Pediatric Inflammatory Bowel Disease

Foreword
Preface
Contents
Contributors
Part I: Etiology and Pathogenesis
1: Genetics of Inflammatory Bowel Diseases
Introduction
Genetic Epidemiology
Ethnic and Racial Variations of Disease
Family Studies
Twin Studies
NOD2 Gene and Crohn Disease
Epidemiology of NOD2 Mutations
Human Leukocyte Antigens in Ulcerative Colitis
Genome-Wide Association Studies in IBD
IL23R Polymorphisms in Crohn Disease and Ulcerative Colitis
Association of the ATG16L1 Autophagy Gene with Crohn Disease
Non-Coding Variation
Meta-Analysis
GWAS Meta-Analysis in Ulcerative Colitis
Association of TNFRSF6B and IL27 with Pediatric Age of Onset IBD
Impact of the Immunochip
Trans-ancestry Association Studies
Next-Generation Sequencing
Sequencing in High-Risk Individuals and Families
Next-Generation Sequencing in Research
Risk Prediction
Genotype-Phenotype Correlations in Pediatric IBD
Genetic Sharing Between Pediatric Age of Onset IBD and Other Autoimmune Diseases
Summary
References
2: Immunologic Regulation of Health and Inflammation in the Intestine
Introduction
The Anatomy of the Intestinal Immune System
The Intestinal Epithelium: Structure and Functional Subsets
Epithelial Cell Function: Interlinked Connection with Microbiome and Dysfunction in IBD
Gut-Associated Lymphoid Tissues
Compartmentalized Gut Lymph Node Drainage
Innate Immune Cell-Dependent Regulation of Intestinal Health
Dendritic Cells
Macrophages
Granulocytes: Neutrophils, Eosinophils, Basophils, and Mast Cells
Adaptive Immunity and Their Contribution to Intestinal Health and Inflammation
T-cells
B-cells
Essential Immunologic Pathways that Regulate Intestinal Health
Innate Lymphoid Cell-Dependent Regulation of Intestinal Health
Causes and Immunologic Drivers of Intestinal Inflammation in Humans
Understanding Intestinal Immunity and IBD in Children
Summary
References
3: Cytokines and Inflammatory Bowel Disease
Introduction
Pro-Inflammatory Cytokines
Tumor Necrosis Factor-Alpha
Interferon-gamma
Interleukin-1
Interleukin-2
Interleukin-6
Interleukin-12
Interleukin-17
Interleukin-23
Interleukin-18
Interleukin-13
Interleukin-33
Interleukin-37
Interleukin-9
Tumor Necrosis Factor-Like Ligand (Tl1a)
Anti-Inflammatory Cytokines
Transforming Growth Factor-Beta
Interleukin-4
Interleukin-10
Interleukin-22
Summary
References
4: The Gut Microbiota and Inflammatory Bowel Disease
Introduction
Characteristics of the Gut Microbiome
Characteristics of the Gut Metabolome
Diet and the Gut Microbiome
Gut Microbiota–Host Interactions at the Mucosal Interface
The Innate Immune System
The Adaptive Immune System
The Intestinal Epithelium
IBD and the Human Gut Microbiome
Diet, IBD, and the Gut Microbiome
The Gut Microbiota as a Therapeutic Strategy
Probiotics and Prebiotics
Enteral Nutrition Therapy
Bacterial Engineering
Fecal Transplantation
Conclusions
References
5: Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease
Introduction
Genomics and VEO-IBD
Clinical Presentation of Very Early-Onset (VEO) IBD
Genetic Variants Associated with VEO-IBD and Their Immunologic Consequences
Genetic Variants Influencing Intestinal Epithelial Barrier Function
Genetic Variants Impairing Development of the Adaptive Immune System
Genetic Variants Impairing Regulatory T cells
Genetic Variants in the IL-10-IL-10R Pathway and Related Cytokine Family Members
Genetic Variants Influencing Bacterial Recognition and Clearance
Autoimmune and Autoinflammatory Disorders
Immunologic Considerations
Perspective and Future Directions in Genetic and Immunologic Analyses of VEO-IBD
References
Part II: Epidemiology and Clinical Features
6: The Epidemiology of Pediatric Inflammatory Bowel Disease
Introduction
Incidence and Prevalence
Changes in Incidence and Prevalence Over Time
Projecting the Future Epidemiology of Pediatric Inflammatory Bowel Disease
Changing Age at Inflammatory Bowel Disease Diagnosis
Ethnocultural Differences in the Epidemiology of Inflammatory Bowel Disease
Environmental Risk Factors
The Hygiene Hypothesis
Breastfeeding
Cesarean Section
Infectious Diseases and Antibiotic Use
Exposure to Cigarette Smoke
Urban Environments, Air Pollution, and Residential Greenspace
Diet
Association vs. Causation
Gaps in Knowledge and Challenges in Determining the Global Epidemiology of Pediatric Inflammatory Bowel Disease
Conclusions
References
7: The Natural History of Crohn Disease in Children
Introduction
Disease Activity
Evolution of Disease Phenotype
Growth
Corticosteroid Dependence
Surgery
Postoperative Recurrence
Cancer Risk
Quality of Life
References
8: Natural History of Ulcerative Colitis in Children
Introduction
Overview
Aminosalicylates
Corticosteroids
Immunomodulators
Biologics
Small Molecules
Antibiotics
Can We Predict the Course of Disease?
