Rudolph's Pediatrics, 22nd Ed.

CHAPTER 410. Inflammatory Bowel Disease

Michael C. Stephens, Subra Kugathasan, and Thomas T. Sato

Crohn disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are idiopathic, lifelong, chronic inflammatory conditions of the gastrointestinal (GI) tract which typically manifest during late childhood to young adulthood. The physical and psychological burden of these chronic relapsing diseases and their devastating effects imposed on affected children and teenagers may be considerable. Crohn disease and ulcerative colitis are grouped together in view of many similarities in their epidemiologic, genetic, immunologic, and clinical features. Diagnostic approaches are similar, but treatment approaches and prognosis differ.

EPIDEMIOLOGY

Inflammatory bowel disease (IBD) is unevenly distributed throughout the world with the highest disease rates occurring in industrialized countries of Europe, North America, and Australia.1,2 However, the incidence of IBD is rapidly increasing in other emerging industrialized countries. European studies have suggested that the incidence of IBD in children and adolescents has significantly increased over the last 35 years.3 Although population-based studies are difficult to perform in North America, an epidemiological population-based study in Wisconsin found the incidence of IBD to be 7 per 100,000 in children under 18 years of age.4 In children, about two thirds of IBD cases are Crohn disease (CD), and one half are ulcerative colitis (UC), and in the adult population the prevalence CD and UC are equal.5 The geographical and chronological variation of IBD since its description early in the 20th century is represented in eFigure 410.1 .

Onset of disease has a bimodal distribution, with the greatest incidence being adolescents and young adults, with a second peak in the fifth to sixth decade of life. Median age of onset of disease is between 10 and 11 years and is not different from CD. However, significant IBD cohorts have been described under 5 years of age.6 Population-based studies have not demonstrated an altered risk of IBD associated with gender, ethnicity, or urban versus rural setting.4 In adults, exposure to tobacco smoke is associated with a lower incidence of UC, but the opposite effect has been seen in CD.7,8 A prospective cohort study of childhood exposure to smoke (active or passive) showed an increased risk with smoke exposure for both CD and UC in adulthood.9 Appendectomy is associated with a decreased incidence of UC but appears to increase the risk for CD, especially for worsening of disease for the first year following surgery.10,11

PATHOPHYSIOLOGY AND GENETICS

Inflammatory bowel disease was recognized as a disease entity during the early 20th century, and the pathogenesis has been linked to a combination of genetic, environmental, and microbial factors.14Inflammatory bowel disease (IBD) is a disease of chronic gut inflammation. The most widely accepted theory of pathogenesis is that in genetically susceptible individuals, an environmental trigger promotes a chronic, dysregulated immune response. The environmental trigger may be an infectious agent such as a commensal organism of the normal gut flora or possibly a ubiquitous environmental agent.15 Following activation of the response, it appears that the mechanisms that attenuate the response may be defective in some individuals with IBD.

Crohn disease is heritable with specific genes associated with an increased risk of IBD.16 The comparative risk for Crohn disease (CD) in first-degree relatives of patients with CD is increased by up to 35 times, but the comparative risk for those of first-degree relatives of ulcerative colitis patients is approximately 3 times. Family history of IBD is present in less than 15% of patients with ulcerative colitis (UC).4,17,18 Sib-pair-based genome-wide linkage analyses showed a non-MHC association at the NOD2 gene on chromosome 16.19 More recently, the application of genome-wide association scanning (GWAS) has identified 30 confirmed loci to date.20

Several genetic susceptibility loci for UC have been identified, some in common with CD and others unrelated to CD. Loci common to both UC and CD include IL23RIL12BHLANKX2-3MST1CCNY, and 3p21.31. However, ECM1PTPN2, HERC2, and STAT3 are associated with UC but not CD.22,23

CLINICAL FEATURES

The clinical features of inflammatory bowel disease (IBD) disease vary widely and depend upon the anatomic location(s) of involvement, extent of disease, and presence of extraintestinal manifestations.14,24The frequency of common clinical features in pediatric patients with IBD is shown in Table 410-1. The diagnosis of ulcerative colitis is classically based on a suggestive history of bloody diarrhea and abdominal pain, which may be associated with fever, whereas in Crohn disease the presentation is often more enigmatic. Up to 50% of children and adolescents with IBD present with mild symptoms, characterized by fewer than four stools per day and only minimal intermittent hematochezia. Children may also present without GI symptoms and only extraintestinal manifestations of IBD.

Common symptoms and signs include abdominal pain, diarrhea, weight loss, rectal bleeding, growth impairment, perirectal disease, and extraintestinal manifestations. Fulminant colitis can occur at initial presentation or later. Patients with fulminant colitis are extremely ill, and often present with fever, chills, abdominal distention, nausea and vomiting, leukocytosis, significant anemia, dehydration, and deranged electrolyte balance. These patients are at risk for the development of toxic megacolon or perforation and require prompt treatment and intervention as detailed below.

Table 410-1. Presenting Clinical Features of Crohn Disease and Ulcerative Colitis in Children

Abdominal pain is the most common symptom at presentation.25 The pain may not be localized, so differentiating pain caused by IBD from other causes of abdominal pain, such as functional abdominal pain, may be difficult. The pain is more likely to be chronic in nature, with a persistant location and severity. Terminal ileal or ileocecal Crohn disease is associated with a chronic history of right lower quadrant discomfort or pain. In contrast, the acute development of right lower quadrant pain without a past history of pain would more likely suggest a diagnosis of appendicitis.

