHNIQUE • Sessile/flat polyps – Up to 7 mm: cold snare – 1‐3 mm: cold biopsy forceps – <5 mm: hot biopsy‐ potential for thermal injury and destroys the tissue (lift and burn) – >15 mm: endoscopic mucosal resection (EMR) with submucosal injection which prevents injury to deeper layer and entrapment of muscularis propria • Injectate‐ variety of solutions, commonly normal saline with methylene blue, amount may vary from few to >30 mL POLYPECTOMY TECHNIQUE • Sessile/flat polyps – Inject proximal to distal at a 30‐45° angle around or into the polyp, start injecting before needle in – >20 mm in size: piecemeal resection – May consider cautery demarcation prior to injection – Important to have a feel for the amount of tissue ensnared (mark the snare handle) – As the sheath is jiggled the polyp should move independently from the colon wall 69 POLYPECTOMY TECHNIQUE • Sessile/flat polyps – Aspirate and lift in order to tent the mucosa from the submucosa prior to resection – Smooth snare closure – Worrisome signs‐ ulcer, induration, friability, and no lift – Consider APC to treat remaining polyp tissue/edges – Tattoo the site Polypectomy video clip ADJUNCT POLYPECTOMY TECHNIQUES • Cap‐assisted polypectomy • Two colonoscopes or combination of two instruments • Double‐channel colonoscope • Side‐viewing duodenoscope • Laparoscopy‐assisted • Wide‐angle colonoscopy • Chromoendoscopy/NBI • Autofluorescence/Confocal laser microscopy • Endoscopic submucosal dissection 70 POLYP RETRIEVAL • Up to 16% specimens lost • Net or snare • Polyp trap for small polyps (≤5 mm) • Use the gravity effect to find specimens • Polyp retrieval video (cold snare/suction) COMPLICATIONS PERFORATION (0.1‐0.3%) • Risk higher with flat or sessile polyps, large polyps, cecum, and longer electrocautery time • Post‐EMR inspection for “target sign” Swan et al. GIE. 2011. 71 COMPLICATIONS PERFORATION • Clip closure for lesions <15 mm • Stent placement • Over The Scope Clip • If perforation not recognized and patient discharged, likely to need surgery Haito‐Chavez et al. GIE. 2014. COMPLICATIONS BLEEDING (0.3‐6%) • Early more likely to occur with the cutting current and late (up to 2 weeks) with the coagulation current • Treatment – Tamponade – Clips – Cautery, but risk of transmural burn – Prophylactic clip or loop • Polyp bleeding video 72 COMPLICATIONS POST‐POLYPECTOMY SYNDROME (2%) • Fever • Leukocytosis • Abdominal pain • Absence of free air on imaging • Thermal energy extending into muscularis propria and serosa • Treatment consists of bowel rest, IV fluids and abx SUMMARY • • • • Be prepared Know your equipment and staff Know your limitations 1‐3 mm polyps can be removed with a cold forceps, 5‐7 mm with a cold snare SUMMARY • >15 mm sessile/flat lesions require submucosal injection • >20 mm piecemeal resection • Consider pre‐treating large pedunculated polyps • Instruct patient/family about possible complications 73 REFERENCES 1. Electrosurgery in Gastrointestinal Endoscopy: Principles to Practice, Morris et al. Am J Gastroenterol. 2009. 2. Electrosurgical generators. Technology Status Evaluation Report. Tokar et al. GIE. 2013. 3. Polypectomy Devices. Technology Status Evaluation Report. Carpenter et al. GIE. 2007. 4. Advanced Colon Polypectomy. Monkemuller et al. Clinic Gastroenterol Hepatol. 2009. 5. Colon Polypectomy. Kedia and Waye. J Clin Gastroenterol. 2013. 6. Advanced Polypectomy. Waye, J. Gastrointest Endoscopy Clin N Am. 2005. 7. Colonoscopic Polypectomy. Tolliver and Rex. Gastroenterol Clin N Am. 2008. Thank you 74 C. difficile: Clostridium “Difficult” But Not Impossible Stacy A. Kahn, MD Assistant Professor of Pediatrics and Medicine Section of Pediatric Gastroenterology, Hepatology, & Nutrition Director, Transitional IBD Clinic The University of Chicago Medicine Disclosures and Disclaimers • Consultant: AbbVie • Fecal microbiota transplantation (FMT) is not an approved therapy. • The FDA considers FMT a biologic and a drug. • The use of FMT for indications other than recurrent Clostridium difficile infection (CDI) or for research purposes requires FDA approval and an Investigational New Drug (IND) application. Learning Objectives • Learn appropriate identification and testing for C. difficile • Understand the current medical management for C. difficile • Understand the role of fecal microbiota transplantation (FMT) in C. difficile 75 CDI: A Significant Healthcare Burden • Leading cause of hospital-associated GI illness • Increasing cause of community-associated GI illness • Costs $3.2 billion annually1 • Rates of CDI have been increasing since 2000 • 2011: CDI was responsible for2 • ~ 500,000 infections • 29,000 deaths 1. Surawicz et.al. American J Gastroenterology 2013. 2. Lessa et. al. NEJM. 2015. Incidence of Nosocomial CDI Leffler DA, Lamont JT. N Engl J Med 2015;372:1539-1548 Rates of Pediatric CDI • Overall Incidence: 24.2/100,000 (2011)1 – Community-Associated: 17.9/100,000 – Health-Care Associated: 6.3/100,000 • Estimated # of cases: 16,900 (2011)1 – Community-Associated: 12,500 – Health-Care Associated: 4,400 • Significant increase of CDI in pediatric IBD2 – 28.6/1,000 (1993-2012) vs. 46.9/1.000 (2009-12) 1. Lessa FC et al NEJM 2015. 2. Hourigan SK et al. Dig Dis Sci. 2014. 76 Severe Pediatric CDI • Far less common than in adults (2% vs 8-20%) • More often hospital-associated (74%) • Underlying conditions: malignancy, HSCT, genetic syndrome, IBD, transplant, CF • Symptoms: Fever (47%), abd pain (35%), bloody stool (17%), ileus (2%) • Diarrhea: mild (22%), moderate (44%), severe (27%) • 5/299 (2%) required ICU admission • 1/299 (0.3%) death in HSCT pt w/CDI + GN sepsis Schwartz KL et al. BMC Pediatrics. 2014. Why is C. Diff so Difficult? • Gram positive spore forming anaerobic bacteria – Vegetative and dormant states • “Bacillus difficile” because it was hard to grow & isolate • Spores are HIGHLY resistant – Heat, acid, disinfectants, antibiotics • C. diff survives: – Vegetative cells survive on surfaces for 24 hr – Spores survive for months to years! Rupnik M. et al. Nature Reviews Microbiology 2009. www.bioquellus.com/technology/microbiology/clostridium-difficile/ Emergence of Virulent and Resistant Strains: NAP1/BI/027 • North American pulse-field type 1 • Associated with epidemics (hospital-acquired) • Hypervirulent – Exhibits quinolone resistance – Produces binary toxin which increases production of toxins A + B – Increased use of quinolones may have contributed to selection of this strain • Highly pathogenic – Mortality 3x higher than other strains 1. Kelly et. al. NEJM. 2008. 2. Surawicz et. al. Nature Reviews: Gastroenterology & Hepatology. 2011. 3. Rupnik M et al. Nature Reviews Microbiology. 2009. 4. Leffler and Lamont. NEJM 2015. 77 CDI Mechanisms and Host Response • Disease caused by enterotoxin A and cytotoxin B – Interfere with protein synthesis – Causes cell membrane disruption and death1 • Host immune response may determine who develops symptoms2 – ~5% of healthy individuals are colonized with C. difficile2 – Development of IgG Abs against toxin A may contribute to asymptomatic state3 – High IgG Abs decrease risk for RCDI by a factor of 444 1. Khanna et. al. Inflamm Bowel Dis. 2013. 3. Surawicz et. al. Nature Reviews: Gastroenterology & Hepatology. 2011 2. Warny et. al. Infect. Immun. 1994. 4. Kelly et. al. NEJM. 2008. CDI in IBD: A Growing Problem • Clinical symptoms of CDI and IBD are the same. • Since 2000: significant increase of CDI in IBD • 1997‐2011: Hospitalization rates 5‐fold increase in children/young adults with IBD and CDI – Compared with < doubling of the hospitalization rates for IBD without CDI2 • Recurrent CDI in up to 1/3 of children and adults • Many IBD therapies increase risk of CDI and worsen its clinical course 1. Russell et. al. Gastroenterology. 2014. 2. Sandberg et. al. Inflamm Bowel Dis. 2014. Risk Factors for CDI in the General Population “Traditional” Risk Factors: • Antibiotic use (number and duration) • Advanced Age (> 65 yo) • Recent/prolonged hospitalization • Immunosuppression • Comorbidities • Proton-pump inhibitors • NG tubes Vardakas et. al. International Journal of Infectious Dis. 2012. 78 Risk Factors are Not the Same in Patients with IBD • Antibiotic use less important – Abx use preceding CDI is less common • 40% of IBD patients vs. 69% in non-IBD patients1 • 39% of IBD patients with CDI: no recent Abx use2 • Advanced age and comorbidities – Average age of CDI in IBD cohorts significantly lower3 1. Bossuyt et. al. J Crohns Colitis. 2009. 3. Jen et. al. Ailment Pharmacol Ther. 2011. 2. Issa et. al. Clin Gastroenterol Hepatol 2007. Risk Factors: A Balancing Act In IBD • Immunosuppression – Risk of therapy in CDI still unclear • Maintenance immunosuppressive therapy associated with 2x risk of CDI1 • No association between use immunosuppressive therapy and heightened CDI risk in UC patients2 – Corticosteroids may heighten risk of infection • Steroid initiation tripled the risk of CDI3 • IBD is an independent risk factor for CDI – 3x increased risk as compared to non-IBD patients4 1. 2. Issa et. al. Clin Gastroenterol Hepatol. 2007. Kariv et. al. J Crohns Colitis. 2011. 3. 4. Schneeweiss et. al. Ailment Pharmacol Ther. 2009. Rodemann et. al. Clin Gastroenterol Hepatol. 2007. Who should we test? • Only patients with diarrhea (> 3 liquid stools/day) should be tested for CDI! • All hospitalized patients with IBD with a disease flare • Ambulatory patients who develop diarrhea (even with no known risk factors) • Patients s/p colectomy and IPAA that are symptomatic Surawicz et. al. The Am Journal of Gastroenterol. 2013. 79 CDI Test Options Nucleic acid amplification tests (NAATs) • • • PCR for toxin genes Superior to A + B EIA testing Risk of false positive even after Tx/asymptomatic pt Toxins A + B Enzyme Immunoassay (EIA) • • Lower sensitivity and specificity Risk of false positive even after Tx/asymptomatic pt Glutamate dehydrogenase (GDH) screening • Used in testing algorithms • Unable to distinguish toxigenic and nontoxigenic strains Surawicz et. al. The Am Journal of Gastroenterol. 2013. Which Test to Choose? TEST SENSITIVITY SPECIFICITY NAAT PCR 100% 99.2% A + B EIA 75 - 95% 83-98% GDH screening 75 - >90% low Surawicz et. al. The Am Journal of Gastroenterol. 2013. The Perfect CDI Drug High level of drug in colon Little systemic absorption Minimal disruption to commensal microbiota Good safety profile Affordable Approved for pediatric use http://www.examiner.com/article/new‐weight‐loss‐pills‐no‐cure‐for‐obesity‐crisis 80 CDI Treatment Options Antibiotics • Metronidazole • Vancomycin • Fidaxomicin • Rifaxamin • Teicoplanin • Nitazoxanide Other Therapies • IVIG • Monoclonal antibodies • C. diff toxoid vaccine • Probiotics • Fecal Microbiota Transplantation (FMT) CDI Treatment Paradigms Severity Clinical Manifestations Treatment Asymptomatic carrier No signs or symptoms No treatment Mild Mild diarrhea (3‐5/d) Afebrile Mild abd pain/tenderness Stop antibiotics Hydration/monitor Metronidazole TID Moderate Moderate nonbloody diarrhea Moderate abd pain/tenderness Nausea +/‐ vomiting, dehyrdation WBC >15,000, Elevated BUN/CR Stop antibiotics. Consider hospitalization. Hydration/monitor. Metronidazole 30 mg/kg/TID OR Vancomycin 40 mg/kg/QID (125 mg) x 14 d Severe Severe/bloody diarrhea, Tm >38.9 Pseudomembranes, ileus, AKI, Severe abd pain/tenderness Vomiting, WBC >20,000, Alb <2.5 Hospitalization. Oral or NG Vancomycin 500 mg QID +/‐ Metronidazole 30 mg/kg/TID OR Fidaxomicin 200 mg BID x 10d Complicated Toxic megacolon, peritonitis Respiratory distress, Hemodynamic instability Antibx for severe infection Surgery consultation Consider FMT Surawicz et. al. The Am Journal of Gastroenterol. 2013. Leffler and Lamont. NEJM 2015 Vancomycin: Superior in Severe CDI Zar et al. NEJM 2008;359:1932-40 based on work by Zar, et al. A comparison of vancomycin and metronidazole for the treatment of C. diff- associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302-7, 81 Fidaxomicin Decreases RCDI Louis T. et al.. NEJM. 2011. Modifying Therapy in CDI • Antimicrobial agent(s) should be discontinued • On-going immunosuppression medications can be maintained • Escalation of therapy in IBD should be avoided during the acute phase Surawicz et. al. The Am Journal of Gastroenterol. 2013. Recurrent CDI, A Recurring Problem • After initial Tx of CDI, chance of RCDI within 8 weeks is 10 – 20 % • After 1st recurrence, rates of recurrence increase to 40 – 65 % • Recurrence can be due to the same or different strain • RCDI may be due to impaired immune response or alteration of the gut microbiota Surawicz et. al. The Am Journal of Gastroenterol. 2013. 82 Treatment Failure Increases Risk of Recurrence Jiang et al. Am J Gastroenterol. 2006,. How is Pediatric RCDI Different? • C. diff is constitutive flora until after 6 months of age, 10 % carriage rate at 1 year • 10-fold rise in incidence from 1991-2009 • Refractory C. diff is rare. Recurrence risk is about 22-30% as in adults. • Community acquired CDI: more common than in adults • 23-43% lack antimicrobial exposure history • Up to 38% of previously healthy children with RCDI have NAP1/B1/027 serotype Benson L, et al. Infect Control Hosp Epidemiol. 2007;28(11):1233–1235. Khanna S BL, et al. Clin Infect Dis. 2013;56(10):1401‐1406. Janqi S, et al. JPGN. 2010; 51:2‐7. CDI Again?! No Easy Answers • 1st recurrence: treat with same regimen • 2nd recurrence: pulsed or tapered vancomycin or fidaxomicin 200 mg BID x 10 days • No consensus on optimal pulsed/tapering regimen **Severe CDI: vancomycin +/- metronidazole and surgery consult Surawicz et. al. The Am Journal of Gastroenterol. 2013. Leffler and Lamont. NEJM 2015. 83 More than 3 Recurrences: Consider FMT • If there is a 3rd recurrence, fecal microbiota transplant (FMT) should be considered1 • Due to reduced efficacy of other antimicrobial therapies, FMT holds promise as effective Tx for RCDI2 • Since 2000, failure rates of metronidazole for uncomplicated CDI have increased from 2.5% to > 18%2 1. Surawicz et. al. Am Journal of Gastroenterol. 2013. 