Postgraduate Course Syllabus

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Washington Hilton Washington, DC October 8, 2015

SYLLABUS

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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

Praveen Goday MBBSProfessor Medical College of Wisconsin Division Pediatric GI, Hepatology & Nutrition Milwaukee, WI

Stefano Guandalini MDProfessor and Chief Section of Pediatric Gastroenterology University of Chicago Founder and Medical Director, Celiac Disease Center Chicago, IL

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

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

Robert E. Kramer MD, FASGECo-Medical Director DHI/ Director of Endoscopy Associate Professor of Pediatrics Digestive Health Institute Children’s Hospital Colorado/ University of Colorado Denver, CO

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

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

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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

Jean P Molleston MD Indiana University/Riley Hospital for Children Indianapolis, IN

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

Marialena Mouzaki MD, MSc Hospital for Sick Children University of Toronto Division of GI, Hepatology and Nutrition Toronto, ON

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

Joel R. Rosh MD Director, Pediatric Gastroenterology Vice Chairman, Clinical Development and Research Affairs Goryeb Children's Hospital/Atlantic Health, Morristown, NJ 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 Corey A. Siegel MD, MS Associate Professor of Medicine, Geisel School of Medicine at Dartmouth Director, IBD Center, Dartmouth-Hitchcock Medical Center Lebanon, NH

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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.

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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

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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

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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

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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

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Obesity and intestinal microbiomeMarialena 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

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Microbiota in obesity

Backhed et al. Proc Natl Acad Sci USA 2004; Turnbaugh et al. Nature 2006

Conventionally raised

ob/ob mice

Germ-free Weight gain

Germ-free obesity

Microbiota in obesityTWINS

Germ-free

Ridaura et al. Science 2013; Vrieze et al Gastroenterol 2012;Wendelsdorf NIH Research Matters 2013

Germ-free Obese

Lean

How can the microbiota contribute to obesity?

Obesity

Appetite

Energy extraction

Energy expenditure

Gene expression

Prebiotics & Probioticsincreased GLP-1, PYY

CHO fermentationSCFA arcuate nucleus

Example:Bacteria produce H2 which is then used by Archea Acetate + H2 CH4+ CO2

Bile acids SCFA

LL: FIAFDNL: SREBP, ChREBPFAO: AMPK

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Intestinal microbiota composition in obesity

Study n - population Results

Ley et al. 2006 17 • Firmicutes/Bacteroidetes

Turnbaugh et al. 2009 14 (vs. 140) • 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


Bottom line and considerations: Results vary; decreased bacterial diversity is consistentDifferences in methodology IM quantification Storage, timing of sample collection, etc.

Bahl et al. FEMS Microbiol Lett 2012; Thaiss et al. Cell 2014


Low bacterial richness Obesity

Pre-DM2, DM2

Dyslipidemia

Inflammation

High bacterial richness Synthesis of organic

acids

Synthesis of SCFA

Methane production

Carisili et al. Curr Opin Clin Nutr Metab Care 2014

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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

David et al. Nature 2014

Plant-based diet Animal-based dietSimilar intakes

No weight change Weight loss by day 3

Bilophila wadsworthia, Alistipes putredinis, Bacteroides

Prevotella genus*

Effect of diet on bacterial metabolism & gene expressionFecal SCFA correlate with diet

Diet alters microbial gene expression

David et al. Nature 2014

• Acetate, butyrate • Gluconeogenesis, glycolysis

• Isovalerate, isobutyrate• B6 metabolism, aromatic

hydrocarbon degradation

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

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Diet and intestinal microbiotaEffect 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

Intestinal microbiota

Diabetes

Dyslipidemia/ Atherosclerosis

Hypertension

NAFLD

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Intestinal microbiota & diabetes

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

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

Intestinal microbiota and insulin sensitivity: human studies

• Systemic insulin resistance

• Improved insulin sensitivity

• Habitual intake correlates withfasting glucose levels

• Consumption leads to insulin resistance

Mehta et al. Diabetes 2010; Vrieze et al. Gastroenterol 2014; Suez et al. Nature 2014




• Habitual intake correlates withfasting glucose levels



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• Fecal transplantation: humans to germ-free mice insulin resistance


Intestinal microbiota and hypertension

Common determinants of outcome

Environ-ment

DietGenes

Low-grade inflammation associated with hypertension

Probiotics improved BPMinocycline improved BP

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-IIinfusion*

Human volunteers(adults)*

Diversity & richness

Firmicutes/Bacteroidetes -

Acetate & butyrate-producing bacteria

No change -

Yang et al. Hypertension 201

* Compared to controls

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SCFA participate in blood pressure regulation

Kidney

Vessels of smallresistance

Colon

Olf78 reninBP

Gpr41 vasodilation

BP

Pluznick et al. Proc Natl Acad Sci USA 2013

Intestinal microbiota and dyslipidemia

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

& FIAF inhibition

Fatty acid oxidation, de novo lipogenesis

Intestinal microbiota and atherosclerosis

Org et al.Atherosclerosis 20

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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

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Thank you

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Redefining Malnutrition in the 21st

Century

Praveen S. Goday, MDProfessor

Pediatric Gastroenterology and NutritionMedical College of WisconsinDirector of Clinical Nutrition

Children’s Hospital of WisconsinMilwaukee, 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 arelikely to be seen by the pediatric gastroenterologist

• Discuss the management of different sub-populationswith malnutrition

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• Are children in US hospitals malnourished?

• Do we care that they are malnourished?

• How do we diagnose malnutrition?

• Where are pediatric gastroenterologists going to seemalnutrition?

• What can we do about malnutrition?

Are children in US hospitals malnourished?

14.0%

8.0%7.1%

21.0%

11.0%

6.1%

0%

5%

10%

15%

20%

25%

UK1990

UK1995

USA1997

France2001

France2005

Germany2008

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.

Malnutrition in hospitalized US children

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0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

1Malnutrition

1.3% severe malnutrition

5.8% moderate malnutrition

25% obesity

17.4% mild malnutrition

Arch Pediatr Adolesc Med 1995; 149:1118–1122

Do we care that they are malnourished?

Subjective global nutrition assessment (SGNA)

Secker. Am J Clin Nutr. 2007 Apr;85(4):1083‐9.

Preoperative nutritional status in 175 children

undergoing surgery

- well nourished

- moderately malnourished

- severely malnourished

- ↑ rates of infection

- Longer post-op length of stay (8.2

vs 5.3 d) (P = 0.002)

Divided into

Malnourished children

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How do we diagnose malnutrition?

JPEN 2013;37:460‐81.

Recommendations

• Use z scores to express individual anthropometricvariables in relation to the population reference standard

• Use a decline in z score for individual anthropometricmeasurement as the indication of faltering growth

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When only one anthropometric data point is available

Malnutrition

Mild Moderate Severe

Weight-for-height or BMI for age z score

-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

Nutr Clin Pract.2015;30:147‐161

When more anthropometric data points are available

Malnutrition


Weight gain velocity (<2 y)

<75% of expected

<50% of expected

<25% of expected



Malnutrition



<75% of expected

<50% of expected

<25% of expected

Weight loss (2–20 y) 5% 7.5% 10%


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Malnutrition



<75% of expected

<50% of expected

<25% of expected

Weight loss (2–20 y) 5% 7.5% 10%

Decline in weight‐for‐length/ BMI z score

↓1 z score ↓2 z scores ↓ 3 z scores



Malnutrition



<75% of expected

<50% of expected

<25% of expected

Weight loss (2–20 y) 5% 7.5% 10%

Decline in weight‐for‐length/ BMI z score

↓1 z score ↓2 z scores ↓ 3 z scores

Inadequate nutrient intake

51‐75% estimatedneeds

26–50% estimatedneeds

≤25% estimated needs


Subjective global assessment (SGA)

√ 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

• Standard method for assessing nutritional status in adults

• SGA status is associated with medical outcomes

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Subjective global nutrition assessment (SGNA)

• History› Appropriateness of height

for age› Appropriateness of weight

for height› Changes in body weight› Oral intake› GI symptoms› Functional status› Metabolic demands

• Physical exam

› Fat stores

› Muscle stores

› Edema / ascites

• Should become the standard method for assessingnutritional status in children

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 for2 weeks or longer

• Symptoms for 3 days or fewer, can bedisregarded

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Functional status

• Has a lack of nutrition affected the child’sphysical function and altered her dailyactivities?

√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

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Albumin and prealbumin

• These proteins are negative acute phase reactants

√ They are, in most instances, not indicative ofmalnutrition

Where are pediatric gastroenterologists going to see malnutrition?

Causes of malnutrition

Non-illness related Starvation- Anorexia nervosa

Acute (<3 months)

- Trauma, burns

OR

+/-

Illness related

Chronic (> 3 months)

- CF, short gut syndrome

Nutrient loss

Hypermetabolism

Altered utilization of nutrients

Malabsorption

Inflammation

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Malnutrition in Pediatric Gastroenterology

0

5

10

15

20

25

Normal Moderate Malnutrition Severe Malnutrition

43% 43%

7%

Of the malnourished • 50% were admitted

with a nutrition‐related diagnosis

• Only 40% received nutrition intervention

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?

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Identify it!

Treatment of malnutrition

Non-illness related Starvation- Anorexia nervosa

Acute (<3 months)

- Trauma, burns

OR

+/-

Illness related

Chronic (> 3 months)

- CF, short gut syndrome

Nutrient loss

Hypermetabolism

Altered utilization of nutrients

Malabsorption

Inflammation

Feed!

Reverse nutrient loss & malabsorption

Treat inflammation

In the outpatient setting…

• High-calorie beverages

• Cyproheptadine

• Enteral nutrition

• Parenteral nutrition

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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

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$3,950 $4,161

$5,304

$6,142

$0

$1,000

$2,000

$3,000

$4,000

$5,000

$6,000

$7,000

Asthma Tonsillitis

Malnutrition

Malnutrition

+38%

+47%

Billable hospital charges

Conclusions

• Malnutrition has a high prevalence and affects outcomes

• Seek out, identify and treat malnutrition

• You will be justified in billing the comorbidity ofmalnutrition if you identify and treat it!

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Management of Food Allergy & FPIES

NASPGHAN 2015October 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 Nature of Relationship

Allertein Therapeutics, LLC Consultant, Minority StockholderRegeneron Therapeutics Consultant

Food Allergy Research & Education Medical Advisory BoardDanone Research Scientific Advisory Board

• RESEARCH INTERESTSI 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 therise in food allergies

Recognize various forms of food allergiesincluding FPIES and other gastrointestinalfood allergic disorders

Diagnose and manage various forms offood allergies including FPIES

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NCHS Data Brief #121; May 2013 Jackson KD et al

“2nd Wave” of Allergy Epidemic

5.1%

3.4%

7.4%

12.5%

~17%%

Prevalence of Food and Skin Allergies in the Pediatric Population

[1 – 17 years] in the US

Prenatal

Genetic factors/family history of allergy

Maternal smoking

Maternal consumption of allergenic foods during

pregnancy

Older parental age

Modified from Allen K & Koplin J. Epidemiology of Food Allergy. In Burks, James, Eigenmann et al. (Eds), Food Allergy 1e.2011.

fetal epigenetic modification through maternal exposure to these factors

Direct infant exposure

Factors associated with the ‘hygiene hypothesis’

e.g. Smaller family size

Maternal vitamin intake, e.g. folate

Perinatal

Failure to initiate breastfeeding

Caesarean section delivery

Factors Thought to Promote Allergy

Exposure to tobacco smoke + other environmental pollutants

Postnatal

Lack of vitamin D (sunlight)

Infant dietary factors

e.g. Later introduction of allergenic foods

Immunizations

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 gmpeanut 3x’s/wk to age 5 yrs & one-half strictly avoided all peanut

Du Toit G et al. NEJM 2015

36

• One PST negative infant & 6 PST pos infantsreacted 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

Randomized Trial of Early Peanut Consumption in High-risk Infants

(LEAP)


LEAP Trial Outcome


85% relative reduction !

70% relative reduction !

<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%Sicherer SH & Sampson HA. Annu Rev Med. 2009; 60:261-278.