The majority of children with IBD also present with diarrhea. Because the intestinal inflammation in ulcerative colitis (UC) is limited to the colon, a change in stool pattern is the most common presenting symptom for UC. Diarrhea in IBD is often nocturnal, and when the distal colon is involved, it can be associated with urgency and tenesmus. Rectal bleeding may vary in severity at presentation. Although gross blood is seen in most of the cases of UC, or in Crohn disease (CD) with colonic involvement, both UC and CD can present with diarrhea alone. Adolescents with CD are less likely to present with rectal bleeding than those with UC.

Weight loss, anorexia, and fatigue also herald the onset of UC or CD. Classically, most children had weight loss prior to the diagnosis of CD. However, more recent studies indicate that most children with inflammatory bowel disease (IBD) have a normal body mass index (BMI) at diagnosis.26 Less than 10% of children with UC have a BMI less than the fifth percentile at diagnosis compared to approximately 25% in CD. Twenty percent to 34% of children with UC have a BMI in the at-risk for overweight or overweight range at diagnosis (approximately 10% in CD). Growth failure is seen in between 13% and 58% of children with IBD28.

Delayed onset of puberty is common in Crohn disease (CD) and occurs less frequently in ulcerative colitis.30 This may have a substantial effect on linear growth because inflammatory bowel disease often presents in young adolescence.

Perirectal disease is common in CD and is not seen in ulcerative colitis. Approximately 25% to 30% of affected children with CD will have nonhealing deep anal fissures, fistulas, perirectal abscesses, or large, multiple anal tags.31Surprisingly, perirectal pain is unusual unless there is actual abscess formation that may require prompt drainage. Enterocutaneous fistulas, such as perianal and perirectal fistulization (see eFig. 410.2 ), are the most common, compromising about 80% of the fistulas seen in CD.

A palpable abdominal mass (typically in the right lower quadrant) is not uncommon in patients presenting with CD. The mass may be inflamed intestine, or on occasion may represent abscess.

Rheumatologic, dermatologic, ocular, and hepatobiliary extraintestinal manifestations of inflammatory bowel disease (IBD) (listed in Table 410-2) are seen in up to 25% to 35% of patients with long-standing IBD. These may also be the sole presenting feature in pediatric IBD with no associated gastrointestinal symptoms. Axial arthritis (ankylosing spondylitis or sacroilitis) and peripheral arthropathy (knees, ankle, hips, wrists, and elbows) may precede the development of intestinal inflammation in IBD. Joint disease activity often corresponds with clinical bowel activity, but in a minority of cases, the course of joint inflammation is independent of any bowel disease. Finger clubbing, a form of hypertrophic osteoarthropathy, can be seen in children with CD, particularly when the small intestine is involved. Erythema nodosum lesions (eFig. 410.3 ) appear as raised, erythematous, and painful nodules that occur over the tibia, lower leg ankle, or extensor surfaces of the arm. Pyoderma gangrenosum (eFig. 410.4 ) appears as a small, painful, sterile pustule that coalesces into a larger abscess, ultimately forming a deep, necrotic ulcer. Extensive small bowel involvement in CD may cause zinc deficiency with characteristic rashes.

Table 410-2. Extraintestinal Manifestations of Inflammatory Bowel Disease (IBD)

Growth failure

Dermatological: Erythema nodosum, pyoderma gangrenosum, sweet syndrome

Eye: Episcleritis, uveitis

Musculoskeletal: Sacroilitis, spondyloarthritis, axial arthritis, osteoporosis/osteopenia, finger clubbing

Hepatobiliary: Sclerosing cholangitis, chronic active hepatitis, fatty liver, gallstones

Hematologic: Anemia of chronic disease, thrombocytosis

Vascular: Thromboembolism, deep vein thrombosis

Pancreatic: idiopathic pancreatitis

Renal: Reanl caliculi (oxalate or uric acid), amoyloidosis

Pulmonary: Granulomatous lung disease, reactive airway disease (rare)

Cardiac: Myopericarditis and pleuropericarditis (rare)

FIGURE 410-1. Large canker sores (Apthous ulcerations in the mouth) in a patient with Crohn disease.

Oral ulcers may be seen in many patients with IBD with varying severity (Fig. 410-1). Granulomatous inflammation involving the orofacial structures such as lips, gums, and face, have been reported to occur in a minority of patients at presentation (eFig. 410.5 ). Aphthous ulcerations involving the mouth and gums can be seen in many adolescents if a careful systemic evaluation is undertaken. Although rare, uveitis, episcleritis (eFig. 410.6 ), and iritis may be seen either as an existing presentation or a sole presenting manifestation of IBD in children. A slit lamp examination by an ophthalmologist is necessary to make such a diagnosis. Liver abnormalities including sclerosing cholangitis (see eFig. 410.7 ) or chronic hepatitis occur in both ulcerative colitis (UC) and Crohn disease (CD). Several reports of idiopathic pancreatitis in patients with IBD, and as the presenting manifestation of CD, suggest that pancreatitis could be an extraintestinal manifestation of IBD. Pancreatitis can also be seen as a result of duodenal disease in CD. Urethral tract abnormalities or urinary obstruction may result secondary to ileocecal inflammation or a mass that involves the right ureter. Iron deficiency anemia secondary to chronic blood loss (either occult or overt) is more common during the initial presentation of CD than UC. When iron deficiency is seen in an older child or in an adolescent without any obvious source of blood loss such as menorrhagia, the suspicion for gastrointestinal blood loss and underlying IBD should be high.

