Key points

Introduction

IBD is a chronic immune-mediated condition of the GI tract in which the goal of treatment is to induce and maintain durable remission. Although classically divided into Crohn disease (CD) and ulcerative colitis (UC), IBD actually has a wide range of phenotypes with varied responses to therapy, which makes the natural history of this chronic disease difficult to predict. Pediatric IBD has several unique considerations in comparison to adult IBD, namely related to growth, development, pubertal maturation, bone health, and the psychological impact on the patient and family. Additionally, the longevity of disease burden and its consequent morbidity is significantly more in children than in adults diagnosed with IBD. The growing incidence and prevalence of IBD further highlight the importance of pediatric primary care providers being knowledgeable about and closely involved in the care of these patients.

IBD can be categorized into CD, UC, and IBD-unspecified. CD may involve any portion of the GI tract, typically with serpiginous and aphthous ulcers often in patchy distribution, known as skip lesions. The pathognomonic feature of CD is noncaseating epithelioid granulomas, but the presence of granulomas is not essential for a diagnosis of CD. Most commonly, children have ileocolonic involvement and approximately one-third have upper tract involvement as well. The inflammation in CD is typically transmural, which can lead to disease complications, including fistulae and subsequent intra-abdominal or perianal abscess formation. Perianal disease, including anal skin tags, fissures, fistulae, and abscesses, are associated only with Crohn disease. A subset of pediatric CD patients presents with stricturing disease at diagnosis, but the natural history of the disease shows that many patients progress from an inflammatory phenotype to stricturing disease over their lifetime.

UC is characterized by continuous mucosal inflammation of the colon starting from the rectum and extending proximally. UC is unique from CD because it does not have small bowel involvement other than the possibility of backwash ileitis (typically nonspecific inflammation in the terminal ileum in UC patients with pancolitis and no ileocecal valve changes) and does not have granulomas on histopathology. Additionally, the depth of inflammation is much more superficial and largely limited to the mucosa in UC.

IBD-unspecified describes those patients with colonic disease but who otherwise have features that are not specific for CD or UC. The full range of clinical phenotypes and the complexity of IBD suggest a multifactorial pathophysiology. The etiology is not completely understood, but it is hypothesized to be the result of a dysregulated immune response to commensal and/or pathogenic organisms in genetically susceptible hosts.

Genome-wide association studies in adults and older children have identified approximately 200 IBD risk-associated loci. This highlights the polygenic nature of the disease, and many of the identified gene polymorphisms associated with CD and UC influence immune-mediated pathways, leading to dysregulation in autophagy, cell-mediated immune responses, or innate immune responses. This dysregulation allows for an altered intestinal microbial composition resulting in dysbiosis, which may induce intestinal inflammation.

Introduction

IBD is a chronic immune-mediated condition of the GI tract in which the goal of treatment is to induce and maintain durable remission. Although classically divided into Crohn disease (CD) and ulcerative colitis (UC), IBD actually has a wide range of phenotypes with varied responses to therapy, which makes the natural history of this chronic disease difficult to predict. Pediatric IBD has several unique considerations in comparison to adult IBD, namely related to growth, development, pubertal maturation, bone health, and the psychological impact on the patient and family. Additionally, the longevity of disease burden and its consequent morbidity is significantly more in children than in adults diagnosed with IBD. The growing incidence and prevalence of IBD further highlight the importance of pediatric primary care providers being knowledgeable about and closely involved in the care of these patients.

IBD can be categorized into CD, UC, and IBD-unspecified. CD may involve any portion of the GI tract, typically with serpiginous and aphthous ulcers often in patchy distribution, known as skip lesions. The pathognomonic feature of CD is noncaseating epithelioid granulomas, but the presence of granulomas is not essential for a diagnosis of CD. Most commonly, children have ileocolonic involvement and approximately one-third have upper tract involvement as well. The inflammation in CD is typically transmural, which can lead to disease complications, including fistulae and subsequent intra-abdominal or perianal abscess formation. Perianal disease, including anal skin tags, fissures, fistulae, and abscesses, are associated only with Crohn disease. A subset of pediatric CD patients presents with stricturing disease at diagnosis, but the natural history of the disease shows that many patients progress from an inflammatory phenotype to stricturing disease over their lifetime.

UC is characterized by continuous mucosal inflammation of the colon starting from the rectum and extending proximally. UC is unique from CD because it does not have small bowel involvement other than the possibility of backwash ileitis (typically nonspecific inflammation in the terminal ileum in UC patients with pancolitis and no ileocecal valve changes) and does not have granulomas on histopathology. Additionally, the depth of inflammation is much more superficial and largely limited to the mucosa in UC.