1

2 3 4 5 6 7 8 9 10 20+

3

5

7

9

11

13

1

% P

reva

len

ce

Prevalence of Food Allergy by Age in the United States

Years of Age

Affects ~12 million Americans

37

Cutaneous Allergies

IgE-Mediated Non-IgE-Mediated

Urticaria Atopic DermatitisAngioedema Dermatitis Herpetiformis

ContactDermatitis

4 month old breastfed infant withan eczematousrash - cleared with exclusion ofegg from mother’sdiet

With permission

Atopic Dermatitis& Food Allergy

Mother ingestedeggs 4 hours beforebreast-feeding -

~30 minutes later, the baby is irritable and has developed facial rash

With permission


38

Erythematousrash on extensor surfaces

With permission


Gastrointestinal Allergies


Oral Allergy EoE EnterocolitisAcute GI AEG Enteropathy

Hypersensitivity - 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:1. Repetitive

vomiting 1- 4hours aftereating thesuspect food

Minor criteria: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 criterionplus 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


Allergic Asthma Heiner’sRhinitis Syndrome

Laryngeal edemaAnaphylaxis

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 considereddiagnostic 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 bylaboratory tests

• Skin tests and in vitro IgE measurements alone can neverbe considered diagnostic

NIAID Expert Panel. J Allergy Clin Immunol. 2010;

Predictive Value of PSTs

Comparison ofPST results & theoutcome of 120 oral milk challenges‐ 37% positive

Sporik R et al. Clin Exp Allergy, 2000

Wheal > 95% PPVMilk > 8 mmEgg > 7 mmPeanut > 8 mm

Predictive Value of Food-specific IgE100%

80%90%

70%60%50%

40%30%20%

10%0%

0.35 0.7 17.5 50 100

IgE Antibody Concentration (kUA/L)UniCAPTM

Pro

bab

ilit

y

Egg white

Logit model using log(kUA /L)

7.03.51.2

Sampson HA JACI 2001

Allergen Decision Pt

(kUA/L)

Egg 7(< 2 yrs of age)+ 2

Milk 15(< 1yr of age)++ 5

Peanut 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

Major Criterion Minor CriteriaVomiting in the 1-4 hour periodafter ingestion of the suspect food and the absence of classic IgE-mediated allergic skin or respiratory symptoms

1. Lethargy 2. Pallor3. Diarrhea in 5-10 hours after

food ingestion 4. Hypotension5. Hypothermia6. Increased PMN’s > 1500

above the baseline count

Challenge: 0.06 – 0.6 gm/kg (up to 3 gm) in 3 doses over 30 mins

Treatment: IV saline bolus (20ml/kg); ondansetron (0.1-0.15 mg/kg IV or IM)

Natural Course of Food Allergy

Birth 2 4 6 8 Years

• Following standard of care: strict food allergen avoidance

Pe

rce

nt

wit

h c

linic

al

foo

d

alle

rgy

100

80

60

40

20

0

Effect of Baking (heat-denaturation) on Sequential & Conformational

Epitopes of Food Proteins

1

2

LLI

M

KM I

Heat &Processing

M II

M

K

LK

L

K

~80% of young children with milk (egg) allergy “outgrow” theirfood allergy; react primarily to conformational epitopes

43

Development of Tolerance

N = 60

N = 57

Milk: Treated vs. Controls

16 x’s more likely to develop fulltolerance at 5 yrs compared tocontrol; p < 0.0001

Kim et al. JACI 2011; 128:125-131

~15 x’s morelikely to tolerateegg at 6 years

Egg: Treated vs. Controls

Leonard S et al. JACI 2012; 130:473-80

Managing Food Allergy & Food-induced 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 amedical 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 “goldstandard” for diagnosis, laboratory tests are becoming more sensitive and specific

• Several therapeutic strategies are underinvestigation, but OIT provides the most protection

• Omalizumab dramatically reduces adverse reactionsto 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 HospitalPhoenix, AZ

Financial Disclosure

I have no financial relationship with any commercial entity to disclose

Objectives

• Review the epidemiology and pathophysiologyof caustic ingestions

• Know the key features of the clinicalassessment

• Review the treatment options and long termmanagement

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 thequantities are larger

• There are limited reports of ingestion injury asa 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 palatableitems 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 thefirst week– From inflammatory process– From vascular thrombosis

• By the third week fibrogenesis and stricturesbecome 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 ofaspiration

• Neutralizing agents, dilution, and charcoal areNOT 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‐ above plus circumferential OR focal but

deep – Grade 3a: grade 2 PLUS focal necrosis that is

brown‐black or grey discoloration• 3b‐ extensive whereas 3a is only focal

2b

3a

51

Outcome by Stage

• 1 or 2a‐ most have a good prognosis and donot develop stricture or outlet obstruction– Risk of stricture with 2a is 4.7%

• 2b and 3‐ 32% to 75% develop strictures in 2band 3 grade burns, respectively

• 3b‐ mortality reported up to 65%; majorityrequire esophagectomy/replacementsurgeries

Management

• Grade 1 or 2a‐ short observationand PO challenge

• Grade 2b and 3– Consider NG placement under

endoscopic guidance• Maintain lumen• Route for future feeding

VS.

• Concern for infection, GER• Concern for long stricture

2a

3a

2b

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 ofinfection 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 andpatient 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 complicationof caustic ingestions

• 32‐75% chance of developing strictures ingrade 2b and 3 injury

• Develop as early as 3wks with 80% ofstrictures by 8 weeks post injury

Strictures

• Diagnostic imaging to evaluate forstricture is usually performed about2‐3 weeks after the injury.

• Dilation typically recommendedstarting 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 Tuckerdilators‐ longitudinal shearing forces

• Currently, endoscopic balloondilation‐ applies radial pressure

• Serial dilations are often requiredand typically are done every 1‐3weeks until oral feeds are tolerated– Prospective studies are needed to

evaluate frequency

Long‐term Management

• Risk of esophageal adenocarcinoma orsquamous cell carcinoma is 1000x theoccurrence rate of the general population.

• Recommended to begin surveillance 15‐20years after the injury and repeat every 1‐3years thereafter.

Summary

• Accidental caustic ingestions are a majorhealth risk for young children

• Clinical symptoms can be misleading soendoscopy 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

1

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

2

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

5

Type Location Symptoms Timing

ButtonBattery

Esophagus YesorNo Emergent

Gastric/SB Yes Emergent

No Urgent(ifage<5andBB≥20mm)

Elective(ifnotmovingonserialX‐ray)

Magnets Esophagus Yes Emergent(ifnotmanagingsecretions,otherwiseurgent)

No Urgent

Gastric/SB Yes Emergent

No Urgent

Sharp Esophagus Yes Emergent(ifnotmanagingsecretions,otherwiseurgent)

No Urgent

Gastric/SB Yes Emergent(ifsignsofperforationthenwithsurgery)

No Urgent

FoodImpaction

Esophagus Yes Emergent(ifnotmanagingsecretions,otherwiseurgent)

No Urgent

Coin Esophagus Yes Emergent(ifnotmanagingsecretions,otherwiseurgent)

No Urgent

Gastric/SB Yes Urgent

No Elective

LongObject Esophagus YesorNo Urgent

Gastric/SB YesorNo Urgent

AbsorptiveObject

Esophagus Yes Emergent(ifnotmanagingsecretions,otherwiseurgent)

No Urgent

Gastric/SB YesorNo Urgent

Emergent (< 30 Min)

Emergent (< 2 hours)

Urgent (<8 Hours)

Elective (<24 Hours)

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

3

Tools of the Trade

7

Raptor Forceps Multi-Prong Forceps Coin Grasper Rubber-Tipped Forceps

Polyp Snare Roth Net Wire Basket Endoscopy Caps

Foreign Body Hood Overtube

The Usual Suspects

8

10

30

20

1

60

50

40

mm

Button Batteries

• Home Movie Demonstration

9

58

4

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

5

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%• Mortality 9.6% 14

1. MacManus J, Am J Surg 1941; 53:393-402.2. Steinbach C, World J Surg 2014; 38(2):371-7.

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 FBingestion

15

• 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

60

6

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

161. 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 tobecome 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

18

1. Chen X, Int J Pediatr Otorhinolaryngol 2006;70:325-9.2. Tander B, J Laroendosc Adv Surg Tech A 2009;19:241-3.

61

7

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

20

Witnessed or suspectedBB Ingestion

Esophageal

Otherwise Stable:

Immediate Endoscopic

Removal

Active Bleeding or Clinically Unstable:

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

Esophagram to exclude leak before

advancing diet as tolerated

Demonstation of injury close to aorta

Continue NPO and Anbx and serial MRI q 5‐7 days until injury seen to recede from

aorta

If presence of hematemesis or UGI bleeding within 21 days of removal, assume aortoenteric fistula and emergently prepare for thoracotomy

with CV surgery

Gastric or Beyond

<5 years of age AND

BB >20 mm

Consider assessment of any esophageal injury

and endoscopic removal if possible, within 24‐48

hours

If esophageal injury present: Admit, NPO, IV anbx and consider CT Angiography, MRI

of chest

≥5 years of ageAND/OR

BB < 20mm

May consider outpatient

observation only

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

Endoscopic removal if

develops GI symptoms or not passed stomach by time of X‐ray

at time described above

Adapted from Kramer RE, et al. JPGN, 2015, PMID 25611037

APPENDIX 2‐MAGNET INGESTION

21

I i i l P i

Determinesingleversusmultiplemagnetingestion

InitialPresentation‐ObtainHistory

‐KnownMagnetingestion‐UnexplainedGIsymptomswithrareearthmagnetsinenvironment

‐ObtainanabdominalX‐ray.Ifmagnetsarepresentonflatplateobtainlateralx‐ray‐Determinesingleversusmultiplemagnetingestion

SingleMagnet MultipleMagnet(orsinglemagnet&metallicobject)

Withinthestomachoresophagus

‐Option1:ConsultPediatricGIifavailable‐Considerremovalifpatientatincreasedriskforfurtheringestion‐Option2:Followserialx‐raysasoutpatientandeducateparents*

Beyondthestomach‐ConsultpediatricGIifavailable.‐Considerremovalifpossible.‐Followwithserialx‐raysasoutpatient‐Educateparents*‐Confirmpassagewithserialx‐ray‐IfdelayedprogressionmayusePEG3350orotherlaxativetoaidpassage

Allwithinthestomachoresophagus

‐IfpediatricGIavailablenotifyforremovalespeciallyiflessthan12hours

‐Ifnotavailable,transfertoreferralcenter

‐Ifgreaterthan12hoursuntiltimeofprocedure,thenconsultpediatricsurgerypriortoendoscopicremoval

Successfulremoval

‐Dischargehomewithfollow‐up&education

Unsuccessfulremoval

‐Refertosurgeryforremoval

Beyondthestomach

‐ConsultpediatricGIandpediatricsurgeonifavailable

‐Ifnotavailablesendtoreferralcenter

‐Managementdependsonwhethersymptomaticorasymptomatic

Symptomatic

‐Refertopediatricsurgeryforremoval

Asymptomatic

‐Ifnoobstructionorperforationonx‐raymayremovebyenteroscopyorcolonoscopyifavailableorfollowwithserialx‐ray

‐Maydoserialx‐rayinEDtocheckforprogressionevery4‐6hours

SuccessfulEndoscopicRemoval‐Dischargeafterfeedingtolerance,withappropriatefollow‐upandeducation

Noprogressionon

serialx‐rays

‐Admitforfurthermonitoringandserialx‐raysorsurgicalremoval

‐MayusePEG3350orotherlaxativetoaidinpassageandtohelpprepareforcolonoscopy

‐Continueserialx‐rayevery8‐12hours.Ifnosymptomsthenproceedwithsurgicalremovalorendoscopicremovalwithsurgicalback‐up

Progressionofmagnetsonserialx‐rays

‐Educateparentsonprecautions*anddischargewithclosefollow‐up

‐Confirmpassagewithserialx‐rays

‐Ifatanytimemagnetsdonotprogressorpatientbecomessymptomatic,admittohospitalforremovalofmagnets

*ParentalEducation:‐Removeanymagneticobjectsnearby‐Avoidclotheswithmetallicbuttonsorbeltswithbuckles‐Ensurenoothermetalobjectsormagnetsareinthechildenvironmentforaccidentalingestion