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC EVALUATION

The diagnosis of inflammatory bowel disease (IBD) should be based on clinical suspicion and subsequent screening laboratory workup that can lead to the definitive endoscopic or radiologic procedures.25 A detailed history and physical examination remain the most important aspects in the evaluation of a child with abdominal pain or symptoms suggestive of IBD. The indicators (“red flags”) in the history and examination that make a clinician suspect IBD in a child are listed in Table 410-3. Disorders that may present similarly to IBD are listed in eTable 410.1 . Exclusion of intestinal infections that can cause rectal bleeding such as enteric pathogens (Salmonella, Shigella, Campylobacter, Yersinia, and E coli 0157/H7) and C difficile is imperative. Other considerations in children with abdominal pain and rectal bleeding include Henoch-Schonlein purpura, Behcet disease, hemolytic-uremic syndrome, tuberculosis, or vasculitis. When an abdominal abscess is found during the investigation of abdominal pain, in addition to CD, a perforated appendix, trauma, and gynecologic diseases must be considered.

Table 410-3. Clinical Indicators (“Red Flags”) in the History and Examination That Are Suspicious for Inflammatory Bowel Disease (IBD) in Children

History

Abdominal pain

Pain distant from the umbilicus

Pain that interferes with normal sleep patterns

Discrete episodes of pain which are of acute onset

Pain precipitated by eating

Dysphagia, odynophagia

Involuntary weight loss

Rectal bleeding

Extraintestinal symptoms

Unexplained low-grade fever

Erythema nodosum, pyoderma gangrenosum

Joint pain, joint swelling

Jaundice

Severe eye pain or persistent conjunctivitis

Growth problems, failure to thrive

Strong family history of IBD

Physical examination

Paleness/anemia

Decreased growth velocity

Delayed sexual maturation

Finger clubbing

Oral ulcerations

Abdominal tenderness, mainly right lower quadrant

Abdominal mass

Perianal fistula, fissures

Erythema nodosum, pyoderma gangrenosum

Hemoccult positive stool

The establishment of a firm diagnosis of IBD is essential before establishing this chronic and lifelong diagnosis in any child. Laboratory, endoscopic, and radiologic evaluation not only aid in the definitive diagnosis, but also help to classify the type of IBD (UC or CD), localize the region(s) involved, and determine the extent as well as the severity of the IBD. These findings aid in determination of the best treatment modalities. Table 410-4 describes the suggested initial diagnostic evaluation in an adolescent suspected of having IBD.

Laboratory Tests

Patients with active inflammatory bowel disease (IBD) typically have anemia that is microcytic (MCV below 78) and hypochromic, hypoalbuminemia (serum albumin 2.0 to 3.5 g/dL), a mild thrombocytosis (above 400,000), and an elevated sedimentation rate (above 20 mm/hr) and elevated C reactive protein (CRP). The absence of these signs should not be used exclusively to rule out Crohn disease (CD) or ulcerative colitis (UC).34 However, findings of a normal hemoglobin, ESR, platelet count, and albumin are found in only 6% of patients with mild IBD (sensitivity of 94%). Recently, a commercial serologic panel was added to the armamentarium of the laboratory evaluation of patients with suspected IBD. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to anti-Saccharomyces cerevisiae(ASCA) have been associated with CD, whereas peri-nuclear antineutrophil cytoplasmic antibody (p-ANCA) has been associated with ulcerative colitis. Although these tests might assist in differentiating between CD and UC, they are not good screening tests. A retrospective review reported that serologic screening that included ASCA, perinuclear antineutrophil cytoplasmic antibody (pANCA), and antibody to Escherichia coli outer-membrane porin (anti-OmpC) demonstrated a sensitivity of 60%, a specificity of 91%, and a positive predictive value of 60%.35 This panel may be a useful adjunct to conventional laboratory tests, but it has not replaced the need for definitive examinations such as endoscopy or radiologic evaluations.

Table 410-4. Diagnostic Evaluation of the Patient with Suspected Inflammatory Bowel Disease (IBD)

Laboratory studies

Complete blood count (CBC) with differential, reticulocyte count

Sedimentation rate and or C-reactive protein (CRP)

Total protein, albumin

Aminotransferases, alkaline phosphatase, bilirubin

Serum iron, ferritin

Stool cultures

For bacteria (including E coli 0157/H7)

Clostridium difficile toxin assay

Stools for ova and parasites

Radiological

Upper gastrointestinal (GI) series with small bowel follow-through

Abdominal and pelvic computerized tomography (CT) scan, if abscess is suspected

White blood cell (WBC) scan, if small bowel disease is suspected

Endoscopy

Upper endoscopy

Colonoscopy, ileoscopy, and biopsies

Video capsule endoscopy

Gastrointestinal Endoscopy and Biopsy

Colonoscopy with intubation of the distal ileum and biopsy is key for the accurate diagnosis of IBD. This approach has replaced radiographic diagnostic methods due to superior sensitivity and specificity. In most pediatric centers, an upper endoscopy is performed at the time of the initial colonoscopy in children with suspected IBD to aid in differentiating the type of IBD, if a diagnosis of IBD is confirmed.