IBD-unspecified describes those patients with colonic disease but who otherwise have features that are not specific for CD or UC. The full range of clinical phenotypes and the complexity of IBD suggest a multifactorial pathophysiology. The etiology is not completely understood, but it is hypothesized to be the result of a dysregulated immune response to commensal and/or pathogenic organisms in genetically susceptible hosts.

Genome-wide association studies in adults and older children have identified approximately 200 IBD risk-associated loci. This highlights the polygenic nature of the disease, and many of the identified gene polymorphisms associated with CD and UC influence immune-mediated pathways, leading to dysregulation in autophagy, cell-mediated immune responses, or innate immune responses. This dysregulation allows for an altered intestinal microbial composition resulting in dysbiosis, which may induce intestinal inflammation.

Epidemiology

The incidence of IBD in the general population is rising. High suspicion and recognition by general practitioners are imperative because IBD is not uncommon in children, with up to 25% of patients with IBD diagnosed before age 20. Environmental factors have been implicated in the rapid rise in IBD especially with the recognition that children who emigrate from underdeveloped countries where the incidence of IBD is low take on an increased risk of IBD when they are established in Western societies. Additionally, the prevalence in children younger than age 20 with CD and UC is higher in the northeast United States than in Western US states.

Although the average age of diagnosis of pediatric IBD is 10 years to 12 years, a growing subcohort of pediatric IBD includes very-early-onset IBD (VEO-IBD). VEO-IBD is diagnosed in children who present with symptoms by age 5 years and accounts for up to 15% of pediatric IBD cases. VEO-IBD may have a distinct phenotype that favors a colonic disease distribution, does not respond to conventional therapies, and can include primary immunodeficiencies with GI manifestations. Monogenic causes of VEO-IBD have been described and whole-exome sequencing has been innovative in identifying these rare novel variants.

Presentation

IBD can initially present with a heterogeneous constellation of symptoms, including but not limited to abdominal pain, diarrhea, rectal bleeding, weight loss or growth failure, constipation, fever, mouth sores, pallor, dizziness, and dehydration. In some rare cases, patients present with peritonitis, small bowel obstruction, appendicitis, or other surgical emergencies. IBD should be considered in previously healthy children who present with an acute intestinal surgical emergency, giving close attention to growth and chronic symptoms that may have been subtle prior to the acute onset of severe symptoms. In pediatrics, growth is one of the most critical factors and a slowed height velocity may precede apparent signs or symptoms of IBD, especially in cases of Crohn disease. Extraintestinal symptoms can involve dermatologic, musculoskeletal, hepatic, ophthalmologic, renal, pancreatic, or hematologic systems, as outlined in Table 1 .

One of the main distinctions between pediatric IBD and adult IBD is the impact of the disease on growth and development. Growth retardation and pubertal delay are common at the time of diagnosis of CD and less commonly associated with UC. Growth failure may be attributed to poor caloric intake as well as the direct effects of inflammation causing growth hormone resistance. Diagnosing and intervening with appropriate medical or surgical therapy before a child has completed puberty are integral for optimizing a patient’s final adult height. Delayed puberty, including absence of breast development, testicular enlargement, or delayed menarche, can lead to growth retardation in itself as well as decreased bone mineralization. It can also lead to psychological sequelae as a child recognizes differences in his/her own sexual maturation compared with other children of similar age.

Differential diagnosis

The differential diagnosis of IBD can vary widely based on the presenting symptoms and disease location in both adults and children ( Table 2 ). The most common symptoms include diarrhea with or without blood, abdominal pain, and poor growth. An acute onset of symptoms, such as abdominal pain, diarrhea, and low-grade fever, suggests infectious gastroenteritis or colitis or acute appendicitis in the differential diagnosis. Celiac disease can present with diarrhea, abdominal pain, weight loss, poor growth, and low bone mineral density but is not associated with bloody diarrhea. Eosinophilic GI disorders are less common but can present similarly and typically are only delineated from other diagnoses by endoscopy. Lactose intolerance with chronic abdominal pain and frequent diarrhea should also be considered but should resolve with dietary changes and not affect growth. Eating disorders, including anorexia nervosa, should be considered in children with weight loss, abdominal pain, and vomiting as well as laxative abuse in children with diarrhea. Additional rare considerations include oncologic etiologies, sarcoidosis, and ischemic colitis. Finally, functional disorders, including irritable bowel syndrome, are likely the most common cause of chronic and recurrent abdominal pain, diarrhea, and/or constipation in children.

Primary immunodeficiencies should be considered in children with a significant infectious history prior to diagnosis as well as in all children who are presenting with symptoms before age 5. The intestinal mucosa is in close proximity to gut-associated lymphoid tissue and is the site of host-microbe interactions, which are critical to the appropriate development of the immune system. Primary immunodeficiencies, including chronic granulomatous disease, common variable immunodeficiency, Wiskott-Aldrich syndrome, Hermansky-Pudlak syndrome, B-cell defects and T-cell defects, phagocyte defects, and antibody-mediated defects, can initially present with an IBD phenotype.