62

8

APPENDIX 3‐ SHARP INGESTION

22

Known or suspected ingestion of sharp object

Radio‐opaque

Esophageal: Urgent endoscopic

removal

Gastric

Consider endoscopic removal unless short object with heavier

blunt end

Small bowel (distal to ligament of Treitz)

Symptomatic

Enteroscopy or surgical removal

Asymptomatic

Follow clinically with serial X‐ray

Enteroscopy or surgical removal considered if develops symptoms or

> 3 days without passage

Radiolucent

Symptomatic self‐reported or

witnessed ingestion:Urgent endoscopic

evaluation and removal

Asymptomatic: Consider CT, ultrasound, MRI or esophagram for further

assessment

Evidence of FB: Endoscopic

removalNo evidence of FB:

Clinical observation, close follow‐up,

reassess if develops symptoms


APPENDIX 4‐ FOOD IMPACTION

23

Suspected EFI

Consider FB series with water‐soluble contrast to identify

obstruction

Not tolerating secretions:Urgent endoscopic

removal

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

Consider repeat endsocopy after 4‐8 weeks of PPI therapy and/or EoE therapy

Eosinophillic inflammation without

stricture

Consider repeat endsocopy after 4‐8 weeks of PPI therapy

No eosinophilic inflammation and no

stricture

Follow clinical status and consider PPI if

nonspecific inflammation present

Tolerating secretions:Endoscopic removal

within 24 hours


APPENDIX 5‐ COIN INGESTION

24

Coin ingestion:PA and lateral films,

ensure no button battery

Esophageal

Symptomatic (drooling, dysphagia, respiratory

compromise):Urgent endoscopic

removal

Asymptomatic:Endoscopic removal

within 24 hoursConsider glucagon if

distal esophageal coin or if endoscopy not readily

available

Gastric

No endoscopy needed: Consider straining stools,

laxatives, repeat x‐ray at 2 weeks

Endoscopic removal if not passed within 2‐4 weeks

Repeat X‐ray immediately prior to removal to ensure

coin still present

Small bowel

Clinical observation: Enteroscopy/surgical

removal if symptomatic


63

THE PROBLEMATIC POLYP

Petar Mamula, MDThe Children’s Hospital of Philadelphia

• I have no financial relationships to disclose

OBJECTIVES

1. Review prerequisites for successfulpolypectomy

2. Discuss techniques for difficult polyps

3. Review polypectomy complications

64

Polypectomy video clip

DEFINITION

• Greek polύpous‐ animal withmouth surrounded by tentacleslike hydra

• Difficult or problematic polyp‐ any polyp thatposes difficulties in removing and can be furtherdefined 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 diameterFlat‐ height < ½ base diameter

• NUMBER: >10 polyps

65

DEFINITION

Gupta et al. Gut. A129. 2011.

SMSA ClassificationLevel 1 (4‐5)Level 2 (6‐9)Level 3 (10‐12)Level 4 (>12)

NASPGHAN Training Guidelines‐ 10 procedures

PREREQUISITES

• PATIENT: anti‐coagulation/NSAIDS,preparation, laboratories

• EQUIPMENT: generator, accessories, irrigationpump, CO2 insufflation

• STAFF: experienced technician, collaborativeanesthesiologist

• 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



• 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


• Video stalk clip placement


• 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


• 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


• 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 TheScope Clip

• If perforation not recognized and patientdischarged, 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 propriaand 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 requiresubmucosal injection

• >20 mm piecemeal resection• Consider pre‐treating large pedunculated

polyps• Instruct patient/family about possible

complications

73

REFERENCES1. 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, MDAssistant Professor of Pediatrics and Medicine

Section of Pediatric Gastroenterology, Hepatology, & Nutrition

Director, Transitional IBD ClinicThe 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 testingfor C. difficile

• Understand the current medical managementfor C. difficile

• Understand the role of fecal microbiotatransplantation (FMT) in C. difficile

75

• Leading cause of hospital-associated GI illness

• Increasing cause of community-associated GIillness

• Costs $3.2 billion annually1

• Rates of CDI have been increasing since 2000

• 2011: CDI was responsible for2

• ~ 500,000 infections

• 29,000 deaths

CDI: A Significant Healthcare Burden

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, geneticsyndrome, IBD, transplant, CF

• Symptoms: Fever (47%), abd pain (35%), bloodystool (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/

• 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

Emergence of Virulent and Resistant Strains: NAP1/BI/027

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

• Disease caused by enterotoxin A and cytotoxin B– Interfere with protein synthesis– Causes cell membrane disruption and death1

• Host immune response may determine whodevelops symptoms2

– ~5% of healthy individuals are colonized withC. difficile2

– Development of IgG Abs against toxin A maycontribute to asymptomatic state3

– High IgG Abs decrease risk for RCDI by afactor of 444

CDI Mechanisms and Host Response

1. Khanna et. al. Inflamm Bowel Dis. 2013. 2. Warny et. al. Infect. Immun. 1994. 3. Surawicz et. al. Nature Reviews: Gastroenterology & Hepatology. 2011 4. Kelly et. al. NEJM. 2008.

• 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

CDI in IBD: A Growing Problem

1. Russell et. al. Gastroenterology. 2014. 2. Sandberg et. al. Inflamm Bowel Dis. 2014.

“Traditional” Risk Factors:

• Antibiotic use (number and duration)

• Advanced Age (> 65 yo)

• Recent/prolonged hospitalization

• Immunosuppression

• Comorbidities

• Proton-pump inhibitors

• NG tubes

Risk Factors for CDI in the General Population

Vardakas et. al. International Journal of Infectious Dis. 2012.

78

• Antibiotic use less important

– Abx use preceding CDI is less common

• 40% of IBD patients vs. 69% in non-IBDpatients1

• 39% of IBD patients with CDI: no recentAbx use2

• Advanced age and comorbidities

– Average age of CDI in IBD cohortssignificantly lower3

Risk Factors are Not the Same in Patients with IBD

1. Bossuyt et. al. J Crohns Colitis. 2009. 2. Issa et. al. Clin Gastroenterol Hepatol 2007.3. Jen et. al. Ailment Pharmacol Ther. 2011.

Risk Factors: A Balancing Act In IBD

• Immunosuppression– Risk of therapy in CDI still unclear

• Maintenance immunosuppressive therapyassociated with 2x risk of CDI1

• No association between use immunosuppressivetherapy 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. Issa et. al. Clin Gastroenterol Hepatol. 2007.2. Kariv et. al. J Crohns Colitis. 2011.

3. Schneeweiss et. al. Ailment Pharmacol Ther. 2009. 4. Rodemann et. al. Clin Gastroenterol Hepatol. 2007.

• Only patients with diarrhea (> 3 liquidstools/day) should be tested for CDI!

• All hospitalized patients with IBD with a diseaseflare

• Ambulatory patients who develop diarrhea(even with no known risk factors)

• Patients s/p colectomy and IPAA that aresymptomatic

Who should we test?

Surawicz et. al. The Am Journal of Gastroenterol. 2013.

79

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

CDI Test Options


Which Test to Choose?

TEST SENSITIVITY SPECIFICITY

NAAT PCR 100% 99.2%

A + B EIA 75 - 95% 83-98%

GDH screening 75 - >90% low


The Perfect CDI Drug

High level of drug in colon

Little systemic absorption

Minimal disruption to commensalmicrobiota

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

• Monoclonalantibodies

• C. diff toxoid vaccine

• Probiotics

• Fecal MicrobiotaTransplantation(FMT)

Severity Clinical Manifestations Treatment

Asymptomatic carrier

No signs or symptoms No treatment

Mild Mild diarrhea (3‐5/d)AfebrileMild abd pain/tenderness

Stop antibioticsHydration/monitorMetronidazole TID

Moderate Moderate nonbloody diarrheaModerate abd pain/tendernessNausea +/‐ vomiting, dehyrdationWBC >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 >38.9Pseudomembranes, ileus, AKI,Severe abd pain/tendernessVomiting, WBC >20,000, Alb <2.5

Hospitalization. Oral or NGVancomycin 500 mg QID +/‐Metronidazole 30 mg/kg/TID ORFidaxomicin 200 mg BID x 10d

Complicated Toxic megacolon, peritonitisRespiratory distress, Hemodynamic instability

Antibx for severe infectionSurgery consultationConsider FMT

CDI Treatment Paradigms

Surawicz et. al. The Am Journal of Gastroenterol. 2013. Leffler and Lamont. NEJM 2015

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,

Vancomycin: Superior in Severe CDI

81

Fidaxomicin Decreases RCDI

Louis T. et al.. NEJM. 2011.

• Antimicrobial agent(s) should be discontinued

• On-going immunosuppression medicationscan be maintained

• Escalation of therapy in IBD should beavoided during the acute phase

Modifying Therapy in CDI


• After initial Tx of CDI, chance of RCDI within 8weeks is 10 – 20 %

• After 1st recurrence, rates of recurrenceincrease to 40 – 65 %

• Recurrence can be due to the same or differentstrain

• RCDI may be due to impaired immuneresponse or alteration of the gut microbiota

Recurrent CDI, A Recurring Problem


82

Jiang et al. Am J Gastroenterol. 2006,.

Treatment Failure IncreasesRisk of Recurrence

How is Pediatric RCDI Different?

• C. diff is constitutive flora until after 6 monthsof 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.

• 1st recurrence: treat with same regimen

• 2nd recurrence: pulsed or tapered vancomycinor fidaxomicin 200 mg BID x 10 days

• No consensus on optimal pulsed/taperingregimen

**Severe CDI: vancomycin +/- metronidazole and surgery consult

CDI Again?! No Easy Answers

Surawicz et. al. The Am Journal of Gastroenterol. 2013. Leffler and Lamont. NEJM 2015.

83

• If there is a 3rd recurrence, fecal microbiotatransplant (FMT) should be considered1

More than 3 Recurrences: Consider FMT

1. Surawicz et. al. Am Journal of Gastroenterol. 2013.2. Kelly et. al. NEJM. 2008.

• Due to reduced efficacy of otherantimicrobial therapies, FMT holdspromise as effective Tx for RCDI2

• Since 2000, failure rates ofmetronidazole for uncomplicated CDIhave increased from 2.5% to > 18%2

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 2. Russel G et al. Pediatric 20103. Kahn S et al. Am J Gastro 2012 4. van Nood et al. NEJM 20135. Kassam Z et a. Am J Gastro 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 should be obtained onall 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 onmedical therapy after 5 days

Surgical Consultation

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 ScreeningDonor 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 therapySerum 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, MDProfessor of Pediatrics

October 8, 2015

Disclosure slide

• Consultant for AbbVie• Consultant for ThermoFisher

86

Objectives

• Identify the three clinical disorders currentlythought to be associated with wheat intake

• Realize the lack of evidence for gluten asresponsible of the so‐called «Non‐celiacgluten sensitivity»

• Be able to approach critically and effectively apatient suspect of having «Non‐celiac glutensensitivity»

Wheat - related disorders

Wheat Allergy~0.1%

Celiac Disease1%

Gluten Sensitivity?0.5-1.0?%

No gene associatedIgE‐mediated

Infants and Bakers

HLA‐DQ2, DQ8Autoimmune disease

Any age

No gene associatedLikely Immune‐

mediatedMostly adults

Serum specific IgE

CD autoantibodiesCD autoantibodiesBiopsy

Nodiagnostic marker

87

Gluten (or Wheat) related disorders

Wheat Allergy~0.1%

Celiac Disease1%

Non-celiacGluten Sensitivity

?%

No gene associatedIgE-mediated

Infants and Bakers

HLA-DQ2, DQ8Autoimmune disease

Any age

No gene associatedImmune-mediated?