Colonoscopic findings that suggest Crohn disease (CD) include aphthous ulcers in the colon, a discontinuous colitis with intervening areas of normal mucosa (skip areas), a relative decrease in the severity of inflammation in the rectum (rectal sparing), or identification of granulomas on biopsy (see Fig. 410-2). In ulcerative colitis, the rectum is always involved, and although the inflammation is continuous, it may be limited to either the left colon or proximally extend to the cecum (Fig. 410-3). Endoscopic findings in both disorders can include friability, erythema, loss of vascularity, and haustrations, and serpigenous ulcerations may be encountered depending on the severity of inflammation. Pseudopolyps that represent heaped-up granulation tissue or surviving patches of mucosa surrounded by areas of denuded mucosa are more frequently seen with ulcerative colitis (UC). Children with UC appear to have more extensive disease at presentation than adults, with 80% to 90% having pancolitis,4,36 compared with 60% of adults.37

FIGURE 410-2. A: Ulceration of the ileum in a patient with Crohn disease. B: Apthous ulcer in the colon of a child with Crohn disease.

Histologic findings in CD include pathognomonic, well-formed mucosal granulomas. These are not always present, and in these cases diagnosis depends upon the distribution of inflammation which is often patchy and often involves the submuscosa and deep layers of the bowel wall in CD. In UC, superficial mucosal inflammation is continuous and homogeneous, with extension proximally to a varying extent along the colon. The inflammation involves the mucosa and superficially the submucosa (deeper layers are only rarely involved, eg, toxic megacolon). Chronicity, with derangement of the crypt architecture (branching and atrophy) and crypt abscesses are typical of IBD.

Assessment for small bowel inflammation is a key component to differentiate between UC and CD when small bowel disease or granuloma is not present. The terminal ileum is the site most frequently involved in older children with CD, but in children under 10 years of age, the colon is the most commonly affected site.38 Thus, inflammation in the ileum strongly supports a diagnosis of CD versus UC, but mild inflammation in the ileum can be seen in UC patients if there is active inflammation in the cecum (termed backwash ileitis). However, the presence of chronic small bowel inflammation usually suggests CD. Wireless capsule endos-copy (WCE) is increasingly used to search for occult small intestinal inflammation and may be useful for initial evaluation in patients with suspected IBD, or for follow-up evaluation of disease activity.

Following diagnosis, differentiation of UC and CD guides treatment strategies and discussions of prognosis. The most helpful findings that differentiate CD from UC are the presence of small bowel involvement, perirectal disease, or granulomas in the histological biopsy findings. The presence of aphthous oral ulcerations or perianal lesions is much more suggestive of the diagnosis of CD. In CD the inflammatory process is asymmetric and segmental, with transmural involvment of any segment of the bowel, from the oral cavity to the anus. In UC only the colon is involved. Approximately two thirds of pediatric patients with CD have some degree of colonic involvement. In the 20% to 30% of patients whose disease is restricted to the large bowel, precise classification of the colitis may be difficult if no skip areas or pathognomonic well-formed mucosal granulomas are found. Hence, even with an expert IBD clinician and an experienced gastrointestinal pathologist, in about 10% to 15% of cases, differentiating CD from UC is not possible despite a full diagnostic evaluation. These patients carry a provisional diagnosis of indeterminate colitis.39

FIGURE 410-3. A: Colonoscopic image from a patient with ulcerative colitis demonstrating diffuse erythema with ulcerations. B: Severe ulceration and exudate in the colon of a patient with ulcerative colitis.

Radiographic Evaluation

Historically, an upper gastrointestinal series with small bowel follow-though (SBFT) has been the primary modality to evaluate for inflammation, manifesting as areas of mucosal ulceration, narrowing, obstruction, or fistula of the small intestine (eFig. 410.8 ), or obstruction or even an enteroenteric fistula. Abdominal and pelvic CT scans are now often used to identify small bowel inflammation (eFig. 410.9 ), or an abdominal or pelvic abscess. Radiolabeled white blood cell (WBC) scan has been proven useful in patients where the mid-small bowel was involved and conventional evaluation failed to demonstrate the pathology. More recently, ultrasound, CT, and MRI enterography have augmented (and in some centers replaced) the SBFT.40,41 The utility of these approaches at present is dependent on the expertise of the radiologist.

TREATMENT PRINCIPLES IN INFLAMMATORY BOWEL DISEASE

The primary goal of treatment of both Crohn disease (CD) and ulcerative colitis (UC) is to induce and maintain remission of the disease in order to minimize the impact on lifestyle, growth, and development. There are established short-term and long-term goals for managing these chronic relapsing conditions.25,38 In the short term, inducing and maintaining remission, improving the quality of life, and treating complications take priority. The long-term goals should be aimed at prevention of relapses and complications, the optimization of growth and pubertal development, the prevention of bone loss, and limiting the need for surgical interventions. The response to therapy is determined by reduction of symptoms, growth parameters, as well as improvement in laboratory studies and rarely endoscopic findings. Although nutritional and probiotic therapy for IBD seems attractive, the mainstay of treatment of IBD is still via pharmacologic agents. When the disease is active, quick-acting potent medications are used to induce remission. Once the disease activity is under control, the goal is to use medications with fewer side effects.

The strategies used for treatment of CD and UC are similar, but the response to specific medical therapies, and the potential for surgical “cure” with UC alter the management approach in individual patients. Outpatient medical therapy achieves remission following diagnosis and during disease exacerbations in many pediatric patients. In others with a more severe presentation or severe disease exacerbation, hospitalization may be necessary. Some present with fulminant colitis, a life-threatening disorder that manifests with tachycardia, orthostatic hypotension, and diffuse abdominal tenderness. It can occur in both UC and CD. Aggressive resuscitation with fluid, electrolyes, and blood product replacement is needed. In those with fever and possible toxic megacolon, broad-spectrum antibiotics should be administered and oral feedings should be discontinued. Generally, corticosteroids should be administered intravenously. Emergent surgical intervention may be required for toxic megacolon or for management of complications of CD or UC. Elective colectomy may be indicated for management of UC that is poorly controlled with medical therapies.