Summary
References
9: Pediatric Inflammatory Bowel Disease: Unclassified
Introduction
Definition
Epidemiology
Diagnosis
Clinical Features
Endoscopic Evaluation
Small Bowel Imaging
Medical Management
Surgical Management
Conclusion
References
10: Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease
Introduction
Growth Failure
Joint Manifestations
Bone Disease
Oral Lesions
Skin Lesions
Eye Lesions
Liver Disease
Other Extraintestinal Manifestations
Hematologic Abnormalities
Vascular
Pancreatitis
Renal
Pulmonary
Neurologic
Cardiac
Summary
References
11: Liver Disease in Pediatric Inflammatory Bowel Disease
Introduction
Abnormal Liver Chemistry
Primary Sclerosing Cholangitis
Epidemiology and Pathogenesis
Primary Sclerosing Cholangitis and IBD
Diagnosis
Outcomes
Treatment
Other Autoimmune Liver Diseases
Autoimmune Hepatitis
Epidemiology and Pathogenesis
Diagnosis
Outcomes and Treatment
Autoimmune Sclerosing Cholangitis
Epidemiology and Pathogenesis
Diagnosis
Outcomes and Treatment
IgG4-Associated Cholangitis
Drug Hepatotoxicity (Table 11.2)
Methotrexate
Thiopurines
Antitumor Necrosis Factor-α (Anti-TNFα)
Other Biologics and Small Molecules
Sulfasalazine and Mesalamine
Glucocorticoids
Hepatosplenic T-Cell Lymphoma
Other Liver Diseases and IBD
Cholelithiasis
Liver Abscess
Portal Vein Thrombosis and Budd-Chiari Syndrome
Non-Alcoholic Fatty Liver Disease
Granulomatous Hepatitis
Hepatic Amyloidosis
A Clinical Approach to Children with IBD and Liver Abnormalities
References
12: Growth Impairment in Pediatric Inflammatory Bowel Disease
Normal Growth and Pubertal Development
Normal Growth Patterns
Normal Growth Physiology
The GH/IGF-1 Axis
The Somatomedin Hypothesis
Growth Hormone and IGF-1
Gender Differences in the GH/IGF-1 Pathway
Insulin-Like Growth Factor Binding Proteins (IGFBPs)
Growth Plate Proliferation, Senescence, and Fusion
Monitoring and Assessment of Growth
Definitions of Impaired Growth
Growth in Pediatric IBD
Prevalence of Growth Impairment in IBD
Crohn Disease
Ulcerative Colitis
Sex Differences in Linear Growth Impairment
Pathophysiology of Growth Impairment in IBD
Chronic Caloric Insufficiency
Direct Cytokine Effects
Disruption of the GH/IGF-1 Axis
IGF-1 Independent Mechanisms
The Role of IL-6 in Growth Impairment
The Interplay Between Nutrition And Cytokines
Disruption of the GH/IGF-1 Axis by Cytokine-Independent Molecular Pathways
Interaction Between the Gut Microbiome and the GH/IGF-1 Axis
Corticosteroid Suppression of Linear Growth
The Pathogenesis of Pubertal Delay and Its Influence on Growth Impairment
Influence of Genetic Factors
Facilitation of Normal Growth in IBD
The Importance of Prompt Recognition of IBD
The Importance of Monitoring Growth
Psychosocial Impact of Impaired Growth
General Principles of Management
Anti-Inflammatory Treatments and Effects on Growth
Enteral Nutrition
Corticosteroids
Immunomodulatory Drugs
Anti-Tumor Necrosis Factor-Alpha (Anti-TNFα)
Surgery
Hormonal Interventions
Summary
References
13: Inflammatory Bowel Diseases and Skeletal Health
Introduction
Growth and Bone Modeling and Remodeling
Measurement of Bone Mass
Bone Cells and Inflammation
Osteocytes
Osteoclasts and the RANKL/OPG System
Osteoblasts
T-Cells and Bone Loss
Novel Pathogenic Pathways in IBD: Osteoimmune Connections
The Gut Microbiome and Bone Health
Effects of Intestinal Inflammation on Bone
Animal Models
Human Studies
Osteoporosis and Fractures in Pediatric IBD
Treatment
Conclusions
References
14: Puberty and Pediatric-Onset Inflammatory Bowel Disease
The Pubertal Process in Healthy Children and Adolescents
The Influence of IBD on Puberty
Potential Causes of Pubertal Delay in IBD
Nutritional Causes of Pubertal Delay
Endocrine Aspects of Pubertal Delay
Proinflammatory Cytokines–Endocrine Interactions
Psychosocial Issues and Puberty
Therapeutic Approach to Addressing Pubertal Issues in IBD
References
15: Classification of Pediatric Inflammatory Bowel Disease
Introduction
Phenotypic Classification of IBD: A Historical Perspective
The Vienna Classification [14]
The Montreal Classification [15]
The Paris Modification of the Montreal Classification for Pediatric IBD [10]
Novel Features of the Paris Classification
The Porto Criteria and the Revised Porto Criteria
IBD-unclassified (IBD-U) and PIBD Classes
Special Considerations
Evolution of Disease Phenotype
Future Directions
References
Part III: Diagnosis
16: The History and Physical Exam
Introduction
History
Physical Exam
Summary
References
17: Differential Diagnosis of Inflammatory Bowel Disease
Acute Onset Diarrhea
Intestinal Infection
Food Allergy
Acute Appendicitis
Chronic or Recurrent Intestinal Symptoms