Diagnostic evaluation

The diagnostic evaluation in a patient suspected of having IBD begins with a thorough history to characterize abdominal pain and diarrhea as well as identify red flags, including blood in stool, nocturnal awakenings to defecate, tenesmus, defecation urgency, fevers, weight loss, mouth ulcers, joint swelling, redness, warmth, and pain ( Table 3 ).

First and foremost, a detailed review of the World Health Organization growth chart to determine if there is a decreased height velocity or change in growth percentiles for age must be performed in every patient in whom there is suspicion for IBD. The physical examination should assess the abdomen for focal tenderness, peritoneal signs, and palpable masses that could be related to stricturing or penetrating disease. A perianal examination and rectal examination should not be overlooked due to the frequency of perianal abscesses and fistulae that are present at the time of diagnosis. Some patients have no discomfort associated with perianal lesions and others are reticent to disclose these details to a physician. Rectal strictures may form if there has been longstanding local inflammation. Additional physical examination findings may be shallow, whitish ulcers in the oropharynx, a flow murmur due to anemia, hepatomegaly, joint swelling, redness or effusions, or limited lumbar spine range of motion. Rashes associated with IBD are typically on the lower extremities, including erythema nodosum, depicted as deep erythematous painful nodules, and pyoderma gangrenosum, characterized by ulceration, necrosis, and vasculitis. Clubbing of digits can be seen in CD as well.

The laboratory evaluation for a patient suspected of having IBD is outlined in Table 4 . Normal laboratory results do not exclude the possibility for IBD. IBD serologies, including anti– Saccharomyces cerevisiae and perinuclear antinuclear cytoplasmic antibody, have been identified as immunologic markers found in some individuals with IBD. The diagnostic role of serology has undergone much study and debate in pediatrics and has been found considerably less sensitive than C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) for the presence of IBD. The high cost and poor overall predictive value make this a less useful addition to the diagnostic work-up for IBD.

Infectious stool studies must be performed to rule out other causes of chronic diarrhea or bloody diarrhea before proceeding with endoscopy, which is the diagnostic gold standard. Clostridium difficile testing; stool culture for Salmonella , Shigella , and Campylobacter ; and ova and parasite testing, including Giardia and Cryptosporidia antigens, are particularly important. If one of these are detected, the patient should be treated or observed appropriately and further evaluation considered if symptoms persist.

In addition to ruling out infection by stool studies, fecal calprotectin has been used to screen for active inflammation. Calprotectin is a calcium-binding and zinc-binding neutrophilic cytosolic protein that can be detected in stool as an indicator of gut inflammation. Testing for fecal calprotectin has been established as a useful screening tool prior to considering endoscopy. Additionally, it correlates closely with endoscopic activity of IBD, and there is growing evidence for serial monitoring as a marker of disease activity and treatment response. Importantly, although fecal calprotectin has a high sensitivity, it is not specific to IBD, especially in children. Other causes of gut inflammation can lead to elevated calprotectin, including nonsteroidal anti-inflammatory drug use, infectious enterocolitis, inflammatory polyps including juvenile polyps, and oncologic processes. Therefore, calprotectin cannot take the place of endoscopic evaluation.

Children and adolescents with suspicion for IBD should be referred for evaluation by a pediatric gastroenterologist. On review of this evaluation, esophagogastroduodenoscopy and colonoscopy should both be performed for appropriate and complete evaluation. In pediatrics, biopsies during these procedures are essential to ensure the diagnosis and that histology is consistent with the chronic inflammation that is characteristic of IBD.

Diagnosis of IBD in very young children who developed symptoms before the age of 5 or those with a suspicious history, including recurrent infections, should have an immunologic evaluation to rule out primary immunodeficiencies, including chronic granulomatous disease and common variable immunodeficiency, among others. This may include dihydrorhodamine flow cytometry assay; measuring immunoglobulin (Ig) A, IgG, IgE, and IgM; and vaccine titers to diphtheria, tetanus, and pneumococcus to assess appropriate specific antibody response in children who have been vaccinated.

A complete evaluation for IBD includes small bowel imaging to assess the intestine that is not evaluable by conventional endoscopy. Upper GI study with small bowel follow-through has been a common method of evaluation for many years but does provide significant exposure to ionizing radiation and has low sensitivity and specificity. More recently, magnetic resonance enterography of the abdomen/pelvis has been growing in popularity because it prevents this radiation exposure. It requires a child to drink contrast and lie still for a prolonged period of time, which may be difficult for certain ages.