2. Kelly et. al. NEJM. 2008. FMT for Recurrent CDI • 1958: – 4 patients with pseudomembranous colitis1 – Resolution of symptoms in 48 hrs • 2010: – First pediatric FMT for recurrent CDI, NAP1/B1/0272 • 2012: – First colonoscopic FMT for a child with recurrent CDI3 • 2013: – Randomized controlled trial of FMT (terminated early)4 – FMT is superior to vancomycin +/- bowel lavage • Present: – FMT is ~89% effective and safe5 1. Eiseman et al. Surgery 1958 3. Kahn S et al. Am J Gastro 2012 5. Kassam Z et a. Am J Gastro 2013 2. Russel G et al. Pediatric 2010 4. van Nood et al. NEJM 2013 http://emedicine.medscape.com/article/186458-overview Regulatory, Safety, and Ethical Issues in FMT Clinical • • • • • • • • • • • Safety Risk Screening of recipients Stigma the “yuck” factor Selection of donors Screening of donors Privacy Access Regulation Cost and insurance coverage Stool banks Research • • • • • • • • • Safety Risk IRB approval Informing subjects and donors of results Invasiveness of sampling Data sharing Privacy Biobanking Regulation 84 Surgical Consultation • Surgical consultation should be obtained on all patients with complicated CDI • Consider surgery: – hypotension requiring vasopressor therapy – clinical signs of sepsis and organ dysfunction – mental status changes; WBC count ≥ 50 – lactate ≥ 5 – complicated CDI with failure to improve on medical therapy after 5 days Surawicz et. Al. Am Journal of Gastroenterol. 2013. Take Home Points • CDI is on the rise… both in the hospital and in the community. • IBD patients are at increased risk for RCDI. • Recurrent CDI demands tailored treatment. • Always use antibiotics judiciously! • Always wash your hands! – Hand sanitizer isn’t effective against CDI. Consensus Guidance on Donor Screening Donor Selection • A family member, close contact, or a well screened universal donor. • Donor questionnaire should be similar to AABB donor Questionnaire Donor Exclusion Criteria • • • • • • Antibiotic treatment 3 months preceding donation. History of GI intrinsic illnesses Autoimmune, atopic disease, or ongoing immune modulating therapy Chronic pain syndromes, neurologic, or neurodevelopmental disorders Metabolic syndrome, obesity (BMI of >30), or moderate‐to‐severe malnutrition History of malignant illnesses, ongoing oncologic therapy Serum Testing (to be performed within 2‐4 weeks of donation) • Hepatitis A,B, C, syphilis testing, HIV (within 2 weeks) Stool Testing (to be performed within 4 weeks of donation) • C. Difficile toxin B (PCR), Culture, O+P (if travel history suggests) 85 Gluten sensitivity: Surely a sensitive but perhaps not a gluten subject Stefano Guandalini, MD Professor of Pediatrics October 8, 2015 Disclosure slide • Consultant for AbbVie • Consultant for ThermoFisher 86 Objectives • Identify the three clinical disorders currently thought to be associated with wheat intake • Realize the lack of evidence for gluten as responsible of the so‐called «Non‐celiac gluten sensitivity» • Be able to approach critically and effectively a patient suspect of having «Non‐celiac gluten sensitivity» Wheat - related disorders Wheat Allergy ~0.1% Celiac Disease 1% Gluten Sensitivity ?0.5-1.0?% No gene associated IgE‐mediated Infants and Bakers HLA‐DQ2, DQ8 Autoimmune disease Any age No gene associated Likely Immune‐ mediated Mostly adults Serum specific IgE CD autoantibodies Biopsy No diagnostic marker 87 Gluten (or Wheat) Wheat - related disorders related disorders Wheat Allergy ~0.1% Celiac Disease 1% Non-celiac Gluten Sensitivity ?% No gene associated IgE-mediated Infants and Bakers HLA-DQ2, DQ8 Autoimmune disease Any age No gene associated Immune-mediated? Mostly adults Respiratory, skin symptoms GI and extra-GI symptoms GI and extra-GI symptoms Gluten (or Wheat) Wheat - related disorders related disorders Wheat Allergy ~0.1% Celiac Disease 1% Non-celiac Gluten Sensitivity ?% No gene associated IgE-mediated Infants and Bakers HLA-DQ2, DQ8 Autoimmune disease Any age No gene associated Immune-mediated? Mostly adults Serum specific IgE CD autoantibodies Biopsy No diagnostic marker Gluten (or Wheat) Wheat - related disorders related disorders Wheat Allergy ~0.1% Celiac Disease 1% Non-celiac Gluten Sensitivity ?% No gene associated Largely IgE-mediated Children and Bakers HLA-DQ2, DQ8 Autoimmune disease Any age No gene associated Immune-mediated? Mostly adults Serum specific IgE CD autoantibodies Biopsy No diagnostic marker 88 An Italian survey on 486 patients: Who suspected it? Volta U et al., BMC Medicine 2014 An Italian survey on 486 patients: Gastrointestinal symptoms Volta U et al., BMC Medicine 2014 An Italian survey on 486 patients: Extra‐intestinal symptoms Volta U et al., BMC Medicine 2014 89 An Italian survey on 486 patients: Anti‐Gliadin Antibodies Volta U et al., BMC Medicine 2014 A study from Australia Inclusion criteria Age older than 16 Symptoms of IBS according to Rome III criteria that improved on a GFD Symptoms well controlled on GFD Celiac disease excluded Biesekierski JR et al., Gastroenterology 2013 90 Design – RDBPCT (Crossover) Low FODMAP diet 1 Week 2 Weeks 1 Week High gluten (16g) Screening Run in / Low FODMAP diet Low Gluten (2g) Placebo (0g) > 2 Weeks Washout Washout Washout Gluten free diet Fermentable Oligosaccharides Disaccharides Monosaccharides And Polyols Shepherd SJ, Am J Gast 2013 Gibson PR, Aliment Pharmacol Ther. 2005 Effect of FODMAP withdrawal No effect of gluten Biesekierski JR et al Gastroenterology 2013 91 Number of studies so far published on NCGS that utilized pure gluten (not wheat) to challenge: (Zero) “Of note, no study on NCGS has specifically used as the re-challenging agent gluten or gliadin” – Molina-Infante J et al., Aliment Pharmacol Ther April 2015 The only study testing the effect of gluten (4.4 g/d) in NCGS Di Sabatino A. et al., Clin Gastroenterol Hepatol, Epub only The only study testing the effect of gluten (4.4 g/d) in NCGS Di Sabatino A. et al., Clin Gastroenterol Hepatol, Epub only 92 The only study testing the effect of gluten in NCGS Di Sabatino A. et al., Clin Gastroenterol Hepatol, Epub only The "GLUTOX" Trial: A Randomised, Double Blind, Placebo Controlled Crossover Study on "Non‐Celiac Gluten Sensitivity" 100 patients with IBS‐like symptoms, no celiac or wheat allergy GFD for 3 wks 19 patients did not improve NCGS excluded 56 patients (75%) did not react Elli L et al., DDW 2015 81 patients improved Gluten challenge 25 patients (25%) reacted NCGS confirmed Guandalini S and Polanco I: J Pediatr 166: 805‐811, April 2015 93 Guandalini S and Polanco I: J Pediatr 166: 805‐811, 2015 The umbrella of WIS: 6 groups of patients! Non IgE‐ wheat ATI allergic Sensitive ? Early‐ stage celiac Gluten sensitive FODMAP sensitive Placebo/ ? Nocebo But wait! What about children? Not 1 mention of children in the whole paper! 94 The only paper in children! • Open‐label (unblinded!) • Challenge with undefined «gluten‐containing food» (gluten 5g/d) • Challenge for 48 hrs with F/U with diary for 2 weeks • Age range: 1.6‐15.0 years (!) WIS – A Practical Approach Pt on GFD Willing to undergo gluten challenge Unwilling to abandon the GFD Gluten for ≥6 weeks HLA‐DQ2, DQ8 TTG and Biopsy Positive Celiac No Celiac Positive Negative Enjoy your GFD: But remember you could be celiac No Celiac: Enjoy your GFD! Negative Symptoms recurred? Yes No WIS WIS ruled out What you have hopefully learned • Wheat can adversely affect humans by three different entities: – Wheat allergy (0.1‐0.2%) – Celiac disease (1%) – Wheat Intolerance Syndrome (0.6%??) • WIS is an umbrella term, encompassing: – Placebo/Nocebo – Early Celiac Disease – FODMAP sensitivity.... Etc. • How to approach a patient suspect of WIS 95 Cureceliacdisease.org 96 Treatment of the Refractory Abdominal Pain Patient Adrian Miranda, M.D. Associate Professor of Pediatrics Division of Pediatric Gastroenterology Medical College of Wisconsin Children’s Hospital of Wisconsin -I am a consultant to QOL Medical -No other financial relationships with any commercial entity to disclose Objectives: Understand the mechanisms of abdominal pain Identifying the patient with refractory abdominal pain Know the available and current treatment options 97 A brief word about abdominal pain (AP) prevalence Male Female Average age (range), years Average age of boys Average age of girls African-American Latino Caucasian Other Asian Demographics AP prevalence 43% 29% 57% 36% 11.8 (8-15) 11.7 11.9 33% 30% 22% 32% 21% 33% 16% 35% 8% 42% *278 subjects with weekly questionnaires for 1 year Saps M et al., J Pediatr. 2009 Geographic distribution of functional abdominal pain in children (pooled-prevalence) Korterink JJ, et al., Epidemiology of Pediatric Functional Abdominal Pain Disorders: A Meta-Analysis. PLoS ONE. 2015. Proposed Underlying Mechanisms for Chronic Functional Abdominal Pain Bacterial Overgrowth Altered Receptor Expression (5HT, NMDA,TRPV1) Autonomic Dysfunction Altered HPA-axis Neuronal Sensitization Descending Pain Modulation Carbohydrate Intolerance Motility Disorder 98 Stressors Psychological stress Inflammatory Sleep Where? Intestinal microbiome 2. Mucosal changes 3. Enteric nervous system 4. Primary afferents 5. Genome 6. CNS 1. spinewave.co.nz Possible associations with psychosocial stress and post-infectious gastrointestinal symptoms Drossman DA. Gut 1999 Effect of acute psychological stress on small intestinal permeability in humans Vanuytsel et al, Gut 2014 99 Important fact in postinfections/inflammatory pain? Not all patients that have stress or gastrointestinal infections develop IBS Not all animals develop visceral hyperalgesia following “stress” Post-inflammatory- Animal Model -24% of rats maintained hyperalgesia at 4 months Zhou et al., Journal of Pain, 2007 Post Infectious IBS Author Year Destination s Study design Follow-up (months) Okhuysen et al. 2004 Stermer et al. 2006 Trivedi et al. 2011 Egypt or Mexico Worldwide Turkey Retrospecti Prospective Prospective ve Pitzurra et al. 2011 6 Nair et al. Lalani et al. 2014 2014 Worldwide Mexico Worldwide Prospective Prospective Prospective 6 up to 7 6 6 6 6 Number of participants 97 (complete follow-up) 405 120 2476 817 515 Male/femal e (complete 47/50 study population) 216/189 89/32 1218/1258 227/590 254/261 IBS occurrence (exposed) 13.6% (16/118) 17.2% (16/93) 3.1% (26/852) 5.7% (20/348) 2.4% (3/126) 3.7% (1/27) 0.7% (12/1624) 2.6% (12/469) 1.8% (7/389) 10.0% (6/60) IBS occurrence 2.4% 0% (0/37) (non(7/287) exposed) 100 Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier Cristina Martínez, Beatriz Lobo, Marc Pigrau, Laura Ramos, Ana Maria González-Castro, Carmen Alonso, Mar Guilarte, Meritxell Guilá, Ines de Torres, Fernando Azpiroz, Javier Santos, María Vicario Gut. 2013 Sleep Pain Autonomic Resoponse Role of Amygdala A critical component of the anxiety neuro-circuitry Associated with fear learning Memory consolidation Hippocampus Descending pain modulation vmPFC Amygdala Suppresses negative affect by inhibiting amygdala output PAG Hypothalamus Ressler, et al 2010 Cullen, et al 2011 Pezawas et al, 2005 101 Amygdala Functional Connectivities Healthy Control IBS Patient VmPFC Subliminal Subliminal VmPFC Liminal Liminal Sood et. al., NASPGHAN 2014 Why is There No Algorithm for Treatment? No data to support decision tree Phenotype is not well understood Mechanism of disease and medications not well understood Very few clinical trials in children How far Have We Really Come? 1959 55 years 8 randomized, controlled trials (4 positive) 421 children studied 102 Why we can’t believe all clinical trials? Patient A: Patient B: 15 y/o with 22 month history of chronic abdominal pain -pain daily, 9/10 -nausea and lightheaded daily, struggles to get out of bed with fatigue -has missed 28 days of school this year 10 y/o with 3 month history of chronic abdominal pain -pain 4 days per week 3/10 on scale -pain only at night -no nausea or fatigue -has not missed school or activities Targeting therapy is not always easy Kovacic, et al. J Peds 2014 Responding to Placebo Does Not Make You “Crazy” Perform distracting tasks activate periaqueductal grey (PAG), Anterior Cingulate Cortex, and orbitofrontal cortex Placebo activates endogenous opioids and induces mild respiratory depression and decreases adrenergic activity ©2005 by Society for Neuroscience Benedetti F et al., J.Neurosci. 2005 Pollo et al., Pain 2003 103 Psychological Therapy Parent Attention Versus Distraction: impact on symptom complaints by children with and without chronic functional abdominal pain. Walker LS et al., 2006 Cognitive-behavioral therapy for children with functional abdominal pain and their parents decreases pain and other symptoms. Levy RL et al., 2010 A randomized controlled trial of a cognitivebehavioral family intervention for pediatric recurrent abdominal pain. Robins PM et al., 2005 Hypnotherapy for children with functional abdominal pain or irritable bowel syndrome: a randomized controlled trial Vlieger AM, Menko-Frankenhuis C, Wolfkamp SC, Tromp E, Benninga MA After therapy At 6 mo followup At 1 y follow-up SMT group (n = 25) HT SMT HT SMT HT group (n group (n group (n group (n group (n = 27) = 24) = 27) = 24) = 27) 56% 15% 66% 7% 46% 4% Improved 32% 26% 17% 22% 29% 11% Clinical 12% remission 59% 17% 71% 25% 85% No effect Gastroenterology, 2007 Biofeedback Changes maladaptive thoughts and pain perception Patient able to visualize changes in RR, HR and temperature 104 Gut Vagal Afferents Differentially Modulate Innate Anxiety and Learned Fear Klarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. J Neurosci. 2014 Project to hypothalamus, amygdala, pre-frontal cortex, periaqueductal grey (PAG) and locus coeruleus (LC) Regulate emotional, autonomic and behavioral responses C.H. Knowles, Q. Aziz. PAIN. 2009 Vagal Nerve Afferents Modulate Autonomic Control Efferent activity is measured noninvasively via heart rate variability (HRV) Afferents may modulate adrenal medullary factors: epi, norepi, dopamine, endogenous opioids, substance P Khasar et al. Eur J Neruosci. 2003 Vagal nerve stimulation Neuro-stimulator (NSS) device very encouraging results in chronic pain trials Stimulation of auricular branch of vagus nerve Could restore autonomic function and pain pathways 105 Pharmacological Treatment Options Mild Pain (no disability) -Peppermint oil -Iberogast -Melatonin -Probiotics? -Acid suppression? Pain (with disability) -TCAs (amitriptyline) -SSRIs (citalopram) -Gabapentin -Antispasmodics (hyoscyamine , dicyclomine) -Cyproheptadine -Rifaximin Constipation -Linaclotide -Lubiprostone Bottom–up Approach for Mild Abdominal Pain Rehabilitation Program SSRI Gabapentin Amitriptyline Adjust school schedule ( sleep, exercise, fluids) Rifaximin (suspected SIBO) Cyproheptadine (follow weight closely) Iberogast Peppermint oil Melatonin Proton pump inhibitor Education and Reassurance Antispasmodic- situational pain Loperamide- situational diarrhea Don’t Forget to Ask the Important Question that will Dictate Therapy? How many days of school or activities have you missed? 