Intestinal Infection
Celiac Disease
Eosinophilic Gastroenteropathy
Primary or Acquired Immunodeficiency Diseases
Intestinal Neoplasm
Vasculitis Disorders
Abdominal Mass
Isolated Esophagogastroduodenal Involvement
Isolated Perineal Disease
References
18: Laboratory Evaluation of Inflammatory Bowel Disease
Introduction
Blood Tests
Anemia
Acute Phase Reactants: Platelets
Acute Phase Reactants: Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) and Other Markers
Other Laboratory Evaluations
Specific Blood Tests: Inflammatory Bowel Disease Serologies
Stool Evaluation
Fecal Calprotectin
Summary
References
19: Fecal Markers in Inflammatory Bowel Disease
Introduction
Overview of Stool Tests
Introduction to Calprotectin
Fecal Calprotectin Collection
Cuffoff Levels
Reliability, Sensitivity, and Specificity
Fecal Calprotectin as a Screening Tool
Fecal Calprotectin Comparison to Endoscopy
Fecal Calprotectin and Comparison to MRI
Fecal Calprotectin and Disease Location
Fecal Calprotectin Use to Monitor Pediatric Inflammatory Bowel Disease
Fecal Calprotectin to Evaluate Post-Operative Recurrence
Fecal Calprotectin to Evaluate for Pouchitis
Fecal Calprotectin to Predict Mucosal Healing
Fecal Calprotectin to Predict Histologic Remission
Fecal Calprotectin to Predict Relapse
Fecal Calprotectin as a Marker of Tight Control—CALM Study
Fecal Calprotectin Recommendations in Clinical Guidelines (Table 19.3)
Summary
References
20: Radiologic Evaluation of Pediatric Inflammatory Bowel Disease
Introduction to Imaging
Crohn Disease
Ulcerative Colitis
Radiographs
Fluoroscopic Examinations
Ultrasound and Contrast-Enhanced Ultrasound of the Bowel
Computed Tomography Enterography (CTE)
CTE Features of CD
CTE Features of UC
Magnetic Resonance Enterography (MRE)
MRE Features of CD
MRE Features of UC
Nuclear Medicine Imaging Studies
White Blood Cell Scans
PET and PET-MR Examinations
Imaging of Complications
Perianal Disease
Stricture
Penetrating Disease—Intraabdominal Abscesses and Enteric Fistulas
Toxic Megacolon
Bowel Obstruction/Perforation
Imaging of Extraintestinal Manifestations
Musculoskeletal System
Hepatobiliary Disease
Urolithiasis
Interventional Radiology in IBD
Percutaneous Abscess Drainage
Additional Applications of Interventional Radiology
Conclusion
References
21: Endoscopy and Inflammatory Bowel Disease
Introduction
Endoscopy: Background History
Patient Preparation
Antibiotic Prophylaxis
Bowel Preparation
Monitoring and Sedation
Endoscopic Techniques in Inflammatory Bowel Disease
Upper Gastrointestinal Endoscopy
Ileocolonoscopy
Equipment
Ileocolonoscopy Basic Technique
Getting Started and Patient Positioning
Practical Tips in Ileocolonoscopy
Rectal Intubation
Sigmoid and Descending Colon
Splenic Flexure and Transverse Colon
Hepatic Flexure and Ascending Colon
Cecum
Ileal Intubation and Its Importance
Ileum
Endoscope Withdrawal
Dilatation of Strictures
Complications of Ileocolonoscopy
Small Bowel Assessment
Wireless Capsule Endoscopy
Enteroscopy
Push Enteroscopy
Instruments and Technique
Double-Balloon Enteroscopy
Instruments and Technique
Endoscopic Findings in Inflammatory Bowel Disease
Ulcerative Colitis
Crohn Disease
Inflammatory Bowel Disease-Undefined (IBD-U)
Follow-Up and Surveillance Ileocolonoscopy
Treatment Targets
Scoring Systems for Endoscopic PIBD Disease Activity
Endosonography
New Endo-Diagnostic Methods
High-Magnification Chromoscopic Colonoscopy (HMCC)
Confocal Laser Endomicroscopy
Therapeutic Endoscopy in IBD
Colon Capsule Endoscopy
Conclusions
References
22: The Pathology of Chronic Inflammatory Bowel Disease
Major Histologic Features Noted in Mucosal Specimens
Preparation and Procedure-Induced Artifacts
Histologic Patterns in Colitis
Acute Self-Limited Colitis and its Distinction from IBD
Histologic Features of Early IBD
Very Early-Onset IBD
Characteristic Features of Ulcerative Colitis and Crohn Disease
“Atypical” Features in the Diagnosis of Ulcerative Colitis
Rectal Sparing and Patchiness
Backwash Ileitis
Upper GI Tract Involvement in UC
Periappendiceal Inflammation in Ulcerative Colitis
Fulminant and Indeterminate Colitis
Pouchitis
References
23: Capsule Endoscopy in Pediatric Inflammatory Bowel Disease
Introduction
Indications
Small Bowel Capsule Endoscopy in IBD
Inflammatory Bowel Disease Undetermined and Ulcerative Colitis
Pan-Enteric Capsule Endoscopy
Monitoring the Mucosa
Capsule Topics of Interest
Contraindications to Capsule Endoscopy
Swallowing the Capsule/Endoscopic Placement for Those Who Cannot Swallow
Bowel Preparation
Interpretation and Scoring Methods
Capsule Retention and Incomplete Procedures
Patency Capsule
Conclusion
References