Mostly adults

Respiratory, skinsymptoms

GI and extra-GIsymptoms

GI and extra-GIsymptoms



Wheat Allergy~0.1%

Celiac Disease1%


?%

No gene associatedIgE-mediated

Infants and Bakers


Any age


Mostly adults

Serum specific IgE


Nodiagnostic marker



Wheat Allergy~0.1%

Celiac Disease1%


?%

No gene associatedLargely IgE-mediated Children and Bakers


Any age


Mostly adults

Serum specific IgE


Nodiagnostic 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

An Italian survey on 486 patients:Extra‐intestinal symptoms


89

An Italian survey on 486 patients:Anti‐Gliadin Antibodies


A study from Australia Inclusion criteriaAge older than 16 Symptoms of IBS according to Rome III criteria

that improved on a GFD Symptoms well controlled on GFDCeliac disease excluded

Biesekierski JR et al., Gastroenterology 2013

90

Design – RDBPCT (Crossover)

ScreeningScreening Run in / Low FODMAP dietRun in / Low FODMAP diet

High gluten(16g)

High gluten(16g)

WashoutWashout

Low Gluten(2g)

Low Gluten(2g)

WashoutWashout

Placebo(0g)

Placebo(0g)

WashoutWashout

1 Week 2 Weeks 1 Week > 2 Weeks

Gluten free diet

Low FODMAP diet

Shepherd SJ, Am J Gast 2013Gibson PR, Aliment Pharmacol Ther. 2005

FermentableOligosaccharidesDisaccharidesMonosaccharidesAndPolyols

Biesekierski JR et al Gastroenterology 2013

No effect of gluten

Effect of FODMAP withdrawalEffect of FODMAP withdrawal

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

92

The only study testing the effect of

gluten in NCGS


The "GLUTOX" Trial: A Randomised, Double Blind, PlaceboControlled Crossover Study on "Non‐Celiac Gluten Sensitivity"

Elli L et al., DDW 2015

100 patients with IBS‐like symptoms, no celiac or wheat allergy

81 patients improved 19 patients did not improve

NCGS excluded

56 patients (75%) did not react

25 patients (25%) reacted

GFD for 3 wks

Gluten challenge

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!

Gluten sensitive

?

ATISensitive

?

FODMAP

sensitive

Early‐stage celiac

Non IgE‐wheat allergic

Placebo/Nocebo

Not 1 mention of children in the whole paper!

But wait! What about children?

94

• 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 (!)

The only paper in children!

WIS – A Practical ApproachWIS – A Practical Approach

Pt on GFDPt on GFDUnwilling to abandon the GFDWilling to undergo gluten challenge

HLA‐DQ2, DQ8

Positive Negative

No Celiac:Enjoy your GFD!

Enjoy your GFD: But remember you could be celiac

Gluten for ≥6 weeks

Positive

TTG and Biopsy

Celiac

Negative

Symptoms recurred?

Yes No

WIS WIS ruled out

No Celiac

What you have hopefully learned

• Wheat can adversely affect humans by threedifferent 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 ofabdominal pain

Identifying the patient with refractoryabdominal pain

Know the available and currenttreatment options

97

A brief word about abdominal pain (AP) prevalence

Demographics AP prevalenceMale 43% 29%

Female 57% 36%

Average age (range), years 11.8 (8-15)

Average age of boys 11.7

Average age of girls 11.9

African-American 33% 30%

Latino 22% 32%

Caucasian 21% 33%

Other 16% 35%

Asian 8% 42%

Saps M et al., J Pediatr. 2009

*278 subjects with weekly questionnaires for 1 year

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

Altered HPA-axis

BacterialOvergrowth

Altered ReceptorExpression(5HT, NMDA,TRPV1)

Autonomic Dysfunction

Neuronal Sensitization

Descending Pain Modulation

Carbohydrate Intolerance

MotilityDisorder

98

Stressors Psychological stress

Inflammatory

Sleep

spinewave.co.nz

Where?1. Intestinal microbiome2. Mucosal changes3. Enteric nervous system4. Primary afferents5. Genome6. CNS

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 post-infections/inflammatory pain?

Not all patients that have stress orgastrointestinal infections develop IBS

Not all animals develop visceralhyperalgesia following “stress”

Post-inflammatory- Animal Model

Zhou et al., Journal of Pain, 2007

-24% of rats maintained hyperalgesia at 4 months

Author Okhuysenet al.

Stermeret al.

Trivedi et al.

Pitzurraet al. Nair et al. Lalani et al.

Year 2004 2006 2011 2011 2014 2014Destinations Mexico Worldwide Egypt or

Turkey Worldwide Mexico Worldwide

Study design Prospective Prospective Retrospecti

ve Prospective Prospective Prospective

Follow-up (months) 6 6 up to 7 6 6 6 6

Number of participants (complete follow-up)

97 405 120 2476 817 515

Male/female (complete study population)

47/50 216/189 89/32 1218/1258 227/590 254/261

IBS occurrence (exposed)

10.0% (6/60)

13.6% (16/118)

17.2% (16/93)

3.1% (26/852)

5.7% (20/348)

2.4% (3/126)

IBS occurrence (non-exposed)

0% (0/37) 2.4% (7/287)

3.7% (1/27)

0.7% (12/1624)

2.6% (12/469)

1.8% (7/389)

Post Infectious IBS

100

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrierCristina 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

Pain

Sleep

Autonomic Resoponse

Role of Amygdala A critical component of the anxiety neuro-circuitry

Associated with fear learning

Memory consolidation

vmPFC

Hippocampus

Amygdala

Hypothalamus

PAG

Ressler, et al 2010Cullen, et al 2011Pezawas et al, 2005

Suppresses negative affect by inhibiting amygdala output

Descending pain modulation

101

Amygdala Functional Connectivities

Healthy Control IBS Patient

Subliminal

Liminal

Subliminal

Liminal

VmPFC

VmPFC

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 medicationsnot well understood

Very few clinical trials in children

How far Have We Really Come?

1959

8 randomized, controlled trials (4 positive)

55 years

421 children studied

102

Why we can’t believe all clinical trials?

Patient A: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

Patient B: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”

©2005 by Society for Neuroscience

Perform distractingtasks activate periaqueductal grey(PAG), Anterior Cingulate Cortex, andorbitofrontal cortex

Placebo activatesendogenous opioidsand induces mildrespiratory depressionand decreasesadrenergic activity

Benedetti F et al., J.Neurosci. 2005Pollo et al., Pain 2003

103

Psychological Therapy Parent Attention Versus Distraction: impact on

symptom complaints by children with and withoutchronic functional abdominal pain.

Walker LS et al., 2006

Cognitive-behavioral therapy for children withfunctional abdominal pain and their parentsdecreases pain and other symptoms.

Levy RL et al., 2010

A randomized controlled trial of a cognitive-behavioral family intervention for pediatricrecurrent abdominal pain.

Robins PM et al., 2005

Hypnotherapy for children with functional abdominal pain or irritable bowel syndrome: a randomized controlled trialVlieger AM, Menko-Frankenhuis C, Wolfkamp SC, Tromp E, Benninga MA

After therapy At 6 mo follow-up At 1 y follow-up

SMT group (n = 25)

HT group (n = 27)

SMT group (n = 24)

HT group (n = 27)

SMT group (n = 24)

HT group (n = 27)

No effect 56% 15% 66% 7% 46% 4%

Improved 32% 26% 17% 22% 29% 11%

Clinical remission 12% 59% 17% 71% 25% 85%

Gastroenterology, 2007

Biofeedback

Changes maladaptive thoughts and pain perception

Patient able to visualize changes in RR, HR and temperature

104

Project to hypothalamus,amygdala, pre-frontalcortex, periaqueductalgrey (PAG) and locuscoeruleus (LC)

Regulate emotional,autonomic andbehavioral responses

C.H. Knowles, Q. Aziz. PAIN. 2009

Gut Vagal Afferents Differentially Modulate Innate Anxiety and Learned FearKlarer M, Arnold M, Günther L, Winter C, Langhans W, Meyer U. J Neurosci. 2014

Efferent activity ismeasured non-invasively via heartrate variability (HRV)

Afferents maymodulate adrenalmedullary factors: epi,norepi, dopamine,endogenous opioids,substance P

Vagal Nerve Afferents Modulate Autonomic Control

Khasar et al. Eur J Neruosci. 2003

Vagal nerve stimulation

Neuro-stimulator (NSS) device veryencouraging results in chronic pain trials

Stimulation of auricular

branch of vagus nerve

Could restore autonomic

function and pain pathways

105

Pharmacological Treatment Options

Pain (with disability)

-TCAs (amitriptyline)

-SSRIs (citalopram)

-Gabapentin

-Antispasmodics (hyoscyamine , dicyclomine)

-Cyproheptadine

-Rifaximin

Constipation

-Linaclotide

-Lubiprostone

Mild Pain (no disability)

-Peppermint oil

-Iberogast

-Melatonin

-Probiotics?

-Acid suppression?

Rehabilitation Program

Education and ReassuranceAntispasmodic- situational pain Loperamide- situational diarrhea

Cyproheptadine (follow weight closely)

MelatoninPeppermint oil

Proton pump inhibitorIberogast

Rifaximin (suspected SIBO)

AmitriptylineAdjust school schedule

( sleep, exercise, fluids)

GabapentinSSRI

Bottom–up Approach for Mild Abdominal Pain

Don’t Forget to Ask the Important Question that will Dictate Therapy?

How many days of school or activities have you missed?

106

Rehabilitation Program

Top-down Approach for Disabled Pain Patient

Education and Reassurance

Rifaximin (bloating, excess gas)

Amitriptyline

Adjust school schedule( sleep, exercise, fluids)

GabapentinSSRI

Cyproheptadine (nausea, pain)

Melatonin (sleep)Proton pump inhibitor (dyspepsia)

Iberogast (nausea, pain, dyspepsia)

Fludrocortisone (orthostatic intolerance)

CoQ10 (fatigue)

Amitriptyline

Bahar RJ et al., J Pediatr. 2008

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 EffectsConstipation, dry mouth, dizziness, somnolence

IBS, FAP and FD patients were randomizedto 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

Campo JV et al., 2004

Methodological limitation: -not placebo controlled or blinded-small group size (n=25)

CitalopramStudy 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

GabapentinNo Data in Children-Increased rectal compliance in adult IBS-D

-Attenuated rectal mechanosensitivity

MechanismBinds 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 Effectsdizziness, somnolence, fatigue, ataxia

Lee KJ, Kim JH, Cho SW. Aliment Pharmacol Ther. 2005

108

-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%

MechanismAlteration in the quantity, location, or quality of the hosts' intestinal microbiota

Dose:8-35mg/kg/d divided 3x/daily (max 3600mg/d)

Side Effectsdizziness, somnolence, fatigue, ataxia

Double-blind, Placebo-controlled Antibiotic Treatment Study of Small Intestinal Bacterial Overgrowth in Children with Chronic Abdominal PainCollins BS, Lin HC. J Pediatr Gastroenterol Nutr. 2011

Pain assessed at 1 and 2 weeks (n=29)

Improvement (87%) vs. placebo (43%)

Primary outcome measure was the self-reported changeof frequency and duration of abdominal pain

Did not use validated questionnaires

MechanismAntagonist of serotonin, histamine and muscarinic receptors

Improved gastric accommodation through 5HT receptors?

Dose:0.25-0.5mg/kg/d divided 2-3x/daily

Side EffectsWeight gain, somnolence, irritability

Cyproheptadine for the Treatment of Functional Abdominal Pain in Childhood: a double-blinded randomized placebo-controlled trialSadeghian M, Farahmand F, Fallahi GH, Abbasi A. Minerva Pediatr. 2008

Study: Retrospective, open label study of 80 children with dyspepsia

Cohort: GER, post fundoplication, diabetes, mitochondrial dysfunction, post Ladd’s procedure

Safety and Efficacy of Cyproheptadine for Treating Dyspeptic Symptoms in ChildrenRodriguez L, Diaz J, Nurko S. J Pediatr. 2013

109

Complementary and Supplementary Therapy

Approximately 12% of non-clinicalpopulation seeks complementary therapiesfor their children with pain

It is NOT always the answer, but plays animportant 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 placebo-controlled studyLu 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 trialMadisch 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 IntoleranceJohn 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)

Peppermint oil

-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%

MechanismCa+ channel blocker (antispasmodic)

Dose(30-45kg) 187mg 3x/daily, (>45kg) 374mg 3x/daily

Side EffectsHeartburn, headache, flushing

Kline et al., J Pediatr. 2001

Enteric-coated, pH-dependent Peppermint Oil Capsules forthe Treatment of Irritable Bowel Syndrome in Children.Kline RM, Kline JJ, Di Palma J, Barbero GJ.