106 Top-down Approach for Disabled Pain Patient Education and Reassurance Amitriptyline SSRI Gabapentin Adjust school schedule ( sleep, exercise, fluids) CoQ10 (fatigue) Melatonin (sleep) Proton pump inhibitor (dyspepsia) Fludrocortisone (orthostatic intolerance) Cyproheptadine (nausea, pain) Rifaximin (bloating, excess gas) Iberogast (nausea, pain, dyspepsia) Rehabilitation Program Amitriptyline Study in Children -RCT in adolescents 8 weeks of 10, 20 or 30mg based on weight (n=33) -Improvement in QOL and pain over placebo -Negative placebo effect for pain Mechanism -Inhibits Na channels, endogenous opioids, NMDA antagonist, anxiolytic. Dose: 0.1-2mg/kg/d at bedtime Side Effects Constipation, dry mouth, dizziness, somnolence Bahar RJ et al., J Pediatr. 2008 IBS, FAP and FD patients were randomized to 4 weeks of placebo or amitriptyline Dose: (10 mg/d, <35 kg, 20 mg/d, >35 kg) Pain was assessed daily with self-report diaries No better than placebo in improving abdominal pain Reduced anxiety scores (P < 0.0001) compared to placebo Saps et al., Gastroenterology. 2009 107 Citalopram Citalopram 12-week open label, flexible dose-trial in children with RAP Initial dose 10mg and increase to 40 mg if no response by week 4 Methodological limitation: -not placebo controlled or blinded -small group size (n=25) Campo JV et al., 2004 Citalopram Study in Children -RCT of 20mg/day vs. placebo for 4 weeks in children with FAP based on Rome III Roohafza et al., Neurogastroenterol Motil. 2014 Gabapentin No Data in Children -Increased rectal compliance in adult IBS-D -Attenuated rectal mechanosensitivity Mechanism Binds alpha 2 delta receptors of Ca channels in CNS (spinal cord, PAG etc.) Dose: 8-35mg/kg/d divided 3x/daily (max 3600mg/d) Side Effects dizziness, somnolence, fatigue, ataxia Lee KJ, Kim JH, Cho SW. Aliment Pharmacol Ther. 2005 108 Double-blind, Placebo-controlled Antibiotic Treatment Study of Small Intestinal Bacterial Overgrowth in Children with Chronic Abdominal Pain Collins BS, Lin HC. J Pediatr Gastroenterol Nutr. 2011 -10-day course of 550 mg of rifaximin vs. placebo TID - No difference in symptoms, including pain -Adult studies show a therapeutic gain over placebo about 9-12% Mechanism Alteration in the quantity, location, or quality of the hosts' intestinal microbiota Dose: 8-35mg/kg/d divided 3x/daily (max 3600mg/d) Side Effects dizziness, somnolence, fatigue, ataxia Cyproheptadine for the Treatment of Functional Abdominal Pain in Childhood: a double-blinded randomized placebo-controlled trial Sadeghian M, Farahmand F, Fallahi GH, Abbasi A. Minerva Pediatr. 2008 Pain assessed at 1 and 2 weeks (n=29) Improvement (87%) vs. placebo (43%) Primary outcome measure was the self-reported change of frequency and duration of abdominal pain Did not use validated questionnaires Mechanism Antagonist of serotonin, histamine and muscarinic receptors Improved gastric accommodation through 5HT receptors? Dose: 0.25-0.5mg/kg/d divided 2-3x/daily Side Effects Weight gain, somnolence, irritability Safety and Efficacy of Cyproheptadine for Treating Dyspeptic Symptoms in Children Rodriguez L, Diaz J, Nurko S. J Pediatr. 2013 Study: Retrospective, open label study of 80 children with dyspepsia Cohort: GER, post fundoplication, diabetes, mitochondrial dysfunction, post Ladd’s procedure 109 Complementary and Supplementary Therapy Approximately 12% of non-clinical population seeks complementary therapies for their children with pain It is NOT always the answer, but plays an important role as adjuvant therapy Placebo in mild pain? Barnes et al. , 2008 Melatonin Melatonin Improves Bowel Symptoms in Female Patients with Irritable Bowel Syndrome: a double-blind placebocontrolled study Lu WZ, Gwee KA, Moochhalla S, Ho KY. Therapeutic effect of melatonin in patients with functional dyspepsia. Klupińska G, Poplawski T, Drzewoski J, Harasiuk A, Reiter RJ, Blasiak J, Chojnacki J Influence of melatonin on symptoms of irritable bowel syndrome in postmenopausal women. Chojnacki C, Walecka-Kapica E, Lokieć K, Pawłowicz M, Winczyk K, Chojnacki J, Klupińska G. (STW 5) Iberogast 9 plant extracts: Chamomile flowers, bitter candytuft, angelica root, caraway fruits, milk thistle, lemon balm leaves, greater celandine, licorice root, and peppermint leaves Mechanism Likely anti-hyperalgesic properties, improve proximal gastric accommodation, and may have pro-secretory and anti-spasmodic properties Dose 10 drops (1 ml) before each meal Cost: 100ml for $32 Side effects Abdominal cramps, diarrhea, nausea, dizziness 110 Treatment of Irritable Bowel Syndrome with Herbal Preparations: results of a double-blind, randomized, placebo-controlled, multi-center trial Madisch A, Holtmann G, Plein K, Hotz J. Aliment Pharmacol Ther. 2004 n=208 Effect of Fludrocortisone Acetate on Chronic Unexplained Nausea and Abdominal Pain in Children With Orthostatic Intolerance John E. Fortunato, Ashley L. Wagoner, Rachel L. Harbinson, Ralph B. D’Agostino Jr, Hossam A. Shaltout, and Debra I. Diz More likely to respond if symptoms are reproducible on tilt table Dose: Start with 0.5 mg daily and titrate as needed (0.1–0.2 mg/day) Enteric-coated, pH-dependent Peppermint Oil Capsules for oilBowel Syndrome in Children. thePeppermint Treatment of Irritable Kline RM, Kline JJ, Di Palma J, Barbero GJ. -RCT in children with IBS (n=42) -pH-dependent, enteric-coated capsules (<45kg 1 cap; >45kg 2 cap) -Reduction in abdominal pain severity in 75% Mechanism Ca+ channel blocker (antispasmodic) Dose (30-45kg) 187mg 3x/daily, (>45kg) 374mg 3x/daily Side Effects Heartburn, headache, flushing Kline et al., J Pediatr. 2001 111 Cause or Effect ? Adverse early life Genetics Anxiety Sleep Stress IBS Dysautonomia Microbiome Epigenetics Adolescent sleep across the last 20 years Keyes et al., Pediatrics. 2015 Sleep disturbances in clinic patients with functional bowel disorders Fass R, Fullerton S, Tung S, Mayer EA. Psychosocial stress in nurses with shift work schedule is associated with functional gastrointestinal disorders Koh SJ, Kim M, Oh da Y, Kim BG, Lee KL, Kim JW. Impact of shiftwork on irritable bowel syndrome and functional dyspepsia Kim HI, Jung SA, Choi JY, Kim SE, Jung HK, Shim KN, Yoo K The impact of rotating shift work on the prevalence of irritable bowel syndrome in nurses Nojkov B, Rubenstein JH, Chey WD, Hoogerwerf WA. Am J Gastroenterol. 2000 J Neurogastroenterol Motil. 2014 J Korean Med Sci. 2013 Am J Gastroenterol. 2010 112 Role of Exercise in Pain Control Rat model: Exercise increased β-endorphin and metenkephalin in rostral ventral medulla (RVM) and periaqueductal grey (PAG) Ameliorated thermal and tactile hypersensitivity Adult IBS Prospective, randomized, controlled, open-label study of 12 weeks (n=102) 20–60 min of moderate-to-vigorous intensive physical activity 3 to 5 days per week IBS scores, physical functioning, emotion, sleep, energy, and social role were significantly improved Stagg, NJ et al. Anesthesiology 2011 Johannesson et al., Am J Gastroenterol 2011 Conclusions Careful evaluation should include assessment of decreased functioning in order to target therapy Combination therapy is necessary in the severe, disabled patients Psychological therapy is key in almost ALL patients We must take advantage of the placebo effect in the less severe patients and encourage healthy lifestyles (sleep and exercise) 113 NAUSEA: UPDATES THAT WON’T MAKE YOU SICK Carlo Di Lorenzo, M.D. Twitter: @carlodilorenzo1 I have no financial relationships relevant to this presentation to disclose Importance Common reason for referral Co-exists with other FGIDs Highly distressing Sparse literature No objective measurement tools No diagnostic algorithms Ineffective treatments 114 Case 15 year old adolescent girl 4 mo hx of waking up every morning with nausea Improves throughout the day Worse on school days when she has to wake up earlier Rarely vomits, no weight loss Case ROS positive for migraines and dizziness Normal growth and development Normal PE Neg HCG, “routine” labs, UA, tox screen, abdominal US Have you seen this before? 115 J Pediatr Gastroenterol Nutr 2013;57:311-5 Nausea in pediatric FGID Kovacic K, et al, JPGN 2013;57:311-5. Disability was related to higher nausea: Full school days missed and unable to do home activities significantly correlated with nausea frequency Associated symptoms Percentages Is functional nausea a pediatric functional GI disorder? It will be in Rome IV! 116 Early morning nausea Morning nausea in adolescents is almost always a manifestation of an anxiety disorder Cortisol levels peak in the early morning hours (usually around 8AM) Cortisol is also released as a response to stress and is a mediator of anxiety Share this FACT with the parents and patient If you look for what is causing the nausea…. You may find this 117 Symptoms of Eosinophilic Esophagitis by age* Feeding disorder Nausea and vomiting Abdominal pain Dysphagia Food impaction *Median and inter-quartile range, n=103 Or you may find duodenal eosinophilia (if you biopsied): Is it relevant? Montelukast in dyspeptic children with duodenal eosinophilia A double blind, randomized, placebo-controlled, cross-over study (n=40) % of patients Friesen CA, at al. J Pediatr Gastroenterol Nutr 2004;38:343-51 45 40 35 30 25 20 15 10 5 0 Montelukast Placebo p<0.005 vs. placebo 10 mg daily 14 days rx Grade 1 (worse) Grade 2 Grade 3 Grade 4 Symptom relief grade Grade 5 (complete relief) 118 More tests? Nuclear Medicine Pediatric normal values? Abell TL et al. J Nucl Med Technol. 2008;36:44-54 Depends upon the meal Use adult data for a solid meal (2 large eggs, 2 slides of bread, jam, water, 345 KCal): Abnormal >10% left in the stomach after 4 hours, >60% after 2 hours No pediatric data available, but look for extremes 119 (JPGN 2013;56: 439–442) • 71 patients (32 boys, average age 10.8 yr) • 62% children had abnormal GES; 23% who had normal values at 2 h had abnormal GES at 4 h (p<0.0001) • Survey: Only 5 of the top 20 pediatric GI centers in the US conducted 4-h GES • Conclusions: Extending GES to 4 h resulted in a considerable increase in diagnosis of gastroparesis SmartPill pH.p Capsule pH SENSOR • • • • 26mm x 13mm 5+ day battery life Senses and records pH, pressure and temperature data from within the GI tract Wirelessly transmits data to the SmartPill Data Receiver TRANSMITTER BATTERIES PRESSURE SENSOR MICROPROCESSOR 120 Wireless Motility Capsule Tracing- Gastroparetic Child Gastric Emptying 5 hr, 25 min J Pediatr. 2013;162:1181-7 22 patients (>8 y/o): All had WMC, 21 had complete scintigraphic gastric emptying study data and 20 had complete antro-duodenal manometry data Conclusion: In symptomatic pediatric patients, the wireless motility capsule test is highly sensitive compared with scintigraphic gastric emptying studies in detecting gastroparesis, and seems to be more sensitive than ADM in detecting motor abnormalities Newest test 121 Treatment Try everything! Old but good… Cyproheptadine First generation anti-histamine with additional anticholinergic, antiserotonergic, and local anesthetic properties 122 J Pediatr 2013 (in press) 80 children (mean age 10 y) 17 pts with chronic idiopathic nausea, with orthostatic intolerance by abnormal tilt table tests (88%) or gastric dysrhythmias (71%) Fludrocortisone: 0.1-0.2 mg/day for 4 weeks Iberogast Iberogast is comprised of the following 9 ingredients: Iberis amara, Angelica, Chamomile, Caraway Fruit, St. Mary’s Thistle, Balm Leaves, Peppermint Leaves, Celandine, and Liquorice Root. 123 Iberogast in Functional Dyspepsia von Arnim U, et al. Am J Gastroenterol. 2007;102:1268-75 Gastrointestinal Symptom score during 8 wk of treatment with STW 5 (Iberogast) or placebo Hypnotherapy for nausea? In five of these studies the participants were children. Studies report positive results including statistically significant reductions in anticipatory and CINV. Meta-analysis revealed a large effect size of hypnotic treatment when compared with treatment as usual, and the effect was at least as large as that of cognitive– behavioural therapy Acupuncture for nausea? 124 Authors’ conclusions: P6 acupoint stimulation prevented PONV. There was no reliable evidence for differences in risks of postoperative nausea or vomiting after P6 acupoint stimulation compared to antiemetic drugs The ReliefBand Botulinum Toxin: 100-200 Units divided in 4 quadrants 125 Gastrointest Endosc. 2012 Feb;75:302-9 Gastric Electrical Stimulation (GES): The nausea Holy Grail in pediatrics? 126 Symptom Severity Improved total score (p<0.0001) p<0.0001 Conclusions • Nausea with or without vomiting is a • • • common symptom in children and adolescents Early morning nausea is often a manifestation of an anxiety disorder EGD and GE studies may clarify underlying pathophysiology and direct treatment Several medical, behavioral, and surgical interventions have the potential to ameliorate nausea 127 New Horizons in Hepatitis C NASPGHAN Postgraduate Course Washington, DC Daniel H. Leung, MD Baylor College of Medicine Texas Children’s Liver Center Pediatrics Disclosures •Research support as Principal Investigator for clinical trials sponsored by Gilead, Merck, BMS, Roche, and Vertex. •Served on medical advisory board for Gilead. •Brand names will be referenced for the purposes of identification and learning of future studies. Objectives •Understand the epidemiology, burden of disease, and natural history of HCV •Become familiar with indications to treat and upcoming all-oral treatment regimens •Appreciate the rapidity and approach of HCV drug development 128 1 Hepatitis C: Burden of disease •Hepatitis C (HCV) is an RNA virus that affects ~200 million worldwide. 