24: Bone Health in Pediatric Inflammatory Bowel Disease
Introduction
Skeletal Modeling and Bone Accrual During Childhood
Changes in Cortical and Trabecular Bone with Growth
Biochemical Markers of Bone Metabolism
Potential Threats to Bone Health in Pediatric IBD
Malnutrition
Decreased Muscle Mass and Biomechanical Loading of the Skeleton
Glucocorticoid-Induced Osteopenia
Inflammation and Bone Loss
Assessment of Bone Status in Children and Adolescents
Classification of Bone Health and Relation to Fracture Risk
Limitations of DXA in Children and Adolescents
Peripheral Quantitative Computed Tomography
Clinical Studies of Bone Health in Pediatric IBD
Accounting for Body Size Differences
Glucocorticoid Effect
Impact of Disease Activity
Longitudinal Studies
Potential Therapies for Bone Health in Pediatric IBD
Physical Activity
Vitamins and Minerals
Bisphosphonates
Summary
References
Part IV: Medical Therapy
25: 5-Aminosalicylate Therapy
Introduction
Mechanism of Action
Pharmacokinetics
Indications and Efficacy
Ulcerative Colitis
Crohn Disease
Surgically Induced Remission of Crohn Disease and Prevention of Postoperative Recurrence
Chemoprevention of Colorectal Carcinoma
Side Effects
Adherence
Conclusion
References
26: Antibiotic Therapy
Introduction
Antibiotic Use in Crohn Disease
Active Crohn Disease
Anti-MAP Therapies
Perianal Disease
Postoperative Recurrence of Crohn Disease
Antibiotics in Active Ulcerative Colitis
Antibiotics in Extra-Intestinal Manifestations of IBD
Additional Considerations
Summary
References
27: Nutritional Management of Inflammatory Bowel Disease
Introduction
Nutritional Impairment in Pediatric Inflammatory Bowel Disease
Dietary Intake and Body Composition in Children with IBD
Dietary Intake
Body Composition
Micronutrient Deficiencies
Elevated Body Mass Index in Inflammatory Bowel Disease
General Management of Nutrition in Inflammatory Bowel Disease
Monitoring Nutritional Status
History of the Use of EEN in CD
Postulated Mechanisms of Action of EEN in CD
The Intestinal Microbiota
Anti-Inflammatory Activities of Enteral Formulae
Epithelial Barrier Function
Effectiveness of Exclusive Enteral Nutrition Therapy in Crohn Disease
Induction of Remission
Comparative Effectiveness of Nutritional and Biological Therapy
Maintenance of Remission
Maintenance of Remission with EN in Adults
Maintenance of Remission with EN in Pediatrics
EN in Combination with Medical Therapy
Repeated EEN and Long-Term Outcomes of Therapy
Additional Effects and Proof of Efficacy of EEN
EEN and Mucosal Healing
EEN and Changes in Fecal Markers of Inflammation
EEN: Nutritional Status and Growth
EEN and Bone Health
EEN and Quality of Life
Pre-/Postoperative Effects
Adverse Effects of Enteral Nutrition
Factors Affecting Response to EEN
Disease-Related Factors
Disease Duration
Disease Location
EEN-Related Factors
Polymeric Versus Elemental/Semi-Elemental Diets
Fat Composition
Exclusive Versus Partial EN (PEN)
Duration of Therapy
Predicting the Response to EEN
Delivery of EEN
Route of Administration of EEN
Approach to Reintroduction of Normal Diet
Geographic Variability and Barriers to Utilization of EEN
Conclusion
References
28: 2021 Corticosteroids
Introduction
The Working Mechanism of Corticosteroids
Systemic Corticosteroids
Topical Corticosteroids
Pharmacokinetics
Topical Steroid Formulations
Efficacy of Oral Budesonide Treatment in Crohn Disease
Side Effects of Budesonide in Children
Maintenance Treatment in Crohn Disease
Budesonide in Ulcerative Colitis
Conclusion
References
29: Mercaptopurine Therapy
Introduction
6-Mercaptopurine Metabolism
Efficacy of Thiopurines in Crohn Disease
Efficacy of Thiopurines in Ulcerative Colitis
Thiopurines and Mucosal Healing
Clinical Indication
Thiopurines in Combination with Anti-TNF
Postoperative Prophylaxis
Testing for TPMT Deficiency
Monitoring of Thiopurine Metabolite Levels
Thiopurine Toxicity
Thiopurines and Risk of Malignancy
Conclusion
References
30: Methotrexate
Introduction
Mechanism of Action
Efficacy
Dose and Administration
Toxicity and Monitoring
References
31: Infliximab Therapy for Pediatric Crohn Disease and Ulcerative Colitis
Introduction
Crohn Disease
Infliximab Is Within REACH for Pediatric CD
Early Use of Infliximab
Combination Therapy Versus Infliximab Monotherapy
Proactive Therapeutic Drug Monitoring and Treat-to-Target in CD
Infliximab Concentration Detection Methods
Incidence of Primary and Repeat Abdominal Surgeries in the Infliximab Era
Ulcerative Colitis
Infliximab in Moderate to Severe UC
Infliximab in Refractory UC
Therapeutic Drug Monitoring and UC
Infliximab and the Incidence of Surgery in Pediatric UC
Infliximab Biosimilars
Infliximab Safety Profile