Many children with the diagnosis of inflammatory bowel disease (IBD) require psychological support during the course of the disease because it is a chronic, lifelong disease, and it can have profound effects on body image and appearance due to drugs and surgery. The psychological and social aspects of chronic inflammatory bowel disease may be intensified during adolescence, and psychological dysfunction associated with delayed puberty may be particularly disconcerting in males. Short stature and delayed puberty often leave children much shorter than their classmates. The quality of life is obviously impaired in teenagers who may need to take multiple pills per day, sometimes as many as 15 or more. In particular, the cosmetic side effects of corticosteroids, the presence of nasogastric or gastrostomy tubes, and ostomies all lead to a sense of being different. Conflicts are common between parents and children with IBD particularly concerning eating habits and compliance with medications. Psychological counseling by a professional who is familiar with IBD and the chronic nature of the disease is essential for some patients. Many parents and teenagers are either too busy or reluctant to go to counseling due to the stigmata of having mental illness. The primary care provider and the gastroenterologist should address these issues openly during the initial diagnosis as well as during subsequent visits. Additionally, the benefit of joining support groups for parents and patients, as well as online “chat groups” for teenagers cannot be underestimated.

TREATMENT OF CROHN DISEASE

Pharmacologic agents used for treatment of Crohn disease (CD) are detailed in Table 410-5. Therapy usually begins with treatment with corticosteroids, followed by treatment with azathioprine or 6-mercaptopurine to maintain remission. When these agents are either ineffective or have intolerable side effects, methotrexate or a biologic agent may be substituted. CD severity and response to therapy are generally monitored by use of clinical judgment and compendium measures such as the Pediatric Crohn Disease Activity Index.

Corticosteroids

Corticosteroids remain the initial treatment choice for acute therapy in moderate to severe CD. In adolescents with active mucosal inflammation, oral prednisone, prednisolone, or medrol, or intravenous solumedrol or hydrocortisone permit rapid improvement in most patients by potent anti-inflammatory activity.42 There is no evidence to suggest that corticosteroids heal the inflamed mucosa or are useful as a maintenance therapy. Therefore, the common strategy is to use corticosteroids in the acute setting as a short-term induction therapy to bridge the gap while slower-acting, more effective maintenance therapy takes effect. Long-term use is associated with bone demineralization and adrenal insufficiency. Other side effects include fluid retention, weight gain, striae, acne, fat redistribution, hirsutism, hypertension, hyperglycemia, cataracts, osteonecrosis, myopathy, emotional disturbances, and benign intracranial hypertension. An alternative to traditional corticosteroids are newer steroids that maintain efficacy but have fewer side effects. The first such agent became available in the United States in late 2001. Budesonide (Entocort-EC™) is a highly potent steroid that is released in the small intestine and right colon in patients with CD. Most of the drug is metabolized on first passage through the liver such that only about 10% to 30% is distributed systemically. It is effective for inducing remission in some patients with terminal ileal and cecal CD but is less effective than conventional corticosteroid therapy, and long-term steroid side effects still occur.43

Table 410-5. Pharmacologic Treatment of Crohn Disease

5-Aminosalicylates

The term aminosalicylates encompasses a wide variety of medications, each with a 5-aminosalicylate (5-ASA) moiety. These medications have proven efficacy in the treatment of ulcerative colitis (see below), but their role as a therapy for CD remains controversial. Controlled studies have found only marginal benefits such that they are rarely used for treatment of CD.44

Thiopurines

Azathioprine and its metabolite, 6-mercaptopurine (6-MP) are a mainstay for treatment of steroid refractory Crohn disease (CD). Following initiation of therapy, clinical remission is common, but these agents may take from 3 to 6 months to achieve their maximal efficacy. 6-MP and azathioprine have many toxic side effects, but their short-term safety has been proven in children with CD.45 As immunomodulators, the mechanism of action is through the blockade of CD-28–dependent T-cell activation.46 Three to six months of therapy may be required to achieve full effect. Up to 30% of patients fail therapy, either from toxicity or lack of efficacy. Side effects include myelosuppresion, hepatotoxicity, pancreatitis, flu-like symptoms, and rash. Genetic polymorphisms in thiopurine methyltransferase identify a small subset of patients that are at high risk for myelosuppression. Genotyping (or measuring enzyme activity) before starting therapy has become standard at most pediatric inflammatory bowel disease (IBD) centers. This does not identify all patients at risk, and monitoring is still required (usually CBC and liver-associated enzymes). Typical doses are 1 to 1.5 mg/kg/day for 6-mercaptopurine and 2 to 3 mg/kg/day for azathioprine. Serum levels are highly variable, but measurement of intra-cellular metabolites (thioguanine nucleotides) can help direct treatment decisions in patients who are not responding.47 Patients should not receive live vaccines while on immunomodulators. Opportunistic infections have been reported in IBD patients taking thiopurines,48 as have malignancies and lymphoproliferative disorders.49,50

Methotrexate

Limited data are available for the use of this agent in children with inflammatory bowel disease, although a substantial amount of data exists documenting its long-term safety in pediatric patients with juvenile rheumatoid arthritis. Adverse effects include myelosuppression, oral ulcers (mucositis), infections, pneumonitis, and hepatitis.