3 million in US. #1 cause of HCC in US •Vertical transmission (5-7%) is the most common route in infants and children with approximately 7,500 new cases/year in the US. •There are an estimated 23,000-46,000 children with chronic HCV (CHC) infection in the US and 6,600 in Canada. Alter MJ et al. Ann Intern Med 2006. Jhaveri R. et al. J Pediatr 2006. El Saadany S. et al. Can J Gastroenterol 2000. Histology of chronic pediatric HCV Goodman ZD, Makhlouf HR, Liu L, et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds‐C Trial. Hepatology 2008; 47: 836–43 Natural History Maternal transmission 5‐7% Spontaneous resolution <2 yrs 25‐40% Persistent CHC 48‐69% Develop CHC but clear at <7 yrs 6‐12% Children/Adolesc ents Most clinically well 15% with mild symptoms 1‐2% develop cirrhosis HCC 5 reports 129 2 Multi-Center European Study 1980-1998 “Mild but Progressive” 200 followed for mean of 6.2 ± 4.7 yrs 87% asymptomatic +HCV RNA 48% N=224 Liver bx n=92 ALT< 2x ULN 6% viral clearance and ALT normalization 79% Genotype 1 Mean Ishak (0‐6) 1.6 ± 1.3 17% Genotype 2/3 ‐Children < 15 yr 1.5 ± 1.3 ‐Children > 15 yr 2.3 ± 1.2 Cirrhosis 1 (1%) Jara et al. Clinical Infect Dis. 2003 Overweight children in US with HCV at risk for increased fibrosis •Peds-C Trial (U.S.) •N=121 • 4.2 % bridging fibrosis • 1.7 % cirrhosis • 44% steatosis (minimal in 34%, mild in 10%) • Steatosis correlated with serum ALT and BMI zscores Ishak BMI‐Z<1.64 BMI‐Z>1.64 Score (n=92) (n=29) 0 16% 7% 1 2 46% 36% 45% 31% 3 4 2% ‐ 11% ‐ 5 6 ‐ ‐ 3% 3% Goodman ZD, Makhlouf HR, Liu L, et al. Hepatology 2008. Obesity and impact on Treatment in US children Obesity MAY • Decreases IFN bioavailability • Alter cytokine function • Increase insulin resistance 1 unit in BMI z‐ score = ‐12% response rate Delgado‐Borrego et al. JPGN 2010 130 3 Why worry? •Recent observations in adults with CHC indicate that hepatocellular carcinoma may develop in the absence of cirrhosis •Children with early stage, treatment-naive HCV demonstrated cognitive impairment with memory most affected Lok AS et al. Gastroenterology 2009. Madhoun MF et al. Am J Med Sci 2010. Faddan et al. Journal of Viral Hepatitis 2014. Screening/Monitoring Infants <3 yrs •-Recommended age:>18 months due to maternal antibody (NASPGHAN 1B; AIII) •-HCV antibody: specificity and sensitivity of the third generation EIAs are >98% and >97% respectively •-HCV RNA quantitative PCR reserved for confirmation (NASPGHAN 2B; BIII)-maternal anxiety Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012. Monitoring in Children •Annual evaluation in children with HCV not on antiviral therapy ‐Ongoing education and physical exams ‐Laboratory investigations (NASPGHAN 2A; BII): •Serum aminotransferases •Bilirubin (total/direct or conjugated) •Albumin •HCV RNA quant •CBC •PT/INR Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012 . 131 4 Monitoring in Children •In children with significant liver disease (hepatic fibrosis or cirrhosis): Abdominal ultrasonography AND Serum alpha-fetoprotein should be considered ANNUALLY to screen for HCC (NASPGHAN 2B; BII*). Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012. Role of HCV genotyping •Predictor of RESPONSE and OPTIMAL DURATION •Genotype 1:<40%* * •Genotype 2 or 3: >80% chance of cure •This has changed with advent of new therapies Wirth, World Journal of Pediatric Gastroenterology, 2012 Role of liver biopsy Liver biopsy may be considered if the result will influence medical decision-making. ‐To investigate clinical hepatic decompensation ‐To assess severity of liver disease for antiviral candidacy ‐May forego pre-treatment liver biopsy in children with HCV genotypes 2 or 3 who have a high (>80%) probability of achieving a virologic cure (NASPGHAN 2B; BII recommendation). Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012. 132 5 Pegylated Interferon + Ribavirin ‐Two U.S. licensed pegylated interferons •Peginterferon alfa2b (Peg-Intron®) •Peginterferon alfa2a (Pegasys®) •Ribavirin: (Rebetol®, Ribasphere®) How effective is current therapy? •5 largest pediatric prospective clinical trials •Overall SVR is 60% •51% in G1 •93% in G2/3 Wirth, World Journal of Pediatric Gastroenterology, 2012 To treat or not to treat? Treat Wait High response rate (Genotypes 2 or 3) Chance for spontaneous clearance Improved tolerability in children Psychiatric disorder Lower viral load Morbid obesity Parental oversight Low response rate (Genotype 1) Family history of HCC or cirrhosis Puberty Reduce social burden More advanced therapies ahead 133 6 Duration of Treatment ‐Children with genotype 1/4 can be treated with peginterferon alfa-2a + ribavirin for 48 weeks ‐Children with genotypes 2 and 3 can be treated with peginterferon alfa-2 + ribavirin for 24 weeks ‐Insufficient/no data to support benefit vs risk in increasing duration and dose of treatment Hadziyannis SJ et al. Ann Intern Med 2004. Zeuzem S, et al. J Hepatol 2006. Dalgard O et al., Gut, 2007. Treatment Endpoints Each outcome has prognostic significance. RVR is the strongest predictor of SVR (gold standard for cure) U.S. Department of Veterans Affairs ‐ 810 Vermont Avenue, NW ‐ Washington, DC 20420 HCV Life Cycle: Understanding the Future Dan 134 7 Future Therapeutics: A new era •HCV encodes one single polyprotein that is cleaved into 10 structural and non-structural proteins by viral enzymes •Direct Acting Antivirals (DAA) are designed to inhibit viral proteins involved in the HCV life cycle. The complexity of the viral machinery allows for numerous potential targets. Personalized HCV Therapy Nature Publishing Group, 2005 HCV Structure: Understanding the Future •Discovery of first two DAA against the NS3/4A serine protease for use in genotype 1 HCV • Ketoamide inhibitors, boceprevir and telaprevir were approved in 2011 135 8 Translation/Processing Protease inhibitors Non‐Nucleoside Polymerase inhibitors Nucleos(t)ide Polymerase inhibitors Ledipasvir Sofosbuvir Dasabuvir Welsch, C. Et al. Gut 2012;61(Suppl 1):i36ei46. doi:10.1136/gutjnl‐2012‐302144 What’s the big deal? •HCV superseded HIV cause of death in US since 2007 •89 investigational medications studied between 1998-2014 to treat HCV •Growing pipeline of potent direct antivirals for HCV currently totals 75 in the US alone! Pharmaceutical Research and Manufacturers of America. 2015 biopharmaceutical research industry profile. Washington, DC: PhRMA; April 2015 SOFOSBUVIR (NS5B): THE NEW “BACKBONE” OF HCV THERAPY ? • Approved in December 2013 • 1st in combo with PEGIFN +ribavirin, >85% SVR in 12 wks • 2nd with ribavirin, the first interferon-sparing treatment regimen for G2 (12 wks) or G3 (24 wks) with >95% Lancet Infect Disease 2013 May;13(5):401‐8 136 9 Timeline of recently FDA approved HCV drugs Telaprevir (Incivek®) and Boceprevir (Victrelis®), May 2011 Sofosbuvir (Sovaldi®), Dec 2013 Ledipasvir (Harvoni®), Oct 2014 Simeprevir (Olysio®), Nov 2014 Ombitasvir, paritaprevir, ritonavir +dasabuvir (Viekira pak®), Dec 2014 Scientific mix & match • + Ledipasvir (NS5A) >90% for G1 in 12 weeks, October 2014 • + Simeprevir (NS3/4A) : 93% in 12 wks G1, 97% in 24 weeks, November 2014 • + Daclatasvir (NS5A) 98% for G1 in 12 weeks (No FDA) Non-Sofosbuvir combinations •Viekira Pak (ombitasvir (NS5A), paritaprevir (NS34A) and ritonavir tablets co-packaged with dasabuvir tablets (NS5B) •95% for G1 and G4 in 12 weeks •Grazoprevir (NS3/4A)/Elbasvir (NS5A) for G1/4 and those with endstage renal disease on dialysis •Daclatasvir (NS5A) + Asunaprevir (NS3) (FDA app withdrawn) 137 10 A genotypic paradigm shift •G3, not G1 is now the most difficult to treat with new DAA’s with higher relapse rates after 12 weeks of treatment. •G3 patients are more responsive to pegylated interferon, but require 24 weeks of Sofosbuvir instead of 12 (G1) •This same trend has been demonstrated with other DAA combinations Empiric approach to pediatric HCV •Treat the child with >75% chance of responding to PEG-IFN (G2 and G3). Really? •For mild inflammation and fibrosis, wait for all-oral DAA drugs or consider trials •Offer children with aggressive inflammation and fibrosis on liver biopsy entry into pediatric DAA trials Summary •HCV progression is mild in children but not without risk •Fibrosis and poor response associated with obesity •Peg IFN+RBV is the current standard of care. Genotype will predict response and duration of treatment differently. • Future: Single pill, 12 weeks, no SE’s, >90% cure 138 11 Renal Complications of Chronic Liver Disease NASPGHAN Post-Graduate Course 2015 Jean Pappas Molleston, M.D. Professor of Clinical Pediatrics Indiana University School of Medicine Disclosures • I have research funding from Lumena, Vertex, Gillead, Abbvie • I have research funding from the CF Foundation • I have received funding from Vindico for a medical education presentation Objectives: • Define renal complications in chronic liver disease • Review mechanisms of ascites, role of the kidney, and diuretic use • Understand fluid balance in cirrhosis • Review definition of Hepatorenal Syndrome (HRS) and treatment recommendations 139 Physiology of Portal Hypertension • Peripheral and splanchnic vasodilation with increased cardiac output • Increased resistance to portal vein inflow due to cirrhosis • Increased portal vein pressure • Consequences: *renal dysfunction *ascites variceal bleeding hypersplenism Fagundes AJKD 2012 Kidney in Portal HTN/Cirrhosis • • • • • • Systemic arterial vasodilation Decreased effective arterial blood volume Renal vasoconstriction Possible role of inflammatory response Possible role of angiogenic factors Renal sodium and water retention 140 Ascites: Physiology • Vasodilation and effective hypovolemia result in stimulation of the renin-angiotensin, aldosterone system; salt and water are retained • Portal hypertension increases hydrostatic pressure in splanchnic circulation, exceeding capacity of lymphatics • Low albumin decreases colloid oncotic pressure, allowing fluid to leak into interstitium Giefer JPGN 2011 Management of Ascites in Cirrhosis • Mild sodium restriction • Diuretics – Spironolactone: inhibits aldosterone (acts distally) 2-3mg/kg/d – Furosemide: loop diuretic 1-2mg/kg/d • Albumin infusion 1g/kg of 25% albumin • Paracentesis +/- albumin • TIPS Giefer JPGN 2011 Hyponatremia in Cirrhosis Cirrhosis/portal hypertension Splanchnic/systemic vasodilation Decreased effective arterial blood volume Activation of neurohumoral systems Renal tubule/water retention Dilutional hyponatremia Adapted from Mohanty Gastroenterol Hepatol 2015 141 Consequences of Hyponatremia in Cirrhosis • • • • Higher mortality More encephalopathy Associated with ascites, HRS Associated with impaired QOL Mohanty Gastroenterol Hepatol 2015 Hyponatremia in Cirrhosis: Treatment Transplant Cirrhosis/portal hypertension Splanchnic/systemic vasodilation Decreased effective arterial blood volume Albumin infusions Hold diuretics Activation of neurohumoral systems: Renal tubule/water retention Dilutional hyponatremia Water restriction ?Vaptans? Adapted from Mohanty Gastroenterol Hepatol 2015 Causes of Renal Dysfunction in Cirrhosis • Intra-renal 29% (glomerulonephritis, interstitial nephritis) • Pre-renal 70% – 66% respond to volume expansion – 34% do not respond to volume HRS • Precipitating factors: – – – – – Infection, esp. spontaneous bacterial peritonitis GI bleeding Excessive diuresis Diarrhea (lactulose) Drugs (including antibiotics, NSAIDS) Charlton Liver Transplant 2009 142 Consequences of Renal Dysfunction in Cirrhosis • Ascites • Hyponatremia • Hepatorenal syndrome – Type 1: acute renal failure – Type 2: chronic renal failure Fagundes AJKD 2012 Hepatorenal Syndrome: Clinical Characteristics • Diagnostic criteria: – Cirrhosis with ascites – Elevated creatinine (Cr) – No improvement of Cr after withdrawal of diuretics for 2 days and albumin infusions to expand plasma volume – No shock, no nephrotoxic drugs – No parenchymal kidney disease (proteinuria, hematuria, abnormal u/s) Fagundes AJKD 2‐12, Wong Nat Rev: Gastro/Hep 2012 Treatment of Hepatorenal Syndrome • Recognize/prevent/treat precipitating factors • Try 1g/kg albumin IV up to 100g in adults • Vasoconstrictor therapy: – Terlipressin* plus albumin (34-43% resolution of HRS in RCT) – Midodrine plus octreotide/albumin (30% effective, uncontrolled studies; compared to terlipressin/albumin 29% vs 70%) – Norepinephrine plus albumin ? equivalent to terlipressin (RCT) *terlipressin not available in US Reviewed in Wong Nat Rev Gast 2012; Gluud Cochrane 2012; Cavallin Hepatol 2015 143 Medical Management of HRS with Vasoconstrictors Wong Nat Rev Gastr/Hep 2012 Hepatorenal Syndrome and Renal Replacement Therapy (RRT) • Decision for RRT depends on fluid balance, metabolic derangements (K+, acidosis), and level of renal dysfunction • CVVHD is preferred to intermittent hemodialysis to minimize hemodynamic instability • There are issues like choice of anticoagulant (role of citrate?) Long Term Outcomes of Children with HRS Receiving RRT then Liver Transplant Survival GFR/years of follow‐up Need for f/u antihypertensives Received RRT (8) Matched controls, no RRT (24) P Value 5/8 (63%) 24/24 (100%) 0.01 97 (60‐122)/3.2yrs 114 (65‐236)/4.9yrs NS 1/5 (20%) 2/22 (9%) NS Adapted from Parsons Liver Transplant 2014 144 Hepatorenal Syndrome and TIPS • Adult studies in type I and II hepatorenal syndrome HRS indicate improvement in renal function after TIPS placement • Use of TIPS in decompensated cirrhosis is problematic: can result in encephalopathy or even liver failure; bili>3-5 considered contraindication Rossle Gut 2010 Effects of a Transjugular Intrahepatic Portosystemic Shunt (TIPS) on Urinary Sodium Excretion and Creatinine concentration. Rossle Gut 2010 . Hepatorenal Syndrome and Transplantation • HRS resolves in 76% of adults in 13 days • 6% increase in chance of not resolving per pretransplant dialysis day • Guidelines recommend isolated liver transplant if duration of RRT is less than 6-12 weeks • Combined liver kidney transplant if duration of RRT is >8 wks – 3 year patient, kidney and liver survival all >65% – Not always better than isolated liver tx Wong Liver Transplant 2015 Davis Liver Transplant 2005 Locke Transplantation 2008 145 Impact of the Etiology of Acute Kidney Injury on Outcomes Following Transplantation: Acute Tubular Necrosis Versus Hepatorenal Syndrome Liver Nadim Liver Transpl 2012 Summary • Peripheral/splanchnic vasodilation, decreased effective blood volume and renal vasoconstriction lead to renal complications of cirrhosis: ascites, hyponatremia, HRS • Treatment of these complications revolves on understanding the kidney’s role in Na and H20 balance in cirrhosis • There are some encouraging data regarding vasoconstrictor + albumin therapy for HRS in adults; pediatric research is needed! Take Home Messages • Carefully monitor renal status in cirrhosis • Avoid over-diuresis & nephrotoxic drugs and treat infection early to avoid precipitating HRS • Try providing colloid when HRS is suspected • Consider adding vasoconstrictor therapy in HRS (need pediatric data) • HRS often reverses after liver transplant 146 Wilson Disease – an update Simon Horslen MB ChB FRCPCH Director Hepatobiliary Program Medical Director Liver & Intestine Transplantation Seattle Children's Hospital Professor Department of Pediatrics University of Washington School of Medicine Disclosure In the past 12 months, I have had no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or providers(s) of commercial services discussed in this CME activity I do not intend to discuss an unapproved or investigative use of a commercial product or device in my presentation Learning Objectives 1. Review the clinical presentations in pediatric population and typical diagnostic evaluation. 