Infusion Reactions
Rapid (One-Hour) Infusions
Infections
Vaccination
Malignancy
Mortality
Summary
References
32: Anti-TNF Therapies Other Than Infliximab for the Treatment of Pediatric Inflammatory Bowel Disease
Introduction
Therapeutic Efficacy and Pivotal Trials
Adalimumab
Efficacy of Adalimumab in Pediatric CD Patients
Efficacy of Adalimumab in Pediatric UC Patients
Efficacy of Adalimumab in Pediatric Patients Exposed to Infliximab
Efficacy of Adalimumab in Adult Patients
Certolizumab
Efficacy of Certolizumab in Pediatric Patients
Efficacy of Certolizumab in Adult Patients
Efficacy of Certolizumab in Adult Patients with Previous Infliximab Exposure
Golimumab
Efficacy of Golimumab in Pediatric Patients
Efficacy of Golimumab in Adult Patients
Additional Clinical Endpoints
Growth and Bone Health
Quality of Life
Postoperative Prophylaxis
Optimizing the Use of Adalimumab, Certolizumab Pegol, and Golimumab
Treat to Target
Combination Therapy
Therapeutic Drug Monitoring
Comparative Effectiveness
Safety Data
Malignancy
Infection
Postoperative Infections
Novel Viral Infections
Immune Reactions (TNFα-Induced Psoriasis, Drug-Induced Lupus, Auto-Immune Hepatitis)
Biosimilars
Future Directions
References
33: Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease
Introduction
Thiopurine Monitoring
Anti-TNF Drug Concentrations
Anti-TNF Drug Antibodies and Outcomes
Immunomodulator Use with Anti-TNF Agents
Proactive Dose Optimization
Practical Use of TDM with Anti-TNF Agents
TDM with Vedolizumab and Ustekinumab
Vedolizumab
Ustekinumab
Conclusion
References
34: New Non-anti-TNF-α Biological Therapies for the Treatment of Inflammatory Bowel Disease
Introduction
Cytokine Targets
IL-12/IL-23
Ustekinumab
Pediatric Data
Safety
Briakinumab
Selective IL23 Inhibition
Brazikumab
Pediatric Data
Safety
Risankizumab
Pediatric Data
Safety
Mirikizumab
Pediatric Data
Safety
Guselkumab
IL-6
Pediatric Data
Safety
IL-13
Tralokinumab
Pediatric Data
Safety
Dectrekumab
Pediatric Data
Bertilimumab
Pediatric Data
IL-17
Vidofludimus
Pediatric Data
Safety
IL-21
ATR-107
NNC0114-0006
Pediatric Data
Blockade of the Downstream Signaling Pathways Mediated by Cytokines
JAK/STAT Pathway
Tofacitinib
Pediatric Data
Safety
Filgotinib
Pediatric Data
Safety
Upadicitinib
Pediatric Data
Safety
Peficitinib
Pediatric Data
Safety
TD-1473
TGF-β
Mongersen
Pediatric Data
Safety
Targeting Chemokines
Anti CXCR3/CXCL10
BMS936557 (MDX-1100, Eldelumab)
Pediatric Data
Safety
Anti CCR9/CCL25
Vercirnon (CCX282-B)
Pediatric Data
Safety Data
Antiadhesion Molecules
Natalizumab
Pediatric Data
Safety
Vedolizumab (MLN-002, MLN-02, Entyvio®)
Pediatric Data
Safety
Etrolizumab (rhuMAb β7)
Pediatric Data
Safety
Ontamalimab
Pediatric Data
Safety
AJM300
Pediatric Data
Safety
Alicaforsen
Pediatric Data
Safety
Abrilumab
Pediatric Data
Firategrast
Pediatric Data
TRK-170
Pediatric Data
GLPG0974
Pediatric Data
Administration of Anti-Inflammatory Cytokine
Interleukin-10 (IL-10)
Pediatric Data
Safety
Blockade of T Cell Stimulation and Induction of Apoptosis
Laquinimod
Pediatric Data
Safety
Cobitolimod (DIMS0150)
Safety Data
Pediatric Data
Monarsen
Pediatric Data
Safety
Sphingosine-1-Phosphate Receptor Modulators
Etrasimod
Pediatric Data
Safety
Ozanimod
Pediatric Data
Safety
Oligonucloetides
GATA3 DNAzyme
STNM01
Miscellaneous Agents
Apremilast (CC-10004)
RDP58 (Delmitide Acetate)
LT02
LYC-30937-EC
TOP-1288
GSK2982772
Rosiglitazone
VB-201
Summary
References
35: Medical Treatment of Perianal Crohn Disease
Background
Case
Classification
Pathogenesis
Natural History
Diagnosis
Medical Therapy of Fistulas
5-Aminosalicylic Acid Derivatives
Corticosteroids
Antibiotics
Azathioprine/6-Mercaptopurine/Methotrexate
Tacrolimus
Cyclosporin A
Infliximab
Adalimumab and Certolizumab Pegol
Other Anti-TNF-α Agents
Vedolizumab
Other Therapies
Conclusions
References
36: Treatment of Acute Severe Ulcerative Colitis
Case
Introduction
Initial Management
Monitoring Response to Corticosteroids
Medical Rescue Therapy
Surgery
Future Directions/Conclusions
References
37: Dietary Therapies for Inflammatory Bowel Disease
Introduction
Diet and Worldwide Trends in IBD
Diet and the Gut Microbiota
Dietary Components and IBD
Macronutrients
Fat
Carbohydrates
Micronutrients and Trace Minerals
Food Additives
Oral Supplements
Curcumin
Iron
Probiotics
Structured Diets
Exclusive Enteral Nutrition
Partial Enteral Nutrition
Parenteral Nutrition
Exclusion Diets
CD-TREAT: Crohn Disease Treatment-with-EATing
Specific Carbohydrate Diet
IBD Anti-inflammatory Diet
Crohn Disease Exclusion Diet
Semi-Vegetarian Diet
Low-FODMAP Diet
Gluten-Free Diet
The Paleolithic Diet
Conclusion
References