111

Cause or Effect ?

IBSSleep

Anxiety

Stress

Dysautonomia

Genetics Adverse early life

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.

Am J Gastroenterol. 2000J Neurogastroenterol Motil. 2014J Korean Med Sci. 2013Am J Gastroenterol. 2010

Psychosocial stress in nurses with shift work schedule is associated with functional gastrointestinal disordersKoh SJ, Kim M, Oh da Y, Kim BG, Lee KL, Kim JW.

Impact of shiftwork on irritable bowel syndrome and functional dyspepsiaKim 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 nursesNojkov B, Rubenstein JH, Chey WD, Hoogerwerf WA.

112

Role of Exercise in Pain ControlRat model: Exercise increased β-endorphin and met-

enkephalin in rostral ventral medulla (RVM) and periaqueductal grey (PAG)

Ameliorated thermal and tactile hypersensitivity

Prospective, randomized, controlled, open-labelstudy of 12 weeks (n=102)

20–60 min of moderate-to-vigorous intensivephysical 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

Adult IBS

Conclusions Careful evaluation should include

assessment of decreased functioning in orderto target therapy

Combination therapy is necessary in thesevere, disabled patients

Psychological therapy is key in almost ALLpatients

We must take advantage of the placeboeffect in the less severe patients andencourage healthy lifestyles (sleep andexercise)

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

ImportanceImportance

Common reason for referral

Co-exists with other FGIDs

Highly distressing

Sparse literature

No objective measurement tools

No diagnostic algorithms

Ineffective treatments

Common reason for referral

Co-exists with other FGIDs

Highly distressing

Sparse literature

No objective measurement tools

No diagnostic algorithms

Ineffective treatments

114

CaseCase

15 year old adolescent girl

4 mo hx of waking up everymorning with nausea

Improves throughout the day

Worse on school days when shehas to wake up earlier

Rarely vomits, no weight loss

CaseCase

ROS positive for migraines anddizziness

Normal growth and development

Normal PE

Neg HCG, “routine” labs, UA, toxscreen, abdominal US

Have you seen this before?

115

J Pediatr Gastroenterol Nutr 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

Disability was related to higher nausea:Full school days missed and unable to do home activities

significantly correlated with nausea frequency

Percentages

Nausea in pediatric FGID

Associated symptoms

Kovacic K, et al, JPGN 2013;57:311-5.

Is functional nausea a pediatric functional GI disorder?

It will be in Rome IV!

116

Early morning nausea

Morning nausea in adolescents isalmost always a manifestation of ananxiety disorder

Cortisol levels peak in the earlymorning hours (usually around 8AM)

Cortisol is also released as aresponse to stress and is a mediatorof anxiety

Share this FACT with the parents andpatient

If you look for what is causing the nausea….

You may find this

117

Symptoms of Eosinophilic Esophagitis by age*

Symptoms of Eosinophilic Esophagitis by age*

*Median and inter-quartile range, n=103

Feeding disorder

Nausea and vomiting

Abdominal pain

Dysphagia

Food impaction

Or you may find duodenal eosinophilia (if you biopsied): Is it relevant?

Or you may find duodenal eosinophilia (if you biopsied): Is it relevant?

Friesen CA, at al. J Pediatr Gastroenterol Nutr 2004;38:343-51

0

5

10

15

20

25

30

35

40

45

Grade 1(worse)

Grade 2 Grade 3 Grade 4 Grade 5(complete

relief)

MontelukastPlacebo

% o

f p

atie

nts

Symptom relief grade

p<0.005 vs. placebo

Montelukast in dyspeptic children with duodenal eosinophilia

A double blind, randomized, placebo-controlled, cross-over study (n=40)

10 mg daily14 days rx

118

More tests?

Nuclear Medicine

Pediatric normal values?Pediatric normal values?

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 stomachafter 4 hours, >60% after 2 hours

No pediatric data available, butlook for extremes

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 stomachafter 4 hours, >60% after 2 hours

No pediatric data available, butlook for extremes

Abell TL et al. J Nucl Med Technol. 2008;36:44-54

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 GESat 4 h (p<0.0001)

• Survey: Only 5 of the top 20 pediatric GIcenters in the US conducted 4-h GES

• Conclusions: Extending GES to 4 h resultedin a considerable increase in diagnosis ofgastroparesis

SmartPill pH.p Capsule

• 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

pH SENSOR

PRESSURE SENSOR

BATTERIES

TRANSMITTER

MICROPROCESSOR

120

Gastric Emptying 5 hr, 25 min

Wireless Motility Capsule Tracing- Gastroparetic Child

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

22 patients (>8 y/o): All had WMC, 21 had complete scintigraphic gastric emptying study data and 20 had complete antro-duodenal manometry data

J Pediatr. 2013;162:1181-7

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

IberogastIberogast

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

Gastrointestinal Symptom score during 8 wk of treatment with STW 5 (Iberogast) or placebo

von Arnim U, et al. Am J Gastroenterol. 2007;102:1268-75

Iberogast in Functional Dyspepsia

Iberogast in Functional Dyspepsia

Hypnotherapy for nausea?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?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 ReliefBandThe 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 Symptom Severity

Improved total score (p<0.0001)

p<0.0001

ConclusionsConclusions

• Nausea with or without vomiting is acommon symptom in children andadolescents

• Early morning nausea is often amanifestation of an anxiety disorder

• EGD and GE studies may clarifyunderlying pathophysiology and directtreatment

• Several medical, behavioral, andsurgical interventions have the potentialto ameliorate nausea

127

1

Pediatrics

New Horizons in Hepatitis CNASPGHAN Postgraduate Course

Washington, DC

Daniel H. Leung, MDBaylor College of MedicineTexas Children’s Liver Center

•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.

Disclosures

•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

Objectives

128

2

•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.

Hepatitis C: Burden of disease

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

Maternal transmission

5‐7%

Maternal transmission

5‐7%

Most clinically well

Most clinically well

15% with mild symptoms

15% with mild symptoms

1‐2% develop cirrhosis

1‐2% develop cirrhosis

HCC5 reports

HCC5 reports

Spontaneous resolution <2 yrs

25‐40%

Spontaneous resolution <2 yrs

25‐40%

Persistent CHC 48‐69%

Persistent CHC 48‐69%

Children/Adolescents

Develop CHC but clear at <7 yrs

6‐12%

Develop CHC but clear at <7 yrs

6‐12%

Natural History

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3

Mean Ishak (0‐6) 1.6 ± 1.3‐Children < 15 yr 1.5 ± 1.3

‐Children > 15 yr 2.3 ± 1.2

Multi-Center European Study 1980-1998“Mild but Progressive”

+HCV RNAN=224

87% asymptomatic

48% ALT< 2x ULN

6% viral clearance and ALT normalization

79% Genotype 1

17% Genotype 2/3

Liver bxn=92

Jara et al. Clinical Infect Dis. 2003

200 followed for mean of 6.2 ± 4.7 yrs

Cirrhosis 1 (1%)

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 z-scores

Goodman ZD, Makhlouf HR, Liu L, et al. Hepatology 2008.

IshakScore

BMI‐Z<1.64 (n=92)

BMI‐Z>1.64(n=29)

0 16% 7%1 46% 45%2 36% 31%3 2% 11%

4 ‐ ‐

5 ‐ 3%

6 ‐ 3%

Obesity and impact on Treatment in US children

Delgado‐Borrego et al. JPGN 2010

Obesity MAY

• Decreases IFN bioavailability

• Alter cytokine function

• Increase insulin resistance

1 unit in BMI z‐score = ‐12% response rate

130

4

•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

Why worry?

Lok AS et al. Gastroenterology 2009. Madhoun MF et al. Am J Med Sci 2010. Faddan et al. Journal of Viral Hepatitis 2014.

•-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

Screening/Monitoring Infants <3 yrs

Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012.

•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

Monitoring in Children

Mack, CL et al. J Pediatr Gastroenterol Nutr. 2012 .

131

5

•In children with significant liver disease (hepatic fibrosis or cirrhosis):

Abdominal ultrasonographyAND

Serum alpha-fetoprotein

should be considered ANNUALLY to screen for HCC (NASPGHAN 2B; BII*).

Monitoring in Children


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

*

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).

Role of liver biopsy


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Pegylated Interferon + Ribavirin

‐Two U.S. licensed pegylated interferons

•Peginterferon alfa-2b (Peg-Intron®)

•Peginterferon alfa-2a (Pegasys®)

•Ribavirin: (Rebetol®, Ribasphere®)

How effective is current therapy?

Wirth, World Journal of Pediatric Gastroenterology, 2012

•5 largest pediatric prospective clinical trials

•Overall SVR is 60%

•51% in G1

•93% in G2/3

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 obesityParental oversight Low response rate

(Genotype 1)

Family history of HCC or cirrhosis

Puberty

Reduce social burden More advanced therapies ahead

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7

‐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

Duration 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

8

•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.

Future Therapeutics: A new era

Personalized HCV Therapy

Nature Publishing Group, 2005

•Discovery of first two DAA against the NS3/4A serine protease for use in genotype 1 HCV

• Ketoamide inhibitors, boceprevir and telaprevirwere approved in 2011

HCV Structure: Understanding the Future

135

9

Sofosbuvir

Nucleos(t)ide Polymerase inhibitors

Ledipasvir

Protease inhibitors

Translation/Processing

Dasabuvir

Welsch, C. Et al. Gut 2012;61(Suppl 1):i36ei46. doi:10.1136/gutjnl‐2012‐302144

Non‐Nucleoside Polymerase inhibitors

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 PEG-IFN +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

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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

Timeline of recently FDA approved HCV drugs

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 (NoFDA)

•Viekira Pak (ombitasvir (NS5A), paritaprevir (NS3-4A) 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)

Non-Sofosbuvir combinations

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11

•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 pegylatedinterferon, but require 24 weeks of Sofosbuvir instead of 12 (G1)

•This same trend has been demonstrated with other DAA combinations

A genotypic paradigm shift

•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

Empiric approach to pediatric HCV

•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

Summary

138

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 CFFoundation

• I have received funding from Vindico for amedical education presentation

Objectives:

• Define renal complications in chronic liverdisease

• Review mechanisms of ascites, role of thekidney, 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 withincreased cardiac output

• Increased resistance to portal vein inflow dueto cirrhosis

• Increased portal vein pressure• Consequences: *renal dysfunction

*ascitesvariceal bleedinghypersplenism

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 resultin stimulation of the renin-angiotensin,aldosterone system; salt and water are retained

• Portal hypertension increaseshydrostatic pressure insplanchnic circulation,exceeding capacityof lymphatics

• Low albumin decreasescolloid oncotic pressure,allowing fluidto 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/kgof 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 hyponatremiaAdapted from MohantyGastroenterol Hepatol 2015

141

Consequences of Hyponatremiain Cirrhosis

• Higher mortality

• More encephalopathy

• Associated with ascites, HRS

• Associated with impaired QOL

Mohanty Gastroenterol Hepatol 2015

Hyponatremia in Cirrhosis: Treatment

Cirrhosis/portal hypertension

Splanchnic/systemic vasodilation

Activation of neurohumoral systems:

Renal tubule/water retention

Dilutional hyponatremia Adapted from MohantyGastroenterol Hepatol 2015

Water restriction?Vaptans?

Albumin infusionsHold diuretics

Transplant

Decreased effective arterial blood volume

Causes of Renal Dysfunction in Cirrhosis

• Intra-renal 29% (glomerulonephritis, interstitialnephritis)

• 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

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Consequences of Renal Dysfunction in Cirrhosis

• Ascites

• Hyponatremia

• Hepatorenal syndrome– Type 1: acute renal failure

– Type 2: chronicrenal 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 toexpand 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; GluudCochrane 2012; Cavallin Hepatol 2015

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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), andlevel of renal dysfunction

• CVVHD is preferred to intermittenthemodialysis to minimize hemodynamicinstability

• There are issues like choice of anticoagulant(role of citrate?)