2. Understand genetics and patterns of inheritance to focus who should be screened. 3. Understand treatment strategies and side effects of current and future therapies 147 Content • • • • • • • • History Presentation of Wilson disease Physiology of copper Genetics of Wilson disease Diagnosis Prognosis Treatment & Monitoring Future directions History • Progressive degeneration of lenticular nuclei associated with hepatic cirrhosis was recognized as a distinct clinical entity in 1912 • John Nathaniel Cumings made the link with copper accumulation in both the liver and the brain in 1948 • Derek Denny-Brown first reported effective treatment with metal chelator British anti-Lewisite in 1951 • Penicillamine, first effective oral agent, was introduced in 1956 by John Walshe. • Gene locus chromosome 13q 1985 • Gene cloned – P-type ATPase 1993 Samuel Alexander Kinnier Wilson Phenotypic Presentation of Wilson Disease Hepatic presentations H1: Acute hepatic Wilson disease H2: Chronic hepatic Wilson disease Neurologic Presentations N1: Associated with symptomatic liver disease N2: Not associated with symptomatic liver disease NX: presence or absence of liver disease not investigated Other (O) 148 Classic Pediatric Presentation • • • • • • • • • 7-16 year old child Previously healthy 2 weeks malaise and increasing jaundice Coomb’s negative hemolytic anemia Modest elevation of transaminases Low alkaline phosphatase Prolonged prothrombin time Low ceruloplasmin level High urinary copper excretion Copper kinetics and metabolism • Regular diet averages 5 mg/d • Exchange ~ 2mg a day (net absorption ≈ net losses) • Total body copper ~100 mg (Liver 20%, Blood 10% Other tissues 70%) • Liver rapidly clears newly absorbed copper • Ceruloplasmin made by hepatocytes, each molecule contains 6 copper atoms incorporated during biosynthesis • Failure to incorporate copper either because of dietary deficiency or Wilson disease leads to a reduced serum ceruloplasmin level Copper kinetics Stable isotope enrichment studies (65Cu) showing normal range and a patient with Wilson disease (blue line) % enrichment 15 10 5 0 0 20 60 40 Hours after oral 65Cu dose 80 149 Copper metabolism in the hepatocyte Ceruloplasmin ER IL-6 TNF Trans-Golgi Network cytochrome oxidase HAH1 Cox17 Bile canaliculus Wilson ATPase metallothionein Ccs Cu/Zn superoxide dismutase To Plasma (secretion) Ctr1 Cu-histidine Cu-albumin Hepatic Sinusoid From: Disorders of Copper Transport: The Online Metabolic and Molecular Bases of Inherited Disease, 2014 Date of download: 6/22/2015 Copyright © 2015 McGraw-Hill Education. All rights reserved Molecular biology of Wilson disease • ATP7B Chromosome 13q14.3 • 21 exons, 60 kb • >500 mutations described • H1069Q most common in Europeans 35-40% • A778L up to 30% of Asian populations • Genotype- phenotype correlation not strong • Genetic modifiers – MTHFR, COMMD1, ATOX1, XIAP • Environmental modifiers - diet Copper-binding domain ATP-binding domain Diagnostic Tests • • • • • • KF rings Ceruloplasmin Serum copper Urinary copper Liver biopsy Molecular genetics 150 Kayser-Fleischer Rings • Occur in 90-95% of WD patients with a neurological presentation • But only 40-65% in hepatic presentations • Slit-lamp examination often necessary • Can occur in other forms of copper toxicosis and chronic cholestatic syndromes (pseudo-rings) Ceruloplasmin • Typically low (<20 mg/dL) in WD • Levels may be normal in 20-50% at presentation • Acute-phase reactant • May be low in copper deficiency, chronic liver disease, nephrotic syndrome and proteinlosing enteropathy Serum copper Serum Copper • Circulating copper may be: • Low - because the ceruloplasmin level is low • High –liver necrosis ‘free’ copper • Normal – a normal level does exclude the diagnosis releases not • Free (non-ceruloplasmin bound) copper • Calculated parameter and subject to error • Better for treatment monitoring than diagnosis • > 25 g/dL in most untreated patients 151 Urinary copper excretion • 24 hour collection • Collected into acid-washed container to prevent copper contamination • Basal copper excretion >5 mol/24 h (320 g/24 h) suggestive of WD • Műller et al 2007 used >1.6 mol/24 h (100 g/24 h) • 94% symptomatic patients • 69% asymptomatic siblings • 22% controls • Penicillamine challenge - >25 mol/24 h (1600 g/24 h) Liver Biopsy • Histology may be supportive but features are not pathognomonic • Copper stains frequently negative • Hepatic copper content • Normal < 50 g/g dry weight • WD > 250 g/g dry weight but may be lower than this in up to 20% of WD patients • Maybe as high in chronic cholestasis • Avoid contamination, place biopsy directly into dry plastic copper-free container. Do not use fixed tissue. Molecular Genetics – ATP7B • Haplotype and targeted mutation analysis • Many laboratories now offer full gene sequence analysis and deletion/duplication analysis • Carrier frequency ~1 in 90 based on case identification • Population based studies using molecular techniques suggest higher rates • No mutation identified in up to 13% but others have had 98% success in identifying gene defect 152 Leipzig Score 8th International conference on Wilson's disease and Menkes Disease. Leipzig/ Germany, April 16-18, 2001 Laboratory Tests Ceruloplasmin (mg/dL) Normal 10-20 < 10 Score 0 1 2 Urinary copper (in absence of acute hepatitis) Normal 1-2x ULN >2x ULN Normal but >5x ULN with penicillamine challenge 0 1 2 2 Liver Cu quantitation Normal <5x ULN >5x ULN -1 1 2 Rhodanine positive hepatocytes (only if hepatic Cu level not available) Absent Present 0 1 Symptoms Score KF rings (slit lamp examination) Present 2 Absent 0 Neuropsychiatric symptoms suggestive of WD (or typical brain MRI) Present 2 Absent 0 Coombs negative hemolytic anemia (+ high serum copper) Present 1 Absent 0 Mutation analysis Disease causing mutations on both chromosomes Disease causing mutation on one chromosome No disease causing mutations detected 4 1 0 Wilson Index for Predicting Mortality Score Bilirubin INR mol/L) AST WCC (IU/L) (x109 /L) Albumin (g/L) 0 0-100 0-1.2 0-100 0-6.7 >45 1 101-150 1.3-1.6 101-150 6.8-8.3 34-44 2 151-200 1.7-1.9 151-300 8.4-10.3 25-33 3 201-300 2.0-2.4 301-400 10.4-15.3 21-24 4 >300 >2.5 >401 >15.4 <20 A score 11 – PPV 92% & NPV 97% Dhawan A et al Liver Transpl. 2005 Treatment • Aim to start chelation therapy asap in symptomatic individuals • Treatment is life-long, including during pregnancy • If one treatment modality is discontinued, an alternative modality must be substituted • Discontinuation of all treatment leads to hepatic and neurologic decompensation, which may be refractory to further medical intervention 153 Treatment • D-Penicillamine (chelator) • Serious side effects can occur in up to 30% of individuals • Severe thrombocytopenia, leukopenia, aplastic anemia, nephrotic syndrome, polyserositis, Goodpasture syndrome, severe skin reactions • Trientine (chelator) • Rash, anorexia, abdominal pain, aplastic anemia, muscle cramps • Zinc (blocks copper absorption) • GI disturbance • Dietary copper restriction Monitoring • Why monitor? • Inadequate therapy, or non-adherence • Adverse drug effects (especially with D-penicillamine treatment) • Excessive long-term treatment may result in copper deficiency • Frequency of monitoring visits depends on time from diagnosis, changing medications and compliance • Serum copper and ceruloplasmin, LFTs, INR, CBC, urinalysis, and physical examination • 24-hour urinary excretion of copper at least annually Liver transplantation for Wilson disease • Primarily indicated for children and adolescents with fulminant presentation • Chronic liver insufficiency • Neurological injury not generally responsive • Outcomes based on UNOS data • Pediatric survival 90% and 89% at 1 and 5 years • Adult survival 88% and 86% • 1 year survival better if transplanted for chronic liver disease than for ALF Arnon R et al. Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults. Clin Transplant. 2011 Jan-Feb;25(1):E52-60. 154 Asymptomatic siblings • The goal is to identify affected siblings of a proband before they become symptomatic • If mutations known, testing with molecular genetics is appropriate • If mutations not known standard clinical testing can be conducted • Treatment with zinc alone may suffice, but is required life-long Future directions: New research • Phenotypic variation • Genetic • Epigenetic • Environmental • New Drug Treatments • (Ammonium tetrathiomolybdate) • Intrahepatic copper chelator • Screening Gateau & Delangle Ann N Y Acad Sci. 2014 Future directions: Population screening • Population frequency 1 in 30,000 • Presymptomatic diagnosis is reliable, treatment can prevent manifestations of disease • Ceruloplasmin and serum copper not useful for infant screening • A novel proteomic screening approach is being investigated using liquid chromatography–multiple reaction monitoring–mass spectrometry (LC-MRM-MS) looking at ATP7B protein levels 155 Conclusion • Understanding copper metabolism helps explain findings in Wilson disease • Scoring systems are available to aid diagnosis and prognosis • Molecular genetic testing is most direct and reliable method of diagnosis • Treat promptly and monitor copper status carefully in follow up • Treatment is life-long • Neonatal screening has the potential to prevent morbidity and death from Wilson disease 156 2015 NASPGHAN POSTGRADUATE COURSE Thursday October 8, 2015; Washington DC Blame the Genes? Familial and Autoimmune Pancreatitis in Children Véronique Morinville MD, FRCP(C) Pediatric Gastroenterology and Nutrition Montreal Children’s Hospital McGill University Health Centre Montreal, QC, Canada I have no financial relationships with a commercial entity to disclose Objectives of Presentation • Understand when to consider familial and autoimmune etiologies in a child presenting with pancreatitis • Review the different genetic factors that may be involved in familial‐type pancreatitis • Recognize factors implicated in autoimmune pancreatitis (AIP) types 1 and 2 and what therapies may be attempted 157 OBJECTIVE 1 When to consider familial and autoimmune etiologies in pediatric pancreatitis? AP = Acute Pancreatitis ARP = Acute Recurrent Pancreatitis CP = Chronic Pancreatitis ETIOLOGIES‐ Single Episode AP Pediatric Series Diagnosis of AP: At least 2 of 3 of: • Pain compatible with pancreas origin • Amylase and/or Lipase ≥ 3 x ULN • Imaging Anatomic Biliary/ Stones Traumatic Medications / Toxins Multi‐Systemic Infections Metabolic Iatrogenic Familial/ Hereditary “Idiopathic” (↓) Morinville 2008; Lautz 2011; Morinville 2012, others Etiologies ARP and CP Etiologies Adults: TIGAR‐O classification – Toxic/ Metabolic (EtOH, smoking) – Idiopathic – Genetic (? %) – Autoimmune (2‐6%) – Recurrent and severe acute pancreatitis‐ associated CP – Obstructive Etiologies Pediatrics: – TIGAR‐O – Multiple risk factors within same child example: cohort of 105 CP children: 80% with ≥ 1 genetic mutation; 30% obstructive, 20% toxic/ metabolic (Uc: INSPPIRE cohort; 2015 DDW) Okazaki 2005; UpToDate; Schwarzenberg 2015, Uc DDW Abstracts 2015, Oracz 2014; B Etemad 2001 158 “FAMILIAL” Pancreatitis Comfort and Steinberg 1952 DEFINITION: “FAMILIAL” Pancreatitis • Acute, Acute Recurrent, or Chronic Pancreatitis that appears to have a genetic basis • “Familial”: any positive family history • “Hereditary”: ≥3 affected, ≥ 2 generations Comfort and Steinberg 1952; Le Marechal 2006; Masson 2008 DEFINITION: Autoimmune Pancreatitis (AIP) • “…Distinct form of pancreatitis characterized clinically by frequent presentation with obstructive jaundice with or without a pancreatic mass, histologically by a lymphoplasmacytic infiltrate and fibrosis and therapeutically by a dramatic response to steroids….”