38: Integrative Health Therapies for Pediatric IBD
Introduction
Integrative Health Use in IBD
Biologically Based Therapies for the Treatment of IBD
Herbal Therapies
Aloe Vera
Triticum aestivium
Andrographis paniculata
Jian Pi Ling
Oenothera biennis
Curcumin
Boswellia
Artemisia absinthium
Tripterygium wilfordii Hook F (TWHF)
Belladonna
Cannabis
Indigo naturalis
Non-herbal Therapies
Fatty Acids
Fish Oil (Omega-3 FFA)
Blond psyllium
N-Acetyl Glucosamine (NAG)
Chitosan
Bromelain
Rutin
Rectal Enema Therapies
Kui Jie Qing (KJQ)
Xilei-San
Bovine Colostrum
Dietary Therapy and Probiotics
Mind Body Therapies for Pediatric IBD
Yoga
Mindfulness and Meditation
Acupuncture and Moxibustion
Exercise and Sleep
Conclusion
References
Part V: Surgical Therapy
39: Management of Intraabdominal Complications of Inflammatory Bowel Disease
Introduction
Intraabdominal and Pelvic Abscess
Pathogenesis
Evaluation
Treatment
Antimicrobial Therapy
Percutaneous Interventional Drainage
Surgical Intervention
Percutaneous Versus Surgical Drainage
Treatment of Phlegmon (Inflammatory Mass)
Crohn Disease-Specific Therapy
Nutritional Considerations
Summary
Other Complications from Internal Penetrating CD
Perforation
Small Bowel Obstruction
Toxic Megacolon
References
40: Surgical Management of Crohn Disease in Children
Introduction
History of Surgical Therapy
Prognostic Indicators and Operative Indications
Surgical Emergencies
Elective Surgery
Surgical Therapy
Small Intestinal or Ileo-colonic Disease
Stricturoplasty
Laparoscopy
Colonic Disease
Perianal Disease
Rectal Strictures
Impact of Medical Therapy
Post-operative Recurrence
Early Recurrence Predictors
Adjuvant Procedures
References
41: Surgical Treatment of Ulcerative Colitis
Indications for Surgical Intervention
Surgical Procedures
Surgical Decision Making
Preparation for Surgery
Outcomes of Surgery
Functional Results
Complications
Pouchitis
Carcinoma
Current Trends and Future Considerations
Summary
References
42: Postoperative Surveillance and Management of Crohn Disease
Risk and Diagnosis of Postoperative Crohn Disease
Risk Factors for Postoperative Recurrence
Risk Stratification for Postoperative Recurrence
Nonbiologic Treatment Options for Preventing Postoperative Crohn Disease
Anti-TNFs for Prevention of Postoperative Crohn Disease
Safety of Postoperative Anti-TNFs
Enteral Nutrition for Postoperative Crohn Disease
Treating Postoperative Crohn Disease: Waiting for Endoscopic Recurrence
Strategies for Postoperative Crohn Disease Management
Conclusions
References
43: Perioperative Immunosuppression in Inflammatory Bowel Disease
Introduction
Effects of Immunosuppression on Operative Outcomes in Pediatric Populations
Glucocorticoids
Immunomodulators
Monoclonal Antibodies
Clinical Recommendations
Conclusion
References
44: Pouchitis and Pouch-Related Complications
Introduction
Pouch Anatomy
Pouch Function
Pouchitis
Definition and Incidence
Etiology and Pathogenesis
Fecal Stasis and Dysbiosis
Immune Dysregulation
Mucosal Ischemia
Crohn Disease of the Pouch
Extraintestinal Manifestations
Cuffitis
Smoking
Diagnosis
Classification
Treatment
Prophylaxis
Acute Pouchitis
Chronic Pouchitis
Surgical
Outcome
Noninflammatory Pouch-Related Complications
Irritable Pouch Syndrome
Floppy Pouch Complex
Fertility
Summary
References
45: Enteral Feeding Devices and Ostomies
Gastrostomy
Complications of Gastrostomy/Gastrojejunostomy Tubes
Infection
Tube Migration and Dislodgement
Leakage, Stomal Erosion, and Peristomal Skin Breakdown
Hypergranulation Tissue
Tube Obstruction
Fistula Formation
Ostomy Education and Management
References
Part VI: Research
46: Clinical Indices for Pediatric Inflammatory Bowel Disease Research
Introduction
Assessment of Instruments Used in Clinical Research
Outcomes in Pediatric Inflammatory Bowel Disease
Crohn Disease Activity Indices
Perianal Crohn Disease
Ulcerative Colitis Disease Activity Indices
Patient-Reported Outcomes
Gastrointestinal Endoscopy Indices
Crohn Disease
Ulcerative Colitis Endoscopic Assessment
Quality of Life, Disability, and Other Related Instruments
Radiographic Indices
Summary of Clinical Outcome Measures
Appendix 1
Appendix 1.1: Pediatric Crohn Disease Activity Index [19] History (Recall, 1 week)
Appendix 1.2: Weighted Pediatric Crohn Disease Activity Index (wPCDAI) [68] History (Recall, 1 week)
Appendix 1.3: The MINI Index
Appendix 2
Appendix 2.1: Perianal Crohn Disease Activity Index [43]
Appendix 2.2: Fistula Drainage Assessment [44]
Appendix 2.3
Appendix 3
Appendix 3.1: Ulcerative Colitis Disease Activity Indices (Adult)
Appendix 3.2: Pediatric Ulcerative Colitis Activity Index
Appendix 4
Appendix 4.1: Crohn Disease Endoscopic Index of Severity [93]