Long Term Outcomes of Children with HRS Receiving RRT then

Liver Transplant

Received RRT (8) Matched controls, no RRT (24)

P Value

Survival 5/8 (63%) 24/24 (100%) 0.01

GFR/years of follow‐up 97 (60‐122)/3.2yrs 114 (65‐236)/4.9yrs NS

Need for f/u antihypertensives 1/5 (20%) 2/22 (9%) NS

Adapted from Parsons Liver Transplant 2014

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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 isproblematic: 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 pre-

transplant 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 2015Davis Liver Transplant 2005Locke Transplantation 2008

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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, decreasedeffective blood volume and renalvasoconstriction lead to renal complications ofcirrhosis: ascites, hyponatremia, HRS

• Treatment of these complications revolves onunderstanding the kidney’s role in Na and H20balance in cirrhosis

• There are some encouraging data regardingvasoconstrictor + albumin therapy for HRS inadults; pediatric research is needed!

Take Home Messages

• Carefully monitor renal status in cirrhosis

• Avoid over-diuresis & nephrotoxic drugs andtreat infection early to avoid precipitating HRS

• Try providing colloid when HRS is suspected

• Consider adding vasoconstrictor therapy inHRS (need pediatric data)

• HRS often reverses after liver transplant

146

Wilson Disease – an update

Simon Horslen MB ChB FRCPCHDirector Hepatobiliary ProgramMedical Director Liver & Intestine TransplantationSeattle Children's Hospital

Professor Department of PediatricsUniversity 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 populationand typical diagnostic evaluation.

2. Understand genetics and patterns of inheritance tofocus who should be screened.

3. Understand treatment strategies and side effects ofcurrent and future therapies

147

Content

• History

• Presentation of Wilson disease

• Physiology of copper

• Genetics of Wilson disease

• Diagnosis

• Prognosis

• Treatment & Monitoring

• Future directions

Samuel Alexander Kinnier Wilson

• 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 chelatorBritish 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

History

Phenotypic Presentation of Wilson Disease

Hepatic presentationsH1: Acute hepatic Wilson diseaseH2: Chronic hepatic Wilson disease

Neurologic PresentationsN1: Associated with symptomatic liver disease N2: Not associated with symptomatic liver diseaseNX: 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 tissues70%)

• 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

Hours after oral 65Cu dose

% e

nric

hmen

t

0

5

10

15

0 20 40 60 80

Stable isotope enrichment studies (65Cu) showing normal range and a patient with Wilson disease (blue line)

149

From: Disorders of Copper Transport: The Online Metabolic and Molecular Bases of Inherited Disease, 2014Date of download: 6/22/2015 Copyright © 2015 McGraw-Hill Education. All rights reserved

Copper metabolism in the hepatocyte

Ceruloplasmin

ER

Trans-Golgi Network

Bile canaliculus

Hepatic Sinusoid

To Plasma(secretion)

cytochromeoxidase

HAH1Wilson ATPase

Ccs

Cu/Zn superoxidedismutase

Cox17

IL-6TNF

Ctr1Cu-histidineCu-albumin

metallothionein

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 notstrong

• Genetic modifiers – MTHFR,COMMD1, ATOX1, XIAP

• Environmental modifiers - dietCopper-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, nephroticsyndrome and protein-losing enteropathy

Serum Copper

• Circulating copper may be:• Low - because the

ceruloplasmin level is low

• High –liver necrosis releases ‘free’ copper

• Normal – a normal level does not exclude the diagnosis

• Free (non-ceruloplasmin bound) copper• Calculated parameter and subject to error

• Better for treatment monitoring than diagnosis

• > 25 g/dL in most untreated patients

Serum copper

151

Urinary copper excretion

• 24 hour collection

• Collected into acid-washed container to prevent coppercontamination

• 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 arenot 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 sequenceanalysis and deletion/duplication analysis

• Carrier frequency ~1 in 90 based on caseidentification

• Population based studies using moleculartechniques suggest higher rates

• No mutation identified in up to 13% but others havehad 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

Symptoms ScoreKF rings (slit lamp examination)

Present 2Absent 0

Neuropsychiatric symptoms suggestive of WD (or typical brain MRI)

Present 2Absent 0

Coombs negative hemolytic anemia (+ high serum copper)

Present 1Absent 0

Mutation analysisDisease causing mutations on both chromosomes 4Disease causing mutation on one chromosome 1No disease causing mutations detected 0

Laboratory Tests ScoreCeruloplasmin (mg/dL)

Normal 010-20 1< 10 2

Urinary copper (in absence of acute hepatitis)

Normal 01-2x ULN 1>2x ULN 2Normal but >5x ULN with penicillamine challenge 2

Liver Cu quantitationNormal -1<5x ULN 1>5x ULN 2

Rhodanine positive hepatocytes (only if hepatic Cu level not available)

Absent 0Present 1

Wilson Index for Predicting Mortality

Score Bilirubin

mol/L)

INR AST

(IU/L)

WCC

(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

Dhawan A et al Liver Transpl. 2005

A score 11 – PPV 92% & NPV 97%

Treatment

• Aim to start chelation therapy asap in symptomaticindividuals

• Treatment is life-long, including during pregnancy

• If one treatment modality is discontinued, an alternativemodality must be substituted

• Discontinuation of all treatment leads to hepatic andneurologic decompensation, which may be refractory tofurther medical intervention

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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 fromdiagnosis, changing medications and compliance

• Serum copper and ceruloplasmin, LFTs, INR, CBC,urinalysis, and physical examination

• 24-hour urinary excretion of copper at least annually

• Primarily indicated for children and adolescents withfulminant 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

Liver transplantation for Wilson disease

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 probandbefore they become symptomatic

• If mutations known, testing with molecular genetics isappropriate

• If mutations not known standard clinical testing can beconducted

• Treatment with zinc alone may suffice, but is requiredlife-long

Future directions: New research

• Phenotypic variation• Genetic

• Epigenetic

• Environmental

• New Drug Treatments• (Ammonium tetrathiomolybdate)

• Intrahepatic copper chelator

• Screening

Gateau & Delangle Ann N Y AcadSci. 2014

Future directions: Population screening

• Population frequency 1 in 30,000

• Presymptomatic diagnosis is reliable, treatment canprevent manifestations of disease

• Ceruloplasmin and serum copper not useful for infantscreening

• A novel proteomic screening approach is beinginvestigated using liquid chromatography–multiplereaction 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

Blame the Genes?Familial and Autoimmune Pancreatitis in Children

Véronique Morinville MD, FRCP(C)Pediatric Gastroenterology and Nutrition

Montreal Children’s HospitalMcGill University Health Centre

Montreal, QC, Canada

2015 NASPGHAN POSTGRADUATE COURSEThursday October 8, 2015; Washington DC

I have no financial relationships with a

commercial entity to disclose

Objectives of Presentation

• Understand when to consider familial andautoimmune etiologies in a child presentingwith pancreatitis

• Review the different genetic factors that maybe involved in familial‐type pancreatitis

• Recognize factors implicated in autoimmunepancreatitis (AIP) types 1 and 2 and whattherapies may be attempted

157

OBJECTIVE 1

When to consider familial and autoimmune etiologies in pediatric pancreatitis?

AP = Acute PancreatitisARP = Acute Recurrent Pancreatitis

CP = Chronic Pancreatitis

ETIOLOGIES‐Single Episode AP Pediatric Series

Morinville 2008; Lautz 2011; Morinville 2012, others

AnatomicBiliary/ StonesTraumaticMedications / ToxinsMulti‐SystemicInfectionsMetabolicIatrogenicFamilial/ Hereditary “Idiopathic” (↓)

Diagnosis of AP:

At least 2 of 3 of:

• Pain compatiblewith pancreas origin

• Amylase and/or Lipase ≥ 3 x ULN

• Imaging

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 withAbsence 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)

Consider Genetics in ALL Children with ARP or CP

CPA1CELCLDN2

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

(R122H; N29I; A16V; rare)

AGA GastroSlides Pancreas

SPINK1: Secretory Trypsin Inhibitor Serine Protease Inhibitor Kazal Type 1

Active site

SPINK1

Trypsin

• 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

161

CFTR: Cystic Fibrosis Transmembraneconductance 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 mutationsmore pancreas‐specific

CFTRCFTR

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/ orw/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– “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

• Type 2– “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– LPSP: lymphoplasmacytic

sclerosing pancreatitis

– Periductal dense infiltrate plasma cells and lymphocytes; storiform fibrosis

– Obliterative phlebitis– No GELs

– Abundant IgG4+ plasma cells( > 10 cells/ hpf)

Type 2: Histology– 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 2010Shimosegawa 2009

163

Diagnosis AIP: Adults

• 2000s: multiple societies/ countries publishing different diagnostic criteria

• 2007‐2011: HISORt and InternationalConsensus 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

Imaging:Ductal

Diffuse enlargement/ delayed enhancement

> 1/3 length main PD or multiple strictures, no upstream dilation

segmental/ focal enlargement, delayed enhancement

Segmental narrowing PD, no upstream dilation (duct <5mm)

Serology IgG4 > 2x ULN IgG4: 1‐2x ULN

Other Organ Involvement

Histology extrapancreatic organsTypical Radiology (CBD, retroperit)

Histology extrapancreatic organsPhysical/ Radiologic evidence

Response totherapy

Diagnostic Steroid TrialImprovement 2w

Diagnostic Steroid TrialImprovement 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 acinarinflammation +

No/ scant IG4+ (0‐10 cells/ hpf)

Both: Granulocytic and lymphoplasmacytic acinarinfiltrate +

No/ scant IgG4 (0‐10 cells/ hpf)

Imaging: Parenchyma

Imaging:Ductal

Diffuse enlargement with delayed enhancement (typical)

Long (> 1/3 main PD) or multiple strictures, no upstream dilatation

Segmental/ focal enlargement with delayed enhancement

Segmental narrowing w/o upstream dilatation (duct <5mm)

Serology ‐ ‐

Other Organs ‐ IBD

Response totherapy

Diagnostic steroid trialImprovement 2w

Diagnostic steroid trialInvolvement 2w

ADULT Criteria. Shimosegawa. International Consensus 2011

164

AIP in Pediatrics: LiteratureCase Reports/ Small Series

• Presentations: Abdo pain (>> adults), V, weight loss, jaundice

• Imaging: globular enlarged, ill‐defined mass panc head; obstructionCBD; 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

• 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

Hart PA. Gut 2013

165

Future Directions: Autoimmune and Genetic Markers within Same Patients?

• Multiple risk factors within same children: 129 CPchildren 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‐diagnoseddue 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 DiseaseGetting to the Bottom of

Perianal Crohn’s Disease

Maria Oliva-Hemker, M.D.Chief, Division of Pediatric Gastroenterology & Nutrition

Stermer Family Professor of Pediatric IBDJohns Hopkins University School of Medicine

Baltimore, MD

DisclosuresDisclosures

• Abbvie Immunology—grant funding• Abbvie Immunology—grant funding

Learning ObjectivesLearning Objectives

• Identify the lesions associated with perianalCrohn’s disease

• Review the pathophysiology andclassification systems for perianal fistulizingdisease

• Understand the approach to assessing andtreating the patient with perianal fistulizingdisease

• Identify the lesions associated with perianalCrohn’s disease

• Review the pathophysiology andclassification systems for perianal fistulizingdisease

• Understand the approach to assessing andtreating the patient with perianal fistulizingdisease

168

PerianalCrohn’s Disease

Fistula AbscessTags

Fissures

www.gicare.com

Prevalence of Pediatric Perianal Crohn’s Disease

Prevalence of Pediatric Perianal Crohn’s Disease

• Up to 38% of pediatric CD develop perianaldisease– 41/276 (15%) newly diagnosed children with

CD had perianal lesions within 30 days ofdiagnosis

– 28/276 (10%) had fistulas and/or abscesses

• 1 in 20 (5%) present with isolated fistulousdisease (and have no evidence ofintestinal involvement at presentation)

• Up to 38% of pediatric CD develop perianaldisease– 41/276 (15%) newly diagnosed children with

CD had perianal lesions within 30 days ofdiagnosis

– 28/276 (10%) had fistulas and/or abscesses

• 1 in 20 (5%) present with isolated fistulousdisease (and have no evidence ofintestinal involvement at presentation)

Keljo DJ et al, Inflamm Bowel Dis 2009

Skin Tags: Prevalence in Crohn’s Disease of Up to 70%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 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