Antibiotics

Although there is no controlled data available that antibiotics are efficacious, they are commonly used in IBD management in clinical practice. They have a limited role in treating intestinal inflammation and should be used primarily to treat complications such as abdominal or perianal abscesses. Agents such as ciprofloxacin and metronidazole are the two most commonly used antibiotics in IBD.

Biological Treatments

Proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) are involved in the pathogenesis of Crohn disease (CD). This has led to the use of new anti-TNF-α monoclonal antibodies; Infliximab (Remicade), Adalilumab (Humira), and a pegylated Certolizumab pegol (Cymzia).51 Several studies have shown infliximab’s excellent beneficial effect in children with treatment-unresponsive (refractory) CD. Side effects of infliximab include infusion reactions, development of anti-infliximab antibodies, delayed hypersensitivity reactions, formation of autoantibodies and Lupus-like reactions. Unusual and aggressive infections have been reported with infliximab.41 Reactivation of quiescent tuberculosis, or histoplasmosis following infliximab therapy can be lethal. Hepatosplenic T-cell lymphoma has been reported in several adolescent and younger adult patients treated with combination infliximab and thiopurines, leading to a now common practice of discontinuing thiopurine therapy prior to initiating biologic therapy.52 Biologic agents have proven to be highly effective in achieving clinical improvement and remission in significantly more patients than conventional therapy. In addition, these biologic agents show superior efficacy in healing perianal and other fistulas. Studies of newer biologicals such as adalilumab and certalizumab in children are yet to be performed.

Nutritional Therapy

Nutritional therapy has been used in pediatric inflammatory bowel disease53,54 to induce remission (primary therapy) in small bowel CD, as supplemental therapy to improve weight gain and growth, and to replenish micronutrient deficiencies. Primary therapy requires that almost all the caloric needs are met by giving elemental or polymeric formula as a whole source of nutrition. Although the supplements can be taken by mouth, due to poor palatability they are often administrated by nasogastric tube or gastrostomy tube. Because adolescents tend to oppose the use of nasogastric tubes on a daily basis, this avenue of treatment has never gained popularity in the United States, but this approach is often used successfully in Canada and Europe with initial remission rates of 50% to 80% in CD.

Supplemental nutritional therapy is used when a patient cannot take the recommended 100% to 150% of daily allowances for energy (85–90 kcal/kg/day and protein 2.5–3 g/kg/day). Children who are unable to increase their enteral intake may require supplemental nocturnal nasogastric feedings. This strategy is used most frequently for children with growth failure that usually is associated with small bowel disease.

Surgical Management of Crohn Disease

The major indication for operative management of Crohn disease (CD) is the inability to control disease activity despite optimal medical management. Additionally, operative intervention is indicated when complications of the disease such as intestinal perforation, abscess, bowel obstruction from inflammation or stricture, enterocutaneous fistula, or hemorrhage occur. Growth failure, delayed puberty, and quality of life issues such as subjective pain, school attendance, and self-esteem are relative indications for operation.

Children and their families should be counseled that there is currently no medical or surgical cure for CD. Therefore, surgical management of CD is aimed at providing relief from symptoms or treating disease complications while preserving as much intestinal length as possible. Successful operations for CD require accurate localization of active disease with endoscopic and directed diagnostic imaging studies coupled with focused intervention. Helical CT scan imaging of the abdomen and pelvis is extremely useful in preoperative identification of anatomic relationships between the involved intestine and adjacent structures such as the ureters or iliac vessels.

The most commonly performed operation for CD is ileocecal resection, and this reflects anatomic disease distribution. Resection of involved bowel is limited to grossly involved disease, as frozen section analysis to clear microscopic margins does not improve outcome.55 Either open or laparoscopic segmental intestinal resection with primary anastomosis is preferred when feasible.56 In the setting of established intra-abdominal infection, large inflammatory phlegmon with fistula, or abscess, resection of the grossly diseased intestine with temporary diverting enterostomy may be required. For a chronically inflamed, fibrotic stricture, site-directed stricturoplasty without resection and anastomosis is an alternative to resection.

Persistent inflammatory symptoms of CD colitis despite optimal medical management are well treated by segmental or total abdominal colectomy. Current data support the concept of performing segmental or total abdominal colectomy with primary anastomosis, avoiding diverting colostomy or ileostomy when possible.57 Although ileoanal pouch reconstruction is the procedure of choice for children with ulcerative colitis, results for pouch procedures with CD have been discouraging secondary to recurrent disease and a higher reoperation and complication rate.58 Perianal disease is observed in approximately 13% of pediatric patients with CD and fissures, fistulas, and tracts may be anatomically complex. Severe, intractable perianal CD generally occurs with established colorectal disease and may require proctocolectomy to control the disease.

Postoperative complications following operations for CD are unfortunately common and include small bowel obstruction and intra-abdominal infection.59 Clinically significant, recurrent disease and future operative intervention should be anticipated, particularly in children with colonic disease or severe, aggressive disease at the time of operation. Recurrence rates of symptomatic disease following an initial operation were reported to be 17% at 1 year, 38% at 3 years, and 60% at 5 years,60 whether contemporary recurrence rates are lowered by the use of maintenance therapy and biological modifiers remains to be determined.