Appendix 4.2: Simple Endoscopic Score for Crohn Disease [97]
Appendix 4.3: Rutgeerts Score for Postoperative Endoscopic Disease Recurrence [101]
Appendix 4.4: Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [65]
Appendix 4.5: Lewis Score [103]
References
47: Clinical Trials (Clinical Perspective)
Introduction
Summary
References
48: Global Regulatory Industry Perspective of Clinical Trials
Key Stakeholders in Drug Development Process
Regulatory Agencies
Industry Sponsors
Academic Researchers
Investigators
Regulations Guiding Pediatric Drug Development
Sulfanilamide Tragedy 1937 and the Food, Drug, and Cosmetic Act of 1938
Thalidomide Tragedy 1957–1961, the Kefauver–Harris Amendments of 1962, and the European Directive 65/65/EEC
Orphan Drug Regulations
Pediatric Drug Regulations (US)
Pediatric Drug Regulations (EU)
Pediatric Drug Regulations (Rest of World)
Overview of Clinical Trials
Phase I Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
Phase IV Clinical Trials
Key Concepts in Clinical Trial Conduct
Institutional Review Board (IRB)
Informed Consent
Pediatric Considerations
Adverse Event Reporting
Data Monitoring Committee
Highlights of the Regulatory Review Process
Regulatory Safeguards for Pediatric Patients Involved in Clinical Trials
Criteria for IRB Approval of Pediatric Research
Pediatric Extrapolation
Pediatric-Specific Issues in IBD Trials
References
Part VII: Special Considerations
49: Infectious Complications of Pediatric Inflammatory Bowel Disease
Introduction
Antibiotic Use for Treatment of IBD
Infections Associated with Underlying IBD
Clostridium difficile
Cytomegalovirus
Coronavirus 2019 (COVID-19)
Increased Risk of Infections Secondary to Therapies
Purine Analogues
Corticosteroids
Tumor Necrosis Factor Antagonists
Conclusion
References
50: Psychological Aspects of Inflammatory Bowel Disease in Children and Adolescents
Introduction
Health-Related Quality of Life
Pain and Symptom Management
Social Functioning and Peer Relationships
Academic Functioning
Body Image
Emotional Functioning
Family Functioning
Adherence and Self-Management
Self-Efficacy and Disease Knowledge
Health Behaviors
Psychotherapy and Other Resources
Summary
References
51: Measurement of Quality of Life in Pediatric Inflammatory Bowel Disease
Introduction
Quality of Life: Concepts/Definitions
Why Measure Health-Related Quality of Life?
Approaches to Health-Related Quality-of-Life Measurement
Health-Related Quality-of-Life Assessment in Pediatrics
Health-Related Quality-of-Life Assessment in Inflammatory Bowel Disease: Adult IBD Perspective
Health-Related Quality-of-Life Assessment in Pediatric Inflammatory Bowel Disease
IMPACT
The Development of the Impact Questionnaire
Description of the Instrument (IMPACT-III)
Practical Issues for Use of IMPACT
Administration and Instructions to Respondents
Scoring
Deficiencies in Current Knowledge and Areas for Future Research
Identifying the Factors which Influence HRQOL
Comparisons of HRQOL Between Patients with IBD, Patients with Other Chronic Pediatric Illnesses, and Healthy Peers
Assessing Disease-Specific HRQOL in Pediatric IBD Patients Not Captured by IMPACT Questionnaire
The Impact of Family on the Assessment of HRQOL in Pediatric IBD Patients
Cross-Cultural Comparisons of HRQOL in Pediatric IBD
References
52: Irritable Bowel Syndrome and Functional GI Disorders in Inflammatory Bowel Disease
Epidemiology
Clinical Features
Pathophysiology
Low-Grade Inflammation
Gut Microbiota
Altered Motility
Biochemical Changes
Genetics
Psychological Factors
Visceral Hypersensitivity and IBD
Diagnosis
Treatment
“Irritable” Pouch Syndrome
Summary
References
53: Inflammatory Bowel Disease in Pregnancy
Introduction
Contraception
Fertility
Effect of IBD on Pregnancy
Effect of Pregnancy on IBD
Management of IBD During Pregnancy
Clinical Assessment
Medical Therapies
Antidiarrheals
Aminosalicylates
Antibiotics
Corticosteroids
Immunosuppressants
Immunomodulators
Biologic Agents
Anti-tumor Necrosis Factors (TNFs)
Anti-integrins
Interleukins 12 and 23
Small Molecules (Janus Kinase Inhibitor)
Breastfeeding
Mode of Delivery
Surgery and Pregnancy
Transition of Care
References
54: Pediatric Inflammatory Bowel Disease Care in Low- and Middle-Income Countries
Introduction
Diagnostic Evaluation
Clinical Evaluation and PIBD Activity Indices
Serological Tests
Microbiological Investigations
Fecal Calprotectin
Imaging
Endoscopic Evaluation
Histopathology
Pharmacological Therapy
Nutritional Therapy
Surgery
Conclusion
References
55: Immunizations in the Child with Inflammatory Bowel Disease
Introduction
Underimmunization
Who and When to Immunize?