• 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 FissuresAnal Fissures

• Prevalence of up to 20%

• Broad based and deep

• Usually painless

• May be associated with large skin tags

• May be multiple and placed at variouslocations around the anal canal

• Spontaneously heal >80% of patients

• Prevalence of up to 20%

• Broad based and deep

• Usually painless

• May be associated with large skin tags

• May be multiple and placed at variouslocations around the anal canal

• Spontaneously heal >80% of patients

Schwartz DA et al Inflamm Bowel Dis 2015Parks AG et al, Br J Surg 1976

Schwartz DA et al Inflamm Bowel Dis 2014Bell SJ et al Aliment Pharmacol Ther 2003

Simple Fistulas Complex Fistulas

170

Assessment of Perianal FistulasAssessment 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 standardimaging technique– Endoanal ultrasound (EUS) may be useful

alternative to MRI (adults)

• 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 standardimaging technique– Endoanal ultrasound (EUS) may be useful

alternative to MRI (adults)

Treatment Goals for Fistulizing DiseaseTreatment 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

• 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

Critical Evaluation of Data from Therapeutic Trials

Medication Evidence Efficacy

Antibiotics B+ 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

Therapy Use By Q8 Nonfistulizing Fistulizing SignificanceYes, %(n) Yes, %(n) (P<0.05)

Antibiotics 45% (99) 73% (19) P=0.012OR=3.1

Immunomodulators 86% (208) 100% (28) P=0.032Infliximab 33% (81) 57% (16) P=0.013

OR=2.7

Medical Therapy in Children With and Without Fistulizing Perianal Disease

Medical Therapy in Children With and Without Fistulizing Perianal Disease

Keljo D et al Inflamm Bowel Dis 2009

Immunomodulators for Treatment of Perianal Fistulas

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 patientssuggested AZA may maximize long-term antibiotic effects

• Retrospective chart review of 21 patients showedenhanced response with AZA or MTX started within 3 months of infliximab therapy

• 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 patientssuggested AZA may maximize long-term antibiotic effects

• Retrospective chart review of 21 patients showedenhanced response with AZA or MTX started within 3 months of infliximab therapy

Lecomte T et al, Dis Colon Rectum 2003Dejaco C et al, Aliment Pharmacol Ther 2003Topstad DR et al, Dis Colon Rectum 2003

Sands BE et al, N Eng J Med 2004

Proportion of Adult Patients with Complete Fistula Closureat Each Study Timepoint

N=306~90% perianal fistula~60% >1 fistula

172

Maintenance of Complete Fistula Closure in Crohn’s Disease with Anti-TNFα Agents

Maintenance of Complete Fistula Closure in Crohn’s Disease with Anti-TNFα Agents

Infliximab at 1 yrN=306

Adalimumab at 1 yrN=117

Certolizumab at 6 mosN=58

17%

36%

Sands BE et al, N Eng J Med 2004Colombel JF et al Gut 2009Schreiber S et al, Alimen Pharmacol Ther 2011

Improved Fistula Healing with Adalimumab and Ciprofloxacin Improved Fistula Healing with Adalimumab and Ciprofloxacin

Dewint P et al, Gut 2014

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

Dupont-Lucas C et al, Aliment Pharmacol Ther 2014

Time to First Loss of Response to Infliximab in 89 Children with Perianal Fistulas

0 2 4 6 8 10

89 84 80 68 62 48

1.0

0.8

0.6

Duration of follow-up (months)

Pa

tient

s w

ith s

usta

ined

per

iana

l res

pons

e (%

)

0.4

0.2

0.0

173

Medical Management of Pediatric Perianal Fistulas

Medical Management of Pediatric Perianal Fistulas

• No large clinical trials or long-term follow-upexists in children

• Various small studies have suggestedhealing rates superior to adults (>70%)following infliximab therapy

• Loss of response and recurrences ascommon as among adults

• No large clinical trials or long-term follow-upexists in children

• Various small studies have suggestedhealing rates superior to adults (>70%)following infliximab therapy

• Loss of response and recurrences ascommon as among adults

Crandall W et al, J Pediatr Gastroenterol Nutr 2009Di Bie CI et al, Inflamm Bowel Dis 2012Hyams J et al, Gastronenterology 2007

Surgical Management of Fistulizing Perianal Disease

Fichera A & Zoccali M, Inflamm Bowel Dis 2015

EUA

I&D, Drains, Setons

Fistulotomy, Glue, Plug,Setons, Advancement Flap

Proctectomy,Total Proctocolectomy

Sepsis control

Definitive surgical treatment

Resolution

Resolution

Failure

Failure

Management of Perianal Abscesses

Schwartz DA et al, Ann Intern Med 2001Fichera A & Zoccali M, Inflamm Bowel Dis 2015

Simple incision& drainage

Placement of mushroomcatheter

Noncutting seton

174

Fistulotomy for Simple FistulasFistulotomy for Simple Fistulas

• 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

• 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 studiesSandborn WJ et al Gastroenterology 2003DA Schwartz et al Ann Intern med 2001

ProbeExternalopening

Fistula

Open fistulatract

Anus

Setons Prevent Premature Fistula ClosureSetons Prevent Premature Fistula Closure

Schwartz DA et al Inflamm Bowel Dis 2014

Per

cent

age

of P

atie

nts

Response (p=0.14) Recurrence (p=0.001)

83%

100%

44%

79%

Response and Recurrence Rates Among Adults with Perianal Fistulas Treated with Infliximab +/- Setons

Response and Recurrence Rates Among Adults with Perianal Fistulas Treated with Infliximab +/- Setons

Regueiro M & Mardini H, Inflamm Bowel Dis 2003

175

Anal Fistula Plug

Bioabsorbable xenograftmade of lyophilized porcineintestinal submucosa

Infection resistant

No foreign body reaction

Within months becomespopulated with host celltissue

24-87% success rates instudies 6-12 months follow-up

Cook®Biodesign® Anal Fistula Plug

Rizzo JA et al Surg Clin N Am 2009

Fibrin GlueFibrin Glue

• Mixture of fibrinogen andthrombin & calcium

• Insoluble clot formed

• Believed to stimulatewound healing andinduce angiogenesis

• Discrepant findings havebeen reported in meta-analysis

• Mixture of fibrinogen andthrombin & calcium

• Insoluble clot formed

• Believed to stimulatewound healing andinduce angiogenesis

• Discrepant findings havebeen reported in meta-analysis

Citocchi R et al, Ann Ital Chir 2010Rizzo JA et al Surg Clin N Am 2009

Colorectalsurgeonsydney.com.au

Endorectal Advancement Flap

Ruffolo C et al Colorectal Dis 2010Fichera A & Zoccali M, Inflamm Bowel Dis 2015

• Success rates 40%->90% reported• Incontinence is a concern• Option for rectovaginal fistula

176

Yassin NA et al, Aliment Pharmacol Ther 2014

Combined Surgical and Medical Therapy Increases Perianal Fistula Healing

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

• 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

Outcome of Patients with Perianal Crohn’s Disease Undergoing Temporary Fecal Diversion

Outcome of Patients with Perianal Crohn’s Disease Undergoing Temporary Fecal Diversion

Fecal Diversionn=138

Successful Stoma Closuren=36

Persistent Stoman=102

Repeat DiversionN=6

Stoma Closuren=30

Indefinite Stoman=45

Permanent Stoman=63

Gu J et al, Colorectal Dis 2014

n=30

n=4

n=60

n=41

n=2

(22%) (33%) (45%)

Simple fistula without rectal inflammation

• Antibiotics and AZA/6MP

• Consider Anti-TNF

Proposed Treatment Algorithm for Simple Perianal FistulasProposed Treatment Algorithm for Simple Perianal Fistulas

Simple fistula with rectal inflammation

Antibiotics, AZA/6-MP& Anti-TNF

(consider monitoring healing with repeat imaging study)

1. Consider seton2. Fistulotomy3. Consider fibrin glue,

fistula plug or endorectaladvancement flap

4. If 1-3 fails, treat as complex fistula

Continue maintenance AZA/6-MP or Anti-TNF if

started

Treat as complex

fistula

Continue maintenance AZA/6-MP &

Anti-TNF

TreatmentFailure

TreatmentSuccess

TreatmentSuccess

TreatmentFailure

Schwartz DA et al, Inflamm Bowel Dis 2015; de Zoeten EF et al, J Pediatr Gastro Nutr 2013

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

177

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

Proposed Treatment Algorithm for Complex Perianal FistulasProposed Treatment Algorithm for Complex Perianal Fistulas

TreatmentSuccess

TreatmentFailure

Schwartz DA et al, Inflamm Bowel Dis 2015; de Zoeten EF et al, J Pediatr Gastro Nutr 2013

ComplexFistula

• Seton placement• Antibiotics, Anti

TNF, AZA/6-MP (consider monitoring

healing with repeat imaging study)

1. Remove seton2. Continue

maintenance AZA/6-MP & Anti-TNF

1. Consider tacrolimusin selected patientsOR

2. Proctocolectomy

Take Home Points for Perianal FistulizingCrohn’s Disease

Take Home Points for Perianal FistulizingCrohn’s Disease

• Use MRI and EUA for suspected disease todefine the anatomy

• Drain abscesses

• Use setons as required to control sepsis

• Treat proctitis/intestinal inflammation

• More definite surgical closure should beconsidered only after intestinal inflammationunder control

• Team approach: gastroenterologists, surgeonsand radiologists

• Use MRI and EUA for suspected disease todefine the anatomy

• Drain abscesses

• Use setons as required to control sepsis

• Treat proctitis/intestinal inflammation

• More definite surgical closure should beconsidered only after intestinal inflammationunder control

• Team approach: gastroenterologists, surgeonsand radiologists

178

“IT’S ALL ABOUT THAT POUCH…”EVALUATION & MANAGEMENT OF

COMPLICATIONS POST ILEAL POUCH ANAL ANASTOMOSIS

Joel R. Rosh, MDDirector, Pediatric Gastroenterology

Goryeb Children’s Hospital/Atlantic HealthProfessor of Pediatrics

Icahn School of Medicine, Mount Sinai School of Medicine

A “Tale” of Two Pouches:The Agony and the Ecstasy

Joel R. Rosh, MDDirector, Pediatric Gastroenterology

Goryeb Children’s Hospital/Atlantic HealthProfessor 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 andprevention 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”

Kelly KA. Advanced Therapy of IBD, 2001

So true when it all goes right…

180

Colectomy Risks

• Bleeding• Post‐op obstruction• Wound infection• Intra‐abdominal infection• Wound hernia• Thromboembolic events• Urinary retention

EIM After Surgery

Usually Resolve

• Peripheral arthritis• Uveitis• Thromboembolic

risk

May Not Resolve

• Skin– Erythema nodosum– Pyoderma

gangrenosum

• 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

} ~1 1/2 inches

Slide courtesy of Dr. Michael Harris

Creating the Pouch


Creating the Pouch

“J” “S” “K”

Tip of “J”

Afferent limb (neo-TI)

Efferent limb

Outlet/cuff/anal transitionalzone

Inlet

Efferent limb

Types of Ileal Pouch

Nipple valve

Slide courtesy of Dr. Bo Shen

182


Mucosectomy vs. 2 Staple IPAA

Disorders of the Ileal Pouch

FunctionalSurgical/Mechanical

Inflammatory/Infectious

• Anastomotic leak• Pelvic sepsis• Sinus• Fistula• Strictures.• Infecundity• Sexual dysfunction• Portal vein thrombi• Prolapse• Twist/volvulus

Pouchitis Cuffitis Crohn’s SBBO Inflammatory

polyps

Neoplastic

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

Irritable pouch Poor

compliance Pseudo-

obstruct megapouch “Pouchalgia

fugax”




• Anastomotic leak• Pelvic sepsis• Sinus• Fistula• Strictures• Infecundity• Sexual dysfunction• Portal vein thrombi• Prolapse• Twist/volvulus

Pouchitis Cuffitis Crohn’s SBBO Inflammatory

polyps

Neoplastic

Pouch/ATZ Neoplasia

Lymphoma Squamous

cell cancer

Systemic/Metabolic




compliance Pseudo-


fugax”