* • Other Possible Findings: AI diseases, autoAbs, high IgG4 *Shimosegawa et al, International Consensus Diagnostic Criteria for Autoimmune Pancreatitis 2011 159 WHEN to Consider “Familial” –Type Pancreatitis? • • • • Presentations: ARP +++, CP +++ (esp. calcific), even AP “Pancreas‐only” manifestations (certain genes) Family History + ; > 1 generation involved +++ “Younger” age of onset (= all pediatrics) • Pancreatitis with Absence of Obvious Trigger (**multiple risks) WHEN to Consider AIP? • • • • • Presentation: CP > AP, ARP (but all possible) HPI: ill‐defined > acute presentation Sx: Abdominal pain, jaundice, weight loss PMHx IBD, Auto‐immunity Imaging: diffuse or focal mass, narrowed PD, dilated CBD • Relatively rare, but ‐ *Any Pancreatitis with Absence of Obvious Trigger * OBJECTIVE 2 Review of Genetic Factors In Familial‐Type Pancreatitis Comfort and Steinberg 1952; AGA Pancreas Gastroslides 160 Familial‐type Pancreatitis: Genetics The trypsin‐dependent pathological model of chronic pancreatitis (Dr. D. Whitcomb, All rights reserved; Special thanks for use) CPA1 CEL CLDN2 Consider Genetics in ALL Children with ARP or CP PRSS1: Cationic Trypsinogen “Hereditary Pancreatitis” • AD; Incomplete Penetrance; often extensive pedigrees • PRSS1 gain‐of‐function mutations: ↑ activation trypsinogen intracellularly ↑ activation zymogen cascade • Other mechanisms described • ARP; CP; Exocrine and Endocrine insufficiency; Cancer AGA GastroSlides Pancreas (R122H; N29I; A16V; rare) SPINK1: Secretory Trypsin Inhibitor Serine Protease Inhibitor Kazal Type 1 • SPINK1 in secretory granules; Binds active site trypsin 1:1 • Clinically: • mostly Co‐factor: disease‐modifying > disease‐”causing” •Tropical calcific pancreatitis‐ India; homozygous N34S “Mutations” / variants ie N34S, P55S Active site Trypsin SPINK1 161 CFTR: Cystic Fibrosis Transmembrane conductance Regulator • Strong association between heterozygous mutations in CFTR gene and Idiopathic Pancreatitis, CP • Pancreas‐sufficient CF (2 CFTR mutations) at risk ARP (lower “PIP score” ↑ risk) • Mechanism‐ “2+ hits” likely necessary in most; some mutations more pancreas‐specific CFTR Sharer 1998; Cohn 1998, Ooi 2011; LaRusch 2014; AGA Pancreas Gastroslides CTRC: Chymotrypsin C • CTRC: degradation of trypsin and trypsinogen (protective) • Loss‐of‐function CTRC variants (reduced secretion or activity) risk factors for CP (idiopathic w/ or w/o family history) – Germany, France – India: mutations in tropical pancreatitis • Gain‐of‐function model (ER stress) also described • CTRC in younger‐age onset ARP, CP Zhou J 2011; Rosendahl 2008; Masson 2008; INSPPIRE 2015 OBJECTIVE 3 AIP Types 1 and 2 •Factors Implicated • Management Sahani 2004; Shimosegawa 2009 162 AIP: History and Terminology • “Chronic inflammatory sclerosis of the pancreas: an autoimmune pancreatic disease?” 1960s • “Autoimmune Pancreatitis” 1990s – Autoimmune propensity: other AI, autoAbs, steroid response – But no specific genes implicated • Types 1 and 2 AIP described‐ 2000s; Sx, associations, histology • Q. Several terms referring to AIP “spectrum”? – Idiopathic sclerosing, primary inflammatory, lymphoplasmacytic Sarles 1961; Chari 1994; Yoshida 1995 CHARACTERISTICS AIP • Type 1 • Type 2 – “pancreatic manifestation of systemic fibroinflammatory disease” (bile ducts, salivary, kidney, LNs, retroperitoneal); “IgG4‐related” – Pain, V, wt loss, jaundice – Elevated IgG4 (*cutoff dif.) – Peak age 60s, M> F, Asia – Mass pancreas head or diffuse enlargement *Can diagnose w/o histology – “pancreas‐specific” (but: 1/3 IBD) – – – – Pain, V, wt loss, jaundice No or low levels IgG4 Peak age 40s, M=F, N.A. Mass pancreas head or diffuse enlargement *Definitive Dx req biopsy HISTOLOLOGY AIP: Core Biopsy, Resection Type 1: Histology Type 2: Histology – LPSP: lymphoplasmacytic sclerosing pancreatitis – Periductal dense infiltrate plasma cells and lymphocytes; storiform fibrosis – Obliterative phlebitis – No GELs – Abundant IgG4+ plasma cells ( > 10 cells/ hpf) Shimosegawa 2009 – IDCP: Idiopathic duct‐centric pancreatitis – periductal lymphoplasmacytic infiltrate; periductal, perilobular fibrosis, duct narrowing – “GEL”: Granulocytic Epithelial Lesion‐ disruption small‐ med duct epithelium/ invasion neutrophilic granulocytes – Low / no IgG4 cells ie < 10/hpf Kusuda 2010 163 Diagnosis AIP: Adults • 2000s: multiple societies/ countries publishing different diagnostic criteria • 2007‐2011: HISORt and International Consensus Diagnostic Criteria (ICDC) – – – – – – Histology (core biopsy) Imaging Serology (IgG4 serum levels): > 2x ULN Other organ involvement +/‐ Response to steroid therapy (2w) “Definitive” and “Probable” diagnoses HISORt: Chari J Gastro 2007; ICDC: Shimosegawa et al Pancreas 2011 Criteria to Diagnose Type 1 AIP Criterion Level 1 Evidence Level 2 Evidence Histology LPSP (core biopsy/ resection) At least 3 criteria within LPSP (core biopsy) 2 criteria within Imaging: Parenchyma Diffuse enlargement/ delayed enhancement segmental/ focal enlargement, delayed enhancement Imaging: Ductal > 1/3 length main PD or multiple strictures, no upstream dilation Segmental narrowing PD, no upstream dilation (duct <5mm) Serology IgG4 > 2x ULN IgG4: 1‐2x ULN Other Organ Involvement Histology extrapancreatic organs Typical Radiology (CBD, retroperit) Histology extrapancreatic organs Physical/ Radiologic evidence Response to therapy Diagnostic Steroid Trial Improvement 2w Diagnostic Steroid Trial Improvement 2w ADULT Criteria. Shimosegawa. International Consensus 2011 Criteria to Diagnose Type 2 AIP Criterion Level 1 Evidence Level 2 Evidence Histology: Core biopsy/ specimen IDCP and: GEL w/ or w/o granulocytic acinar inflammation + Both: Granulocytic and lymphoplasmacytic acinar infiltrate + No/ scant IG4+ (0‐10 cells/ hpf) No/ scant IgG4 (0‐10 cells/ hpf) Imaging: Parenchyma Diffuse enlargement with delayed enhancement (typical) Segmental/ focal enlargement with delayed enhancement Imaging: Ductal Long (> 1/3 main PD) or multiple strictures, no upstream dilatation Segmental narrowing w/o upstream dilatation (duct <5mm) Serology ‐ ‐ Other Organs ‐ IBD Response to therapy Diagnostic steroid trial Improvement 2w Diagnostic steroid trial Involvement 2w ADULT Criteria. Shimosegawa. International Consensus 2011 164 AIP in Pediatrics: Literature Case Reports/ Small Series • Presentations: Abdo pain (>> adults), V, weight loss, jaundice • Imaging: globular enlarged, ill‐defined mass panc head; obstruction CBD; irreg/ multiple narrowings PD; DDx tumors but rarer • Serology: Negative AI markers in most; IgG4 often N; rare > 2x ULN • Other Organs: Few extrapancreatic manifestations‐ except IBD • Histology: EUS‐guided trucut biopsy or laparoscopic bx via duo; laparotomy; AIP 2 > AIP 1 or NOS (histology not always obtained) • Steroid response: not frequent empiric trial * No Pediatric‐Specific Criteria for Diagnosis * AIP type 2 > type 1 tendency suspected in recent years Fukumori 2005; El‐Matary 2006; Blejter 2008; Refaat 2009; Gargouri 2009; Mannion 2011; Friedlander 2012; Fujii 2013; Oracz 2014; Zen 2014; Long 2015 Management AIP • Surgical Resections (e.g. Whipple) – esp. older series, adults – Not 1st line in kids‐ if concern dx/neoplasm intra‐op biopsy • Conservative Management: ↑ recent cases • Biliary/ Pancreatic Stents to relieve obstruction (x few weeks) • Corticosteroid therapy: Mainstay +/‐ Diagnostic (AIP 1 adult) – Prednisone 1 mg/kg/d x 2‐4 weeks; taper 2.5‐5 mg/w; +/‐ long term • Immunomosuppression : if maintenance needed – MMF*, 6MP*, azathioprine, rituximab (*peds) • Monitoring for recurrences/ complications‐ long‐term – Resolution? Atrophy? Other organs? Exocrine/ endocrine insufficiencies? Fukumori 2005; El‐Matary 2006; Blejter 2008; Refaat 2009; Gargouri 2009; Mannion 2011; Friedlander 2012; Fujii 2013; Oracz 2014; Zen 2014; Long 2015 Management AIP: Long‐Term Outcomes Adults Hart PA. Gut 2013 • • • • • • * Retrospective: 23 institutions/ 10 countries/ 1064 patients High response steroids: AIP 1‐ 99%, AIP 2‐ 92% Biliary stents: for jaundice Surgery: not primary Tx for AIP; done when unclear Dx Relapses : AIP 1 ‐ 31%; AIP 2 ‐ 9% Relapses: response to steroids +/‐ other (x 1‐3y) No data in children Hart 2013 165 Future Directions: Autoimmune and Genetic Markers within Same Patients? • Multiple risk factors within same children: 129 CP children tested for AIP (no tissue); genetics (CFTR, PRSS1, SPINK1) – Autoimmune Abs: 75/129. Of these: 32/75 genetic mutation; 16/75 anatomic AbN – IgG4 ↑: 24/68. Of these: 17/24 mutation; 5/24 anatomic – Suspicion AIP: 6 (5M): 11‐17y; 2 treated with steroids – Chronic autoimmune condition: 13 (UC 6, PSC 3, CD 1, others) * High rate AutoAbs in pediatric CP. Significance? * Interactions of Co‐factors? Further research indicated Oracz G. Prz Gastroenterol 2014 TAKE HOME POINTS: Familial and Autoimmune Pancreatitis in Children 1. Consider in all children – especially when without obvious etiology (metabolic, anatomic) or if recurrent/ chronic (ARP, CP) 2. Virtually all “familial” patterns pancreatitis have a genetic predisposition (PRSS1, SPINK1, CTRC, CFTR‐ and others NYD) • • Multiple risks within one patient Many: genetic risk found / No known family history! TAKE HOME POINTS: Familial and Autoimmune Pancreatitis in Children 3. Autoimmune Pancreatitis: rarer , likely under‐diagnosed due to need for tissue (for Type 2) • Suspect Type 2 > Type 1 in children 4. Management AIP: #1 Corticosteroids; Observation; +/‐ Stents; +/‐ Immunomodulators; Surgery ↓ u lized; Long‐term Follow‐up necessary 5. Future Research: Risk Factor Interactions ? 166 Thank you 167 Getting to the Bottom of Perianal Crohn’s Disease Maria Oliva-Hemker, M.D. Chief, Division of Pediatric Gastroenterology & Nutrition Stermer Family Professor of Pediatric IBD Johns Hopkins University School of Medicine Baltimore, MD Disclosures • Abbvie Immunology—grant funding Learning Objectives • Identify the lesions associated with perianal Crohn’s disease • Review the pathophysiology and classification systems for perianal fistulizing disease • Understand the approach to assessing and treating the patient with perianal fistulizing disease 168 Perianal Crohn’s Disease Fissures Fistula Abscess Tags www.gicare.com Prevalence of Pediatric Perianal Crohn’s Disease • Up to 38% of pediatric CD develop perianal disease – 41/276 (15%) newly diagnosed children with CD had perianal lesions within 30 days of diagnosis – 28/276 (10%) had fistulas and/or abscesses • 1 in 20 (5%) present with isolated fistulous disease (and have no evidence of intestinal involvement at presentation) Keljo DJ et al, Inflamm Bowel Dis 2009 Skin Tags: Prevalence in Crohn’s Disease of Up to 70% • Type 1: “Elephant ear” tags – – – – – Flat or round, smooth Soft/compressible Flesh colored Varying sizes Painless • Type 2: arise from healed fissures, ulcers or hemorhoids – – – – – Edematous, usually hard Red, blue or cyanotic Larger than Type1 Irregular surface Painful Bonheur JL et al, Inflamm Bowel Dis 2008 169 Anal Fissures • • • • • Prevalence of up to 20% • Spontaneously heal >80% of patients Broad based and deep Usually painless May be associated with large skin tags May be multiple and placed at various locations around the anal canal Parks AG et al, Br J Surg 1976 Schwartz DA et al Inflamm Bowel Dis 2015 Simple Fistulas Complex Fistulas Schwartz DA et al Inflamm Bowel Dis 2014 Bell SJ et al Aliment Pharmacol Ther 2003 170 Assessment of Perianal Fistulas • Flexible sigmoidoscopy or colonoscopy – to evaluate for rectosigmoid involvement (predicts more aggressive course) • Exam under anesthesia (EUA) – gold standard (for experienced surgeon) • Pelvic MRI is considered gold standard imaging technique – Endoanal ultrasound (EUS) may be useful alternative to MRI (adults) Treatment Goals for Fistulizing Disease • Short Term – Drainage of abscesses/control sepsis – Relief of symptoms • Long Term – – – – Resolution of drainage Fistula closure Improve quality of life Avoid proctocolectomy and permanent ostomy Critical Evaluation of Data from Therapeutic Trials Medication Evidence Antibiotics B+ Efficacy Good Corticosteroids D Poor 6-Mercaptopurine /Azathioprine C+ Good Methotrexate C+ Good/Fair Cyclosporine C+ Fair Tacrolimus C+ Good Infliximab A+ Excellent Adalimumab A Excellent Certolizumab Pegol A Excellent Vedolizumab A Good Schwartz DA et al, Inflamm Bowel Dis 2015 171 Medical Therapy in Children With and Without Fistulizing Perianal Disease Therapy Use By Q8 Nonfistulizing Fistulizing Yes, %(n) Yes, %(n) Antibiotics 45% (99) 73% (19) Immunomodulators Infliximab 86% (208) 33% (81) 100% (28) 57% (16) Significance (P<0.05) P=0.012 OR=3.1 P=0.032 P=0.013 OR=2.7 Keljo D et al Inflamm Bowel Dis 2009 Immunomodulators for Treatment of Perianal Fistulas • Observational study of 92 patients showed 29% response rate for all perianal CD – Those with fistulas had a cumulative probability of response at 24 months of 0.16 • Prospective open-label study of 52 patients suggested AZA may maximize long-term antibiotic effects • Retrospective chart review of 21 patients showed enhanced response with AZA or MTX started within 3 months of infliximab therapy Lecomte T et al, Dis Colon Rectum 2003 Dejaco C et al, Aliment Pharmacol Ther 2003 Topstad DR et al, Dis Colon Rectum 2003 Proportion of Adult Patients with Complete Fistula Closure at Each Study Timepoint N=306 ~90% perianal fistula ~60% >1 fistula Sands BE et al, N Eng J Med 2004 172 Maintenance of Complete Fistula Closure in Crohn’s Disease with Anti-TNFα Agents Infliximab at 1 yr N=306 Adalimumab at 1 yr N=117 Certolizumab at 6 mos N=58 36% 17% Sands BE et al, N Eng J Med 2004 Colombel JF et al Gut 2009 Schreiber S et al, Alimen Pharmacol Ther 2011 Improved Fistula Healing with Adalimumab and Ciprofloxacin Patients received Ada 160 mg wk 0, 80 mg wk 2 and then 40 mg qo wk. Then Randomized to Cipro 500 mg bid or placebo Dewint P et al, Gut 2014 Patients with sustained perianal response (%) Time to First Loss of Response to Infliximab in 89 Children with Perianal Fistulas 1.0 0.8 0.6 0.4 0.2 0.0 89 84 0 2 80 68 4 6 Duration of follow-up (months) 62 48 8 10 Dupont-Lucas C et al, Aliment Pharmacol Ther 2014 173 Medical Management of Pediatric Perianal Fistulas • No large clinical trials or long-term follow-up exists in children • Various small studies have suggested healing rates superior to adults (>70%) following infliximab therapy • Loss of response and recurrences as common as among adults Crandall W et al, J Pediatr Gastroenterol Nutr 2009 Di Bie CI et al, Inflamm Bowel Dis 2012 Hyams J et al, Gastronenterology 2007 Surgical Management of Fistulizing Perianal Disease EUA Sepsis control Resolution Failure I&D, Drains, Setons Definitive surgical treatment Resolution Fistulotomy, Glue, Plug, Setons, Advancement Flap Failure Proctectomy, Total Proctocolectomy Fichera A & Zoccali M, Inflamm Bowel Dis 2015 Management of Perianal Abscesses Simple incision & drainage Placement of mushroom catheter Noncutting seton Schwartz DA et al, Ann Intern Med 2001 Fichera A & Zoccali M, Inflamm Bowel Dis 2015 174 Fistulotomy for Simple Fistulas Probe External opening Open fistula tract Fistula Anus • Initial healing rates in adults – 80%-100% in 13 studies – 60-79% in 5 studies – ≤59% in 3 studies • Recurrence rates 0-20% in 7 of 10 studies Sandborn WJ et al Gastroenterology 2003 DA Schwartz et al Ann Intern med 2001 Setons Prevent Premature Fistula Closure Schwartz DA et al Inflamm Bowel Dis 2014 Response and Recurrence Rates Among Adults with Perianal Fistulas Treated with Infliximab +/- Setons Percentage of Patients 100% 83% 79% 44% Response (p=0.14) Recurrence (p=0.001) Regueiro M & Mardini H, Inflamm Bowel Dis 2003 175 Anal Fistula Plug Bioabsorbable xenograft made of lyophilized porcine intestinal submucosa Infection resistant No foreign body reaction Within months becomes populated with host cell tissue 24-87% success rates in studies 6-12 months followup Cook®Biodesign® Anal Fistula Plug Rizzo JA et al Surg Clin N Am 2009 Fibrin Glue • Mixture of fibrinogen and thrombin & calcium • • Insoluble clot formed • Discrepant findings have been reported in metaanalysis Believed to stimulate wound healing and induce angiogenesis Colorectalsurgeonsydney.com.au Citocchi R et al, Ann Ital Chir 2010 Rizzo JA et al Surg Clin N Am 2009 Endorectal Advancement Flap • Success rates 40%->90% reported • Incontinence is a concern • Option for rectovaginal fistula Ruffolo C et al Colorectal Dis 2010 Fichera A & Zoccali M, Inflamm Bowel Dis 2015 176 Combined Surgical and Medical Therapy Increases Perianal Fistula Healing • Systematic review of 24 articles; 1139 patients – 40% received single treatment (Anti-TNF ± immunomodulator or surgical intervention) – 60% combo therapy • Outcomes – Single therapy 191/448 (43%) in complete remission • 34% had no response – Combo 180/349 (52%) in complete remission • 23% had no response Yassin NA et al, Aliment Pharmacol Ther 2014 Outcome of Patients with Perianal Crohn’s Disease Undergoing Temporary Fecal Diversion Fecal Diversion n=138 Successful Stoma Closure n=36 Persistent Stoma n=102 n=41 Repeat Diversion N=6 n=30 n=4 Stoma Closure n=30 Indefinite Stoma n=45 (22%) n=60 n=2 Permanent Stoma n=63 (33%) (45%) Gu J et al, Colorectal Dis 2014 Proposed Treatment Algorithm for Simple Perianal Fistulas History and physical exam (digital exam for stricture) Colonoscopy (assess for proctitis; dilation if needed) Exam under anesthesia (EUA) Imaging (EUS or MRI) to delineate perianal disease Simple fistula without rectal inflammation • • Antibiotics and AZA/6MP Consider Anti-TNF Simple fistula with rectal inflammation Antibiotics, AZA/6-MP & Anti-TNF (consider monitoring healing with repeat imaging study) Treatment Success Treatment Failure Treatment Success Treatment Failure Continue maintenance AZA/6-MP or Anti-TNF if started 1. Consider seton 2. Fistulotomy 3. Consider fibrin glue, fistula plug or endorectal advancement flap 4. If 1-3 fails, treat as complex fistula Continue maintenance AZA/6-MP & Anti-TNF Treat as complex fistula Schwartz DA et al, Inflamm Bowel Dis 2015; de Zoeten EF et al, J Pediatr Gastro Nutr 2013 177 Proposed Treatment Algorithm for Complex Perianal Fistulas History and physical exam (digital exam for stricture) Colonoscopy (assess for proctitis, dilation if needed) Exam under anesthesia (EUA) Imaging (EUS or MRI) to delineate perianal disease Complex Fistula • • Seton placement Antibiotics, Anti TNF, AZA/6-MP (consider monitoring healing with repeat imaging study) Treatment Success Treatment Failure 1. Remove seton 2. Continue maintenance AZA/6MP & Anti-TNF 1. Consider tacrolimus in selected patients OR 2. Proctocolectomy Schwartz DA et al, Inflamm Bowel Dis 2015; de Zoeten EF et al, J Pediatr Gastro Nutr 2013 Take Home Points for Perianal Fistulizing Crohn’s Disease • Use MRI and EUA for suspected disease to define the anatomy • • • • Drain abscesses • Team approach: gastroenterologists, surgeons and radiologists Use setons as required to control sepsis Treat proctitis/intestinal inflammation More definite surgical closure should be considered only after intestinal inflammation under control 178 “IT’S ALL ABOUT THAT POUCH…” EVALUATION & MANAGEMENT OF COMPLICATIONS POST ILEAL POUCH ANAL ANASTOMOSIS Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children’s Hospital/Atlantic Health Professor of Pediatrics Icahn School of Medicine, Mount Sinai School of Medicine A “Tale” of Two Pouches: The Agony and the Ecstasy Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children’s Hospital/Atlantic Health Professor of Pediatrics Icahn School of Medicine, Mount Sinai School of Medicine Disclosures • Grant Support: – Abbvie, Janssen • Consultant: – Abbvie, Janssen, Receptos 179 Objectives • Review the data for evaluation, treatment and prevention of pouchitis • Understand other complications of IPAA • Review cancer screening /surveillance recommendations The Allure “Patients will be better off after operation…Their colitis will be cured…feeling of good health and a satisfactory quality of life will return” Kelly KA. Advanced Therapy of IBD, 2001 The Allure “Patients will be better off after operation…Their colitis will be cured…feeling of good health and a satisfactory quality of life will return” So true when it all goes right… Kelly KA. Advanced Therapy of IBD, 2001 180 Colectomy Risks • • • • • • • Bleeding Post‐op obstruction Wound infection Intra‐abdominal infection Wound hernia Thromboembolic events Urinary retention EIM After Surgery May Not Resolve Usually Resolve • Peripheral arthritis • Skin – Erythema nodosum • Uveitis – Pyoderma • Thromboembolic gangrenosum risk • PSC • AIH • Central arthritis (spondylitis) Surgical Options After Colectomy • Brooke Ileostomy – Noise, odor, leak, local skin breakdown • Kock Pouch (continent ileostomy) – Pouchitis, need for revision of reservoir • Ileal anal anastomosis – A more culturally acceptable Kock pouch – Mechanical issues, pouchitis, ischemia 181 Creating the Pouch } ~1 1/2 inches Slide courtesy of Dr. Michael Harris Creating the Pouch Slide courtesy of Dr. Michael Harris Types of Ileal Pouch Afferent limb (neo-TI) Tip of “J” “J” “S” Inlet “K” Nipple valve Efferent limb Outlet/cuff/ anal transitional Efferent limb zone Slide courtesy of Dr. Bo Shen 182 Mucosectomy vs. 2 Staple IPAA Slide courtesy of Dr. Michael Harris Disorders of the Ileal Pouch Surgical/ Mechanical • • • • • • • • • • Inflammatory/ Infectious Anastomotic leak Pelvic sepsis Sinus Fistula Strictures. Infecundity Sexual dysfunction Portal vein thrombi Prolapse Twist/volvulus Functional Pouchitis Cuffitis Crohn’s SBBO Inflammatory polyps Neoplastic Irritable pouch Poor compliance Pseudo obstruct megapouch “Pouchalgia fugax” Pouch/ATZ Neoplasia Lymphoma Squamous cell cancer Systemic/ Metabolic Anemia Bone loss Vit D/B12 def. Renal stone Celiac dis. High PTH Modified from Shen B, et al. AJG 2005;100;93-101 Disorders of the Ileal Pouch Surgical/ Mechanical • • • • • • • • • • Inflammatory/ Infectious Anastomotic leak Pelvic sepsis Sinus Fistula Strictures Infecundity Sexual dysfunction Portal vein thrombi Prolapse Twist/volvulus Functional Pouchitis Cuffitis Crohn’s SBBO Inflammatory polyps Neoplastic Irritable pouch Poor compliance Pseudo obstruct megapouch “Pouchalgia fugax” Pouch/ATZ Neoplasia Lymphoma Squamous cell cancer Systemic/ Metabolic Anemia Bone loss Vit D/B12 def. Renal stone Celiac dis. High PTH Modified from Shen B, et al. AJG 2005;100;93-101 183 Disorders of the Ileal Pouch Surgical/ Mechanical • • • • • • • • • • Inflammatory/ Infectious Anastomotic leak Pelvic sepsis Sinus Fistula Strictures Infecundity Sexual dysfunction Portal vein thrombi Prolapse Twist/volvulus Functional Pouchitis Cuffitis Crohn SBBO Inflammatory polyps Neoplastic Irritable pouch Poor compliance Pseudo obstruct megapouch “Pouchalgia fugax” Pouch/ATZ Neoplasia Lymphoma Squamous cell cancer Systemic/ Metabolic Anemia Bone loss Vit D/B12 def. Renal stone Celiac dis. High PTH Modified from Shen B, et al. AJG 2005;100;93-101 Disorders of the Ileal Pouch Surgical/ Mechanical • • • • • • • • • • Inflammatory/ Infectious Anastomotic leak Pelvic sepsis Sinus Fistula Strictures Infecundity Sexual dysfunction Portal vein thrombi Prolapse Twist/volvulus Functional Pouchitis Cuffitis Crohn SBBO Inflammatory polyps Neoplastic Irritable pouch Poor compliance Pseudo obstruct megapouch “Pouchalgia fugax” Pouch/ATZ Neoplasia Lymphoma Squamous cell cancer Systemic/ Metabolic Anemia Bone loss Vit D/B12 def. Renal stone Celiac dis. High PTH Modified from Shen B, et al. AJG 2005;100;93-101 Disorders of the Ileal Pouch Surgical/ Mechanical • • • • • • • • • • Inflammatory/ Infectious Anastomotic leak Pelvic sepsis Sinus Fistula Strictures Infecundity Sexual dysfunction Portal vein thrombi Prolapse Twist/volvulus Functional Pouchitis Cuffitis Crohn SBBO Inflammatory polyps Neoplastic Irritable pouch Poor compliance Pseudoobstruct megapouch “Pouchalgia fugax” Neoplasia Lymphoma Squamous cell cancer Systemic/ Metabolic Anemia Bone loss Vit D/B12 def. Renal stone High PTH Modified from Shen B, et al. AJG 2005;100;93-101 184 Pouch Evaluation • Stool cultures including C. Difficile • Pouchoscopy with biopsy – Rule out mucosal disease (inflamm vs malig.) • Imaging – If suspect mechanical issue – Cross-sectional – “pouchagram” (emptying, leak) Pouchoscopy—Owl Eye View Endoscopic Patterns in Pouchitis Classic Pouchitis ImmuneMediated Pouchitis Ischemic Pouchitis Slide courtesy of Dr. Bo Shen 185 Pouchitis Therapy • Antibiotics/Probiotics – Metronidazole – Cipro – Rifaximin – VSL #3 (?prophylaxis) – ???Fecal Microbial Transplant (FMT) • Anti-Inflammatory – Topical – Systemic Ischemic Pouchitis: Think Tension Shen B, et al, Inflamm Bowel Dis 2010;16:836–46 Crohn’s Disease of the Pouch Inflammatory Fibrostenotic Fistulizing Slide courtesy of Dr. Bo Shen 186 Algorithm for Pouch Evaluation Symptomatic Pouch Patients Exclusion of Mechanical Complications Inflammatory Disorders Pouchitis Cuffitis Microbe-related Crohn’s Disease Immune-mediated Ischemia-related Slide courtesy of Dr. Bo Shen Algorithm for Pouch Evaluation Symptomatic Pouch Patients Exclusion of Mechanical Complications Inflammatory Disorders Cuffitis Pouchitis Microbe-related PSCassociated Immune-mediated IgG4associated Autoimmune Disorderassociated Crohn’s Disease Ischemia-related Autoinflammatory Disorderassociated Modified from Shen B, et al. AJG 2005;100;93-101 Presacral Anastomotic Sinus Lian L, et al. Endoscopy 2010;42 Suppl 2:E14 Slide courtesy of the authors 187 IPAA: Pediatric Outcomes • 202 children over 30 years at Mayo • 87% returned questionnaires • Median follow up 181.5 months (7.8-378.5) Polites SF. J Pediatr Surg 2015 epub IPAA: Pediatric Outcomes • • • • • UC pouch survival 92% 16% diagnosed with CD (61% pouch survival) 12% chronic pouchitis 7% pouch failure QOL excellent in majority Polites SF. J Pediatr Surg 2015 epub IPAA: Cancer Risk • 42 reports of pouch adenocarcinoma • Possibly due to “Islets” after mucosectomy • Potential contributing factors: – ?pouchitis – ?Primary Sclerosing Cholangitis (PSC) • Previous neoplasia is main risk factor Cancer 2011;117:3081–3092 Colorectal Dis 2012;14:92–97 Gastroenterology 2014;146:119–128 188 Pouch Cancer: Dutch Study • • • • Population based (national pathology registry) 1200 IPAA patients Found low rate of neoplasia (1.83%) Prior Neoplasia was major risk factor Gastroenterology 2014;146:119–128 IPAA Cancer: Prior Neoplasia is Major Risk Factor 4X risk for prior dysplasia 25X risk for prior colon cancer Gastroenterology 2014;146:119–128 Pouch Cancer: Dutch Study • Conclusion—stratified by neoplasia history: – No prior history: limited surveillance program – Prior history: targeted surveillance program Gastroenterology 2014;146:119–128 189 Pouch Surveillance: Society Guidelines • ACG, AGA, ASGE—none • British Society of GI: – Yearly if high risk: Neoplasia, PSC, atrophy, inflammation – Every five years in all others Summary • Pouch surgery improves quality of life • Mechanical and inflammatory complications • Technical expertise of surgeon • Importance of team approach Summary Pouchitis: multiple potential etiologies —Bacteria-related (C. difficile is emerging) —If antibiotic refractory consider: • Immune-mediated (including De novo Crohn’s) • Ischemia-related 190 Summary Cancer of the pouch rarely occurs • Prior neoplasia is biggest risk factor • PSC, chronic pouchitis also contribute • Surveillance guidelines are not yet optimized • ?3-5 years unless high risk 191 Communicating the Benefits and Risks of IBD Therapy to Patients and Families Corey A. Siegel, MD, MS Geisel School of Medicine at Dartmouth Dartmouth-Hitchcock Medical Center NASPGHAN 2015 Postgraduate Course Disclosures Consultant/Advisory Board Abbvie, Given Imaging, Janssen, Salix, Lilly, Pfizer, Prometheus, Takeda, UCB Speaker for CME activities Abbvie, Janssen, Takeda, UCB Grant support CCFA, AHRQ (1R01HS021747-01) Abbvie, Janssen, UCB, Salix Intellectual property Dartmouth-Hitchcock Medical Center and Cedars-Sinai Medical Center have a patent pending for a “System and Method of Communicating Predicted Medical Outcomes”, filed 3/34/10. Dr. Corey Siegel and Dr. Lori Siegel are inventors. Different aspects decision making Severity of illness Benefits and Risks of Treatment Medical Decision Making Patient and Family Preferences 192 Hierarchy of Needs for the IBD Patient Physician focus Histologic Remission Endoscopic Remission Clinical Remission Diarrhea, Bleeding, Pain, Fatigue, Incontinence Just feel normal Avoid hospitals and surgery Patient focus Leaving the house, going to school or work Ability to eat and maintain weight Staying Alive Learning Objectives » To review the risks of immunomodulators and biologics » To discuss decision making between anti-TNF monotherapy or combination therapy » To learn about tools that can be used to better communicate the benefits and risks of IBD therapy 193 Crohn’s disease causes damage Typical Course of a Crohn’s Patient Damage occurs in UC as well 1. Proximal extension of disease 2. Stricturing 3. Pseudopolyposis 4. Dysmotility 5. Anorectal dysfunction 6. Impaired permeability Torres, et al. Inflamm Bowel Dis 2012;18:1356. 194 Two Drugs Are Better Than One Corticosteroid-Free Clinical Remission at Week 50 All randomized patients (N=508) p<0.001 p=0.028 41/170 p=0.035 59/169 78/169 Colombel, JF, et al. NEJM 2010 But we can’t forget about the tradeoffs What our patients hear (and see)… Why are people so afraid? Risk Unknown Unknown Not Observable Risk New Risk • Nuclear accidents • Biologics and NEW drugs Not Dreadful Controllable Equitable Voluntary Dreadful Dread Uncontrollable Catastrophic Risk Involuntary • Steroids • Downhill skiing • 5-ASAs • Immunomodulators Known Risks Observable Old Risk Slovic P. Perception of Risk. Science 1987. 