TREATMENT OF ULCERATIVE COLITIS

Pharmacologic agents used for treatment of ulcerative colitis (UC) are similar to those for Crohn disease (CD) but because 5-ASA agents are far more effective, the approach to therapy differs. Therapy usually begins either with treatment with corticosteroids for moderate to severe disease, followed by treatment a 5-ASA agent to maintain remission, or may be initiated with only 5-ASA therapy in mild disease. Thiopurines are the front-line immunomodulator for UC. As in CD, when these agents are not either ineffective or have intolerable side effects, methotrexate or a biologic agent may be substituted. However, surgical therapy is a real option in UC, so the risk and benefits of long-term immunosuppressive therapy need to be considered.

Corticosteroids

Corticosteroids are frequently used to control the symptoms of UC at the time of initial diagnosis and during acute exacerbations. The initial treatment dose is the prednisone equivalent of 2 mg/kg/day followed with a rapid taper, usually over 1 to 2 months. In pediatric UC, steroids are typically used to help stabilize patients who are threatening to develop fulminant colitis, or to control symptoms in patients with acute exacerbations during chronic therapy with other agents. Side effects and lack of long-term efficacy in maintaining remission make corticosteroids undesirable for long-term management of UC. Side effects are described in the section above pertaining to use of corticosteroids in CD. The alternative use of rectally administered budesonide appears to be less efficacious then rectal 5-ASA.

The efficacy of intravenous corticosteroid treatment for severe exacerbations was reviewed in a retrospective longitudinal cohort study.61 Half of the patients hospitalized responded to steroids in the short term. Predictors of treatment failure determined by multivariable modeling at days 3 and 5 were C reactive protein, number of nocturnal stools, and three disease activity indices.

5-Aminosalicylates

5-Aminosalicylates (5-ASA) include 5-amino-salicylic acid, mesalamine, mesalazine, and sulfasalazine. These medications act as anti-inflammatory agents at the level of the mucosa rather than by systemic absorption, possibly by blocking the production of prostaglandin E2 and leukotrienes.

Sulfasalazine was the first such agent employed to treat ulcerative colitis. It contains 5-ASA linked to sulfapyridine by an azo bond, that when cleaved by the colonic bacteria releases 5-ASA. The sulfa moiety is absorbed systemically and is responsible for the many of the side effects of sulfasalazine. Newer formulations do not have the sulfa moiety and have different time release formulations to target specific regions of the alimentary canal. Adherence has been a challenge historically, because the preparations required multiple doses per day with multiple large pills. The most recent formulations allow once or twice daily dosing. In younger patients, capsules can be opened and mixed with soft food, and sulfasalazine can be administered as a suspension. These agents can also be given rectally as suppositories or enemas. The side effects of 5-ASA drugs are listed in Table 410-6 and occur in 10% to 45% of patients. Agranulocytosis, oligospermia, hemolytic anemia, and folate deficiency are unique to sulfasalazine. Monitoring renal function is recommended because of the long-term risk of interstitial nephritis.65,66

Thiopurines

There are no published studies on the efficacy of thiopurines 6-mercaptopurine and azathioprine) for ulcerative colitis (UC) in pediatric patients. In adults, thiopurines are clearly beneficial for UC, but the evidence is less convincing than for Crohn disease (CD). Retrospective data suggest that thiopurines will maintain remission in 75% of pediatric patients with UC69 and are generally the immunomodulator used for maintenance therapy in UC patients who cannot maintain remission with only 5-ASA.70 As in CD, 3 to 6 months of therapy may be required to achieve full effect. Side effects, monitoring, precautions, and dosing are the same as for CD, discussed above.

Table 410-6. Side Effects of 5-Aminosalicylate Medications

Cyclosporine A/Tacrolimus

Because of toxicity, cyclosporine A (CSA) and tacrolimus are typically reserved for rescue therapy, serving as a bridge to other maintenance medications (such as a thiopurine) or to surgery. CSA is a calcinurin inhibitor and works by inhibiting cytokine production by T-helper cells. Side effects are renal toxicity, hypertension, hyperkalemia, seizures, paresthesias, gingival hyperplasia, headache, tremor, elevated liver function tests, infection, and lymphoma and other neoplasms. The typical scenario for use of CSA is the hospitalized patient with subfulminant colitis, who is steroid refractory (not responding after 5 to 7 days of IV corticosteroids. In children, remission is induced in up to 80% of patients, but most require colectomy within 1 year.71 Because of the side effects, careful monitoring of CSA levels and renal function is required when initiating treatment. Tacrolimus has also been used in adults72 and children with UC, typically under the same circumstances as CSA. Pediatric response rates in the short term have been reported near 70%, but long-term benefit is similarly disappointing to CSA therapy.73 Given the significant toxicities associated with calcinurin inhibitors and the poor long-term outcome, many pediatric IBD centers are using infliximab, particularly in patients already failing thiopurines, for rescue therapy.

Biological Treatments

Infliximab is a monoclonal antibody that binds tumor necrosis factor alpha (TNF-α). Initially used in CD, it is now approved by the Food and Drug Administration (FDA) for use in adults with UC. Pediatric case series show short-term response rates of between 77% and 88%, with 66% in remission beyond 9 months.74,75 Side effects and risks are similar to those described above for treatment of CD.

Surgical Management of Ulcerative Colitis

Operative intervention for ulcerative colitis (UC) is often viewed as a treatment of last resort in a hospitalized, ill child or adolescent. In part, this may reflect the acute and relatively severe course in symptomatic pediatric patients with UC. However, it is important to recognize that UC may be effectively cured by a well-designed operation with complete cessation of immunosuppressive or anti-inflammatory medications. In contrast to operations for Crohn disease (CD), UC can be surgically cured with acceptable morbidity and demonstrated excellent long-term outcome.81 Therefore, timing of operative intervention for pediatric UC should account for symptom severity, quality of life issues, surgical experience, and patient/parent preferences.