Inactivated Vaccines in Children with IBD
Immunizing the Child with IBD: Practical Aspects
COVID-19 Infection and Vaccine Development: Relevance to Inflammatory Bowel Disease
Summary
References
56: Colitis-Associated Cancers
Clinical Presentation of Colitis-Associated Cancers
Pathogenesis and Genomic Alterations in Colitis-Associated Bowel Cancers
Spectrum of Genomic Alterations in Colitis-Associated Cancer
Epidemiology and Incidence
Conditions Increasing the Risk of Colitis-Associated Cancers
Duration of Colitis
Age of Onset of Inflammatory Bowel Disease
Anatomic Extent of Colitis
Histologic Inflammation
Primary Sclerosing Cholangitis
Family History of Colorectal Cancer
Prevention of Colitis-Associated Cancers
Pharmacotherapy and Chemoprevention
Sulfasalazine/5-Aminosalicylates
Thiopurines
Biologics/Small Molecule Agents
Folic Acid
Ursodeoxycholic Acid
Screening, Surveillance, and Risk-Reducing Surgery
Screening and Surveillance
Endoscopic Detection
Endoscopic Resection
Risk-Reducing Surgery
Biomarkers
Systemic Therapy for Advanced Colitis-Associated Cancers
Small-Bowel Adenocarcinoma in Crohn Disease Patients
Other Malignancies
Summary
References
57: Quality Improvement in Inflammatory Bowel Disease
Introduction
Variation in Care
The Chronic Illness Care Model
The Need for Quality Improvement in IBD
The Improvement Model
Improvement Collaborative
The ImproveCareNow Network
Learning Health Network
Maintaining Improvement
Improvement Science in the Business of Health Care
Conclusion
References
58: Fostering Self-Management and Patient Activation
Introduction
Defining Self-Management
Self-Management Tasks
Self-Management Skills
Self-Management for Kids
Does Self-Management Really Matter?
How to Cultivate Self-Management
Parent and Patient Activation
Co-production
Pill Cases
Shot Anxiety
Spanish Language Educational Videos
The Need for Reliable Education
Conclusions
References
59: Advocacy for Pediatric Patients with IBD
Introduction
Advocacy Directed at Schools
Advocacy Directed at Insurance Companies
Obtaining Health Insurance and the Options Your Patients Have
Navigating Insurance Company Denials and Prior Authorizations
Social Security Disability Benefits
Family and Medical Leave for Caregivers
Summary
Appendix 1
References
60: Advocacy for Pediatric Patients with Inflammatory Bowel Disease
Introduction
Advocacy Directed at Schools
COVID-19 Considerations
Advocacy Directed at Insurance Companies
Social Security Disability
Family and Medical Leave for Caregivers
Restroom Access Act
Summary
Appendix 1: Sample Letter for Patient’s Student File Regarding Educational Accommodations Needed for an IBD Diagnosis
Appendix 2: Preparing an Effective Insurance Company Letter of Medical Necessity
Appendix 3: Letter of Medical Necessity for Ustekinumab
Appendix 4: Sample Letter to Support Maintenance of Infusion at Infusion Center
Appendix 5: Sample Letter for Appeal of Denial of Mental Health Benefits
Appendix 6: Social Security Listing of Impairments for Children with IBD
Appendix 7: Preparing an Effective Letter for Family Medical Leave Act provisions
61: Transition from Pediatric to Adult Care
Introduction
Background
Challenges and Barriers to Transition for Adolescent IBD Patients
Transition Steps
Overview of the Transition Process
Patients (Age 12–14)
Skill Set 1
Skill Set 2
Parents/Family (Age 12–14)
Pediatric Team (Age 12–14)
Focus on Independence
Patients (Age 14–17)
Skill Set 3
Skill Set 4
Parents (Age 14–17)
Pediatric Team (Age 14–17)
Self-Management: Health and Lifestyles
Patients (Age 17–18)
Skill Set 5
Skill Set 6
Parents (Age 17–18)
Pediatric Team (Age 17–18)
Adult Team (Age 18+)
Monitoring the Process
Conclusion
References
Index