195 What are the most important side-effects of 6MP/Azathioprine? Frequency Estimate Event Stop therapy due to adverse event 11% Allergic reactions 2% Nausea 2% Hepatitis 2% Pancreatitis 3% Serious infections 5% 0.04%-0.09% (49/10,000) Non-Hodgkin’s lymphoma Siegel CA, et al. APT 2005 (weighted average); Siegel CA, et al. CGH 2009 Beaugerie et al, Lancet 2009;7:374. Solid tumors and thiopurines in IBD (non-GI and non-skin cancers) Study Armstrong 2010 Types of cancer Number of patients Statistically significant lung, breast 1955 NO Fraser 2002 breast, bronchial, renal 6262 NO Connell 1994 gastric, lung, breast, cervical 755 NO No clear association between thiopurines and solid tumors in IBD Methotrexate and Lymphoma »Not a lot out there in IBD › PubMed search for “(Crohn’s OR ulcerative colitis) AND methotrexate AND lymphoma” – 1 case report › Farrell study: 2 of 4 cases of NHL were treated with MTX (2 out of 31 patients treated with MTX!) »More info available for RA › Sweden: 348 lymphomas in RA patients, 37 were EBV+, 29/37 exposure to MTX › Australia: SIR 5.1 (95% CI 2.2-10) › United States: OR 1.4 (0.7-2.9) Farrell, et al. Gut 2000. Baecklund, et al. Curr Opin Rheumatol 2004. Burchbinder, et al. Arthritis Rheum 2008.Wolfe, et al. Arhthritis Rheum 2007. 196 Adverse Events Associated with anti-TNF Treatment Event Estimated Frequency Stop therapy due to adverse event 10% Infusion or injection site reactions 3%-20% Drug related lupus-like reaction Serious infections Same Mono or Combo 1% 3% Tuberculosis 0.05% (5/10,000) Non-Hodgkin’s lymphoma (combo) 0.06% (6/10,000) Multiple sclerosis, heart failure, serious liver injury Case reports only Siegel CA. The inflammatory bowel disease yearbook, volume 6.; Infliximab package insert; Vermeire Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003 Risk of Dying from Sepsis on Infliximab: Systematic Review Reference Study Design # Deaths from sepsis thought attributable to infliximab # of Patients Ljung et al. Gut 2004 Population Based Cohort 1 191 Seiderer et al. Digestion 2004 Single-Center Cohort 0 92 Colombel et al. Gastroenterology 2004 Single-Center Cohort 5 500 Sands et al. NEJM 2004 Randomized Controlled Trial 2 282 Hanauer et al. Lancet 2002 Randomized Controlled Trial 1 573 Rutgeerts et al. Gastroenterology 1999 Randomized Controlled Trial 0 73 Risk of death from sepsis = 4/1000 pt-yrs Siegel et al. Clin Gastroenterol Hepatol. 2006;4:1017-1024. BUT it is a subgroup of patients at this high risk »Older › Average age = 63 (systematic review); 67 (Mayo) »Multiple co-morbidities »Concomitant steroids and/or narcotics »Long-standing disease Young “healthy” patients are not in the clear, but probably at much less risk Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008 197 Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis » 8905 patients representing 20,602 pt-years of exposure » 13 Non-Hodgkin’s lymphomas 6.1 per 10,000 pt-years » Mean age 52, 62% male » 10/13 exposed to IM* (really a study of combo Rx) NHL rate per 10,000 SIR 95% CI SEER all ages 1.9 - - IM alone 3.6 - - Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9 Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1 Siegel et al, CGH 2009;7:874. *not reported in 2 Risk of Developing non-Hodgkin’s Lymphoma Patient receiving Immunomodulator +/- anti-TNF Therapy for 1 year Risk without medication of lymphoma with immune suppression Siegel CA, Inflamm Bowel Dis 2010;16:2168. What do we know about the risk of solid tumors and anti-TNF? » Rheumatoid arthritis » 13,000 patients, ½ on biologics » Inflammatory bowel disease » Fairly limited data Type of Cancer Odds Ratio Type of study All cancers 1.0 (0.8-1.2) Population based SIR 0.7 (0.2-1.7) 651 patients All solid tumors 1.0 (0.8-1.2) Colon 0.8 (0.3-1.7) Lung 1.1 (0.7-1.8) Breast 0.9 (0.5-1.3) Pancreas 0.5 (0.1-2.6) Melanoma 2.3 (0.9-5.4) Non-melanoma 1.5 (1.2-1.8) Single center 734 patients Associated risk OR 0.97 (0.56-1.65) Wolfe, Arthritis and Rheumatism 2007;56:2886. Mason, Inflamm Bowel Dis 2013;19:1306. 198 Risks of anti-TNF in pediatric IBD patients Dulai PS, Siegel CA, Dubinsky MC. Inflamm Bowel Dis 2013:19:2927. Dulai PS, et al. Clin Gastroenterol Hepatol. 2014;12:1443. Systematic Review: Risks of Serious Infection and Lymphoma with anti-TNF Therapy in Pediatric IBD Risk with anti-TNF Serious Infections 35/1000 Lymphoma 2/10,000 Risk with comparator SIR (95% CI) Immunomodulator 33/1000 Prednisone 73/1000 1.06 (0.83-1.36) 0.48 (0.40-0.58)* Pediatric population 0.58/10,000 Thiopurines 4.5/10,000 Adults with anti-TNF 6.1/10,000 3.5 (0.35-19.6) 0.47 (0.03-6.44) 0.34 (0.04-1.51) Scariest standard lymphomas are early postmononucleosis in EBV-seronegative young male. Consider avoiding thiopurines in EBV-seronegative males Dulai PS, et al. Clin Gastroenterol Hepatol. 2014;12:1443. Magro F et al. J Crohns Colitis 2014;8:31. Funny how it’s easy to forget about prednisone Event Any side-effect leading to stopping prednisone Estimated Frequency 55% Ankle swelling 11% Facial swelling 35% Easy bruising 7% Acne 50% Psychosis - confusion/agitation 1% Infections 13% Cataracts 9% Increased intraocular pressure 22% High blood pressure 13% Osteoporosis Diabetes 33% Chance increases 10x Present IBD 2001, Rutgeerts APT 2001, Rutgeerts NEJM 1994 199 Are serious infections more common if taking more than 1 medication? »TREAT registry › Corticosteroids (HR 2.0, 95% CI 1.4-2.9) › Narcotics (HR 2.7, 95% CI 1.9-4.0) »Opportunistic infections Prednisone, 6MP/AZA, Infliximab Odds Ratio (95% CI) 1 medication 2.9 (1.5–5.3) 2 or 3 medications 14.5 (4.9–43) Lichtenstein CGH 2006; Toruner, Gastro 2008 Closer look at the Mayo experience with opportunistic infections Herpes zoster Candida albicans Herpes Simplex CMV EBV Histoplasmosis Blastomycosis Streptococcus E. Coli Mycobacterium marinum Mycobacterium fortuitum Cryptococcus Mycobacterium gordonae 28\ 26 18 12 8 2 1 1 1 1 1 1 1 Toruner et al. Gastro 2008;134:929 200 Closer look at the Mayo experience with opportunistic infections Number of meds 0 1 2 or 3 Cases 38 38 24 Specific combinations Corticosteroids alone 6MP/AZA alone IFX alone AZA/6MP + steroids AZA/6MP + IFX AZA/6MP + IFX + steroids Controls 129 59 12 16 20 3 16 1 5 OR 1.0 (ref) 2.9 (1.5-5.3) 14.5 (4.9-43) 27 31 2 6 5 0 2.2 (1.0-4.9) 3.4 (1.5-7.5) 11.1 (0.8-148) 17.5 (4.5-68) 1.6 (0.1-19) 1.1 (1.0-1.2) Toruner et al. Gastro 2008;134:929 COMMIT and SONIC Safety Results MTX (n=63 COMMIT SONIC Placebo (n=63) Blood and lymphatic system disorders 6.3% 11.1% GI disorders 71.4% 76.2% Infections 58.7% 61.9% Connective tissue disorders 44.4% 38.1% Respiratory disorders 20.6% 23.4% AZA + placebo (n=161) IFX + placebo (n=163) IFX + AZA (n=179) (n=503) Pts with 1 AE, n (%) 138 (85.7%) 139 (85.3%) 156 (87.2%) 433 (86.1%) Pts with 1 SAE, n (%) 39 (24.2%) 26 (16.0%) 25 (14.0%) 90 (17.9%) 8 (5.0%) 4 (2.5%) 6 (3.4%) 18 (3.6%) Serious infections Total Feagan et al. Digestive Disease Week, San Diego, CA 2008. Sandborn, WJ et al. ACG 2008 Risk of HSTCL is related to duration of thiopurine use Thiopurine only 6 Number of cases Number of cases Anti-TNF + Thiopurine 8 7 6 5 4 3 2 1 0 N=19 0-2 >2 to 4 >4 to 6 >6 to 8 >8 to 10 >10 Years exposure prior to HSTCL 5 4 N=11 3 2 1 0 0-2 >2 to 4 >4 to 6 >6 to 8 >8 to 10 >10 Years exposure prior to HSTCL Consider this: Even in young males Induce with our “best” Estimated risk+ anti-TNF) in “at risk” group with combo therapy (thiopurine and stop thiopurine after 6-12 ≈ 1-3/10,000 months when in deep remission Kotlyar et al. Clin Gastroenterol Hepatol. 2011;9:36. Magro F et al. J Crohns Colitis 2014;8:31. 201 It’s not so easy! Siegel, et al. DDW 2011. Numbers are hard! »Numeracy (quantitative literacy) › ½ of patients were unable to convert: » 1% to 10 in 1000 › 80% of patients were unable to convert: » 1 in 1000 to 0.1% › Patient have difficulty determining which is the higher risk: » 1 in 27 versus 1 in 37 Schwartz LM et al. Ann Intern Med. 1997;127(11):966-72. Sheridan SL, Pignone M. Eff Clin Pract. 2002;5:35. 202 Fair and Clear Communication of Risks and Benefits »Beware of framing1,2 › Relative risk = 34% reduction in heart attacks › Absolute risk = 1.4% reduction in heart attacks BOTH show that treatment decreases chance of Heart Attack from 4.1% 2.7% 1. Malenka DJ et al. J Gen Intern Med. 1993;8:543-8. 2. Hux JE, Naylor CD. Med Decis Making. 1995;5:152-7. Explaining risk of the disease »The future risk of their disease is very difficult to explain to patients »When patients are feeling well, they don’t worry about complications of their disease »When patients are sick, they just want to feel better »We need to help patients understand that Crohn’s and ulcerative colitis are progressive diseases that can lead to complications in the future Patients are Willing to Take High Risks in Exchange for Improved Health Maximal Acceptable Risk (Annual %) 1.0 N = 580 PML 0.9 Serious infection 0.8 Lymphoma 0.7 0.6 0.5 0.4 0.5 0.2 Risk of dying from side-effect all < 1 per 1000 0.1 0 Moderate to Mild Moderate to Remission Severe to Moderate Severe to Mild Severe to Remission Johnson et al. Gastroenterology 2007. 203 Parents are willing to take even higher risks of lymphoma…but only if their kids are sick! 1.2 1 0.8 Maximal Acceptable Risk of 0.6 Lymphoma (%) 0.4 Adult patients Parents 0.2 0 Severe to Remission Moderate to Mild Johnson et al. Risk Analysis 2009 Crohn’s Disease Decision Aid Sample Clips Benefits Risks Early Therapy 204 Ulcerative Colitis Decision Aid Video Sample Clips Medical Therapy for UC Surgical Options for UC Option Grids http://www.optiongrid.co.uk/ Crohn’s Disease Treatments (Pediatrics) Use this grid to help you and your clinician decide on the best treatment for your disease Combination Therapy Anti-TNF Infliximab (Remicade); Adalimumab (Humira); Certolizumab pegol (Cimzia) An anti-tumor necrosis factor (TNF) drug blocks one specific chemical An immunomodulator is a medicine Using an immunomodulator and an (TNF) in the body. Blocking TNF What type of medication that is taken to regulate or quiet down regulates or quiets down the immune anti-TNF drug together. is this? the immune system which then system which then decreases decreases inflammation. inflammation. Infliximab is given intravenously (injected into the vein) three times in the Daily, as a pill (azathioprine or 6MP), first 6 weeks, then every 6-8 weeks. Daily pills (or weekly shots if Adalimumab is given subcutaneously or weekly as a pill or shot methotrexate) PLUS injections either (injected under the skin) every other How is this treatment (methotrexate). It may take weeks to months to be fully effective, so your intravenous (into the vein) or week, and Certolizumab is given administered? subcutaneous (under the skin). subcutaneously monthly. These doctor may prescribe a steroid, such as medications act faster than prednisone, to start. immunomodulators, so you likely won’t need steroids. After 6 months of There are no research studies in children directly comparing immunomodulators to anti-TNF drugs to combination therapy. treatment, how many But, we do have good estimates based on research in children and adults for each of these options. people get relief of their symptoms and don’t Approximately 40 people out of 100 Approximately 55 people out of 100 Approximately 60 people out of 100 need steroids (e.g., (40%). (55%). (60%). prednisone)? Approximately 3 people out of 100 (3%) develop pancreatitis, where the With combination therapy, possible to Allergic reactions like a rash or What are some common, pancreas becomes inflamed and get side effects from both shortness of breath from an infusion, or painful. Other short-term side-effects but short-lasting, side immunomodulators and anti-TNF pain or swelling at the injection site can may include nausea, fever, fatigue, effects? drugs. occur. lowering of the white blood cell count, or increase in liver tests. Frequently Asked Questions Immunomodulator Azathioprine (Imuran, Azasan); 6-mercaptopurine (6MP, Purinethol), Methotrexate 205 Crohn’s Disease Treatments (Pediatrics) Use this grid to help you and your clinician decide on the best treatment for your disease Frequently Asked Questions How common are serious infections? Immunomodulator Azathioprine (Imuran, Azasan); 6-mercaptopurine (6MP, Purinethol), Methotrexate Anti-TNF Infliximab (Remicade); Adalimumab (Humira); Certolizumab pegol (Cimzia) Combination Therapy Approximately 3%-6% (between 3-6 people of out 100) experience serious infections for each treatment option. How many people stop taking the medication because of side effects? Approximately 10 out of 100 (10%). Approximately 6-7 people out of 100 (6%-7%). What is the risk of getting lymphoma (lymph node cancer)? Approximately 4 people out of 10,000 (0.04%) for azathioprine and 6MP. It is not clear if methotrexate has any risk of lymphoma, but not enough research has been done to prove this. It is not clear that anti-TNF therapy on its own increases the risk of lymphoma at all, but not enough research has been done to prove this. If side-effects occur, it might be possible to stop one of the medications and continue the other. There does not seem to be a meaningful increase in the risk of lymphoma if adding an anti-TNF to an immunomodulator. The risk is approximately 4 people of out 10,000 (0.04%) What is the risk of getting lymphoma if not taking these medications? The risk of developing lymphoma in the general pediatric population is 0.0058% This is equal to approximately 0.58 per 10,000 or 5-6 people out of 100,000 What else should I know about the risks of these treatments? A rarer form of cancer is hepatosplenic T-cell lymphoma. We don’t know exactly how often it occurs, but it is very rare (less often than the type of lymphoma described above). It is seen mostly in young males. It is usually not treatable. This lymphoma has occurred in people taking 6-MP or azathioprine by itself or as combination therapy with an anti-TNF drug. There have not been cases reported in Crohn’s disease with either methotrexate or anti-TNF therapy on its own. For women, it is important to note that methotrexate cannot be taken when trying to become pregnant. Summary »Immunomodulators and biologics have real, measurable risks »But the absolute risk is still very small »Clearly communicating these data is hard! »Shared decision making tools can make this easier 206