183





Pouchitis Cuffitis Crohn SBBO Inflammatory

polyps

Neoplastic

Pouch/ATZ Neoplasia

Lymphoma Squamous

cell cancer

Systemic/Metabolic




compliance Pseudo-


fugax”







polyps


compliance Pseudo-


fugax”

Neoplastic

Pouch/ATZ Neoplasia

Lymphoma Squamous

cell cancer

Systemic/Metabolic








Neoplastic

Neoplasia Lymphoma Squamous

cell cancer

Systemic/Metabolic


polyps


compliance Pseudo-


fugax”


def. Renal stone High PTH


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

Immune-MediatedPouchitis

Ischemic Pouchitis


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


186

Algorithm for Pouch Evaluation

Symptomatic Pouch Patients

Exclusion of Mechanical Complications

Inflammatory Disorders

Cuffitis Pouchitis Crohn’s Disease

Microbe-related Immune-mediated Ischemia-related


Symptomatic Pouch Patients

Exclusion of Mechanical Complications

Inflammatory Disorders

Cuffitis Pouchitis Crohn’s Disease

Microbe-related Immune-mediated Ischemia-related

PSC-associated

IgG4-associated

Autoimmune Disorder-

associated

AutoinflammatoryDisorder-

associated

Algorithm for Pouch Evaluation


Presacral Anastomotic Sinus

Lian L, et al. Endoscopy 2010;42 Suppl 2:E14Slide 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;117:3081–3092Colorectal Dis 2012;14:92–97Gastroenterology 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 dysplasia25X risk for prior colon cancer

Pouch Cancer: Dutch Study

• Conclusion—stratified by neoplasia history:– No prior history: limited surveillance program

– Prior history: targeted surveillance program


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

NASPGHAN2015 Postgraduate Course

Disclosures

Consultant/Advisory BoardAbbvie, Given Imaging, Janssen, Salix, Lilly, Pfizer, Prometheus, Takeda, UCB

Speaker for CME activities Abbvie, Janssen, Takeda, UCB

Grant supportCCFA, AHRQ (1R01HS021747-01)

Abbvie, Janssen, UCB, Salix

Intellectual propertyDartmouth-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

Medical Decision Making

Severity of illness

Benefits and Risks of

Treatment

Patient and Family Preferences

192

Hierarchy of Needs for the IBD Patient

Leaving the house, going to school or workAbility to eat and maintain weight

Staying AlivePatient focus

Physician focus

Just feel normalAvoid hospitals and surgery

Diarrhea, Bleeding, Pain, Fatigue, Incontinence

Endoscopic Remission

Clinical Remission

Histologic Remission

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 OneCorticosteroid-Free Clinical Remission at Week 50

All randomized patients (N=508)

p<0.001

p=0.028 p=0.035

41/170 59/169 78/169

Colombel, JF, et al. NEJM 2010

But we can’t forget about the tradeoffsWhat our patients hear (and see)…

Why are people so afraid?

Dread Risk

Unknown Risk

• Nuclear accidents

• 5-ASAs

• SteroidsNot DreadfulControllable

EquitableVoluntary

Known RisksObservable

Old Risk

DreadfulUncontrollableCatastrophicInvoluntary

Risk Unknown Not Observable

New Risk

Slovic P. Perception of Risk. Science 1987.

• Biologics and NEW drugs

• Immunomodulators• Downhill skiing

195

What are the most important side-effects of 6MP/Azathioprine?

Siegel CA, et al. APT 2005 (weighted average); Siegel CA, et al. CGH 2009Beaugerie et al, Lancet 2009;7:374.

EventFrequency Estimate

Stop therapy due to adverse event 11%

Allergic reactions 2%

Nausea 2%

Hepatitis 2%

Pancreatitis 3%

Serious infections 5%

Non-Hodgkin’s lymphoma0.04%-0.09% (4-

9/10,000)

Solid tumors and thiopurines in IBD(non-GI and non-skin cancers)

Study Types of cancer Number of patients

Statistically significant

Armstrong 2010 lung, breast 1955 NO

Fraser 2002breast, bronchial,

renal6262 NO

Connell 1994gastric, lung,

breast, cervical755 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

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

Event Estimated Frequency

Stop therapy due to adverse event 10%

Infusion or injection site reactions 3%-20%

Drug related lupus-like reaction 1%

Serious infections 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

Same Mono or Combo

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 2004Population

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

Siegel et al. Clin Gastroenterol Hepatol. 2006;4:1017-1024.

Risk of death from sepsis = 4/1000 pt-yrs

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

Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006; Toruner, Gastro 2008

Young “healthy” patients are not in the clear, but probably at much less risk

197

» 8905 patients representing 20,602 pt-years of exposure

» 13 Non-Hodgkin’s lymphomas

» Mean age 52, 62% male

» 10/13 exposed to IM* (really a study of combo Rx)

Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis

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

6.1 per 10,000 pt-years

Risk without medicationRisk of lymphoma with immune suppression

Risk of Developing non-Hodgkin’s LymphomaPatient receiving Immunomodulator +/- anti-TNF Therapy for 1 year

Siegel CA, Inflamm Bowel Dis 2010;16:2168.

What do we know about the risk of solid tumors and anti-TNF?

Type of Cancer Odds Ratio

All cancers 1.0 (0.8-1.2)

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)

» Rheumatoid arthritis

» 13,000 patients, ½ on biologics

Wolfe, Arthritis and Rheumatism 2007;56:2886.Mason, Inflamm Bowel Dis 2013;19:1306.

Type of study Associated risk

Population based651 patients

SIR 0.7 (0.2-1.7)

Single center734 patients

OR 0.97 (0.56-1.65)

» Inflammatory bowel disease

» Fairly limited data

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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 Risk with comparator SIR (95% CI)

Serious Infections35/1000

Immunomodulator 33/1000Prednisone 73/1000

1.06 (0.83-1.36)0.48 (0.40-0.58)*

Lymphoma2/10,000

Pediatric population 0.58/10,000Thiopurines 4.5/10,000Adults 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)

Dulai PS, et al. Clin Gastroenterol Hepatol. 2014;12:1443. Magro F et al. J Crohns Colitis 2014;8:31.

Scariest standard lymphomas are early postmononucleosis in EBV-seronegative young male.

Consider avoiding thiopurines in EBV-seronegative males

Funny how it’s easy to forget about prednisone

Event Estimated Frequency

Any side-effect leading to stopping prednisone

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 33%

Diabetes Chance increases 10x

Present IBD 2001, Rutgeerts APT 2001, Rutgeerts NEJM 1994

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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

Lichtenstein CGH 2006; Toruner, Gastro 2008

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)

Closer look at the Mayo experience with opportunistic infections

Herpes zoster \Candida albicans

Herpes SimplexCMV

EBVHistoplasmosis

BlastomycosisStreptococcus

E. ColiMycobacterium marinum

Mycobacterium fortuitumCryptococcus

Mycobacterium gordonae

2826

1812

82

11

11

11

1

Toruner et al. Gastro 2008;134:929

200

Number of meds Cases Controls OR 0 38 129 1.0 (ref)

1 38 59 2.9 (1.5-5.3)2 or 3 24 12 14.5 (4.9-43)

Specific combinations

Corticosteroids alone 16 27 2.2 (1.0-4.9)6MP/AZA alone 20 31 3.4 (1.5-7.5)

IFX alone 3 2 11.1 (0.8-148) AZA/6MP + steroids 16 6 17.5 (4.5-68)

AZA/6MP + IFX 1 5 1.6 (0.1-19) AZA/6MP + IFX + steroids 5 0 1.1 (1.0-1.2)

Closer look at the Mayo experience with opportunistic infections

Toruner et al. Gastro 2008;134:929

COMMIT and SONIC Safety Results

AZA+ placebo(n=161)

IFX+ placebo(n=163)

IFX+ AZA

(n=179)

Total

(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%)

Serious infections 8 (5.0%) 4 (2.5%) 6 (3.4%) 18 (3.6%)

COMMIT

SONIC

Feagan et al. Digestive Disease Week, San Diego, CA 2008. Sandborn, WJ et al. ACG 2008

MTX (n=63

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%

012345678

0-2 >2 to 4 >4 to 6 >6 to 8 >8 to10

>10

Nu

mb

er o

f ca

ses

Years exposure prior to HSTCL

Anti-TNF + Thiopurine

0

1

2

3

4

5

6

0-2 >2 to 4 >4 to 6 >6 to 8 >8 to10

>10

Nu

mb

er

of

case

s

Years exposure prior to HSTCL

Thiopurine only

N=19 N=11

Kotlyar et al. Clin Gastroenterol Hepatol. 2011;9:36. Magro F et al. J Crohns Colitis 2014;8:31.

Risk of HSTCL is related to duration of thiopurine use

Estimated risk in “at risk” group with combo ≈ 1-3/10,000

Consider this: Even in young males Induce with our “best” therapy (thiopurine + anti-TNF) and stop thiopurine after 6-12

months when in deep remission

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

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.

BOTH show that treatment decreases chance of Heart Attack from 4.1% 2.7%

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

Ma

xim

al

Acc

ep

tab

le R

isk

(An

nu

al %

)

0

0.1

0.2

0.9

1.0

0.5

0.6

0.7

0.8

Moderate to Mild

Moderate to Remission

Severe to Mild Severe to Remission

Severe to Moderate

0.4

0.5

Patients are Willing to Take High Risks in Exchange for Improved Health

Johnson et al. Gastroenterology 2007.

Serious infection

Lymphoma

PML N = 580

Risk of dying from side-effect all < 1 per 1000

203

Parents are willing to take even higher risks of lymphoma…but only if their kids are sick!

0

0.2

0.4

0.6

0.8

1

1.2

Severe to Remission Moderate to Mild

Maximal Acceptable

Risk of Lymphoma

(%)

Adult patients

Parents

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

Surgical Options for UC

Medical Therapy for UC

Option Gridshttp://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

Frequently Asked Questions

ImmunomodulatorAzathioprine (Imuran, Azasan);

6-mercaptopurine (6MP, Purinethol), Methotrexate

Anti-TNFInfliximab (Remicade); Adalimumab (Humira);

Certolizumab pegol (Cimzia)

Combination Therapy

What type of medication is this?

An immunomodulator is a medicine that is taken to regulate or quiet down

the immune system which then decreases inflammation.

An anti-tumor necrosis factor (TNF) drug blocks one specific chemical (TNF) in the body. Blocking TNF

regulates or quiets down the immune system which then decreases

inflammation.

Using an immunomodulator and an anti-TNF drug together.

How is this treatment administered?

Daily, as a pill (azathioprine or 6MP), or weekly as a pill or shot

(methotrexate). It may take weeks to months to be fully effective, so your

doctor may prescribe a steroid, such as prednisone, to start.

Infliximab is given intravenously (injected into the vein) three times in the

first 6 weeks, then every 6-8 weeks. Adalimumab is given subcutaneously (injected under the skin) every other

week, and Certolizumab is given subcutaneously monthly. These

medications act faster than immunomodulators, so you likely won’t

need steroids.

Daily pills (or weekly shots if methotrexate) PLUS injections either

intravenous (into the vein) or subcutaneous (under the skin).

After 6 months of treatment, how many

people get relief of their symptoms and don’t need steroids (e.g.,

prednisone)?

There are no research studies in children directly comparing immunomodulators to anti-TNF drugs to combination therapy. But, we do have good estimates based on research in children and adults for each of these options.

Approximately 40 people out of 100 (40%).



What are some common, but short-lasting, side

effects?

Approximately 3 people out of 100 (3%) develop pancreatitis, where the

pancreas becomes inflamed and painful. Other short-term side-effects may include nausea, fever, fatigue,

lowering of the white blood cell count, or increase in liver tests.

Allergic reactions like a rash or shortness of breath from an infusion, or pain or swelling at the injection site can

occur.

With combination therapy, possible to get side effects from both

immunomodulators and anti-TNF drugs.

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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

ImmunomodulatorAzathioprine (Imuran, Azasan);

6-mercaptopurine (6MP, Purinethol), Methotrexate

Anti-TNFInfliximab (Remicade); Adalimumab (Humira);

Certolizumab pegol (Cimzia)

Combination Therapy

How common are serious infections?

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%).

If side-effects occur, it might be possible to stop one of the medications

and continue the other.

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.

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

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Documents

Postgraduate Course Syllabus