Approximately 25% of children and adolescents with UC will require urgent or emergent operation for failure of optimal medical management, gastrointestinal bleeding, intestinal perforation, toxic megacolon, or systemic sepsis from severe colitis. In an emergent setting in a child on high-dose corticosteroids and immunosuppressive agents, most surgeons prefer removal of the colon with retention of the distal rectal stump (Hartmann pouch) and diverting end ileostomy. Restoration of gastrointestinal continuity and reconstructive procedures are electively performed following metabolic recovery several weeks to months later.

Definitive management of pediatric ulcerative colitis includes removal of the rectal mucosa—this can be performed using an endorectal technique that excises the distal rectal mucosa and preserves the rectal musculature, making injury to the adjacent nerves and structures responsible for urinary and sexual function less likely. The most commonly performed operations for pediatric ulcerative colitis include total abdominal proctocolectomy with either a direct (straight) ileoanal anastomosis or construction of an ileoanal pouch (J-pouch) anastomosis (IPPA).82 These procedures are currently being performed using minimally invasive surgical techniques with similar excellent outcome.83

Most symptomatic children and adolescents report good to excellent quality of life following colectomy and ileoanal reconstruction.84 A reasonable long-term functional goal is normal fecal continence, stool frequency of 3 to 6 bowel movements per 24 hours, with normal urinary and sexual function. Given the absence of a colon, children and adolescents will require modification of eating behavior for optimal outcome, and initially, antidiarrheal medications such as loperamide or diphenoxylate and supplemental bulk fiber agents are commonly used.

Immediate postoperative complications are common and include anastomotic leak or stenosis, infection, and small bowel obstruction. Other complications include bladder dysfunction, impotence, dyspareunia, infertility, and ileovesical or ileovaginal fistula. Intractable diarrhea is more common following straight ileoanal reconstruction. Children with ileoanal pouch reconstruction may develop pouchitis which is discussed below.

POUCHITIS

Pouchitis describes the presence of idiopathic inflammation in the ileal reservoir following ilealanal pouch anastomosis (IPAA). In adults who underwent IPAA for UC, 15% to 53% of adults develop pouchitis, compared with a much lower rate in adults who undergo the same procedure for familial polyposis syndromes (3% to 14%).85 Pouchitis can occur at any time following IPAA, but it occurs most often within the first 6 months.

The cause of pouchitis is unknown. Undiag-nosed Crohn disease (CD) is frequently considered. This represents a minority of patients, affecting only 6% to 15% of pediatric patients who develop pouchitis.86,87 Pouchitis is classified as acute or chronic (greater than 4 weeks) and by responsiveness to antibiotics (responsive, dependent, or resistant).

Symptoms of pouchitis are increased stool frequency, hematochezia, abdominal pain, the development or worsening of incontinence, and low-grade fever. Endoscopically, inflammation is seen in the pouch, especially the distal and posterior portions. Significant inflammation in the neoterminal ileum suggests undiag-nosed CD, but differentiating pouchitis from CD is difficult because there is an overlap between the acute and chronic inflammatory changes seen histologically in both. In healthy ileal pouches, the ileal mucosa frequently develops histologic features that resemble colonic mucosa. This is suspected to be stimulated by changes in bacterial population, bile salts, and short-chain fatty acids. In pouchitis, villous blunting, crypt hyperplasia, and increased inflammatory cells in the lamina propria are seen. Also, crytitis, crypt abscesses, and mucin or foreign body granulomas may be present. Some of the histologic features of pouchitis bear similarity to histologic features of CD,89 but mild inflammation in the neoterminal ileum does not confirm the diagnosis of CD.90

Other causes of pouchitis symtoms include infections (particularly Clostridium difficile and cytomegalovirus), irritable pouch syndrome, cuffitis, and stenosis of the pouch. In newer pouches, one must also consider anastomotic leak.

The vast majority of acute episodes of pouchitis respond to antibiotic therapy.88 The front-line therapy remains ciprofloxacin or metronidazole for 7 to 14 days. Therapies for chronic pouchitis include prolonged antibiotics, combination antibiotics, and probiotics such as VSL-3.91 For patients who remain refractory, anti-inflammatory or immunomodulator therapy is considered. Takedown and creation of an ileostomy is only rarely required.

Irritiable pouch syndrome (IPS) is indistinguishable from pouchitis based on symptoms. In contrast to pouchitis, patients with IPS do not have active inflammation. Over 40% of symptomatic patients have IPS.92 IPS has an equivalent impact on patient function and quality of life when compared to pouchitis.93 Current therapies for IPS are similar to symptomatic therapies for irritable bowel syndrome, including antidiarrheal, anticholenergic, or antidepressant medications.

CANCER RISK IN INFLAMMATORY BOWEL DISEASE

It is well recognized that patients with ulcerative colitis (UC) have an increased risk of colorectal cancer (CRC).94,95 The risk is related to extent and duration of disease, increasing with both. Other risk factors are family history of CRC, primary sclerosing cholangitis (PSC), and age at diagnosis (early age increases risk). The estimated risk of developing CRC after 8 to 10 years of disease is 0.5% to 1%.

Adult guidelines for the management of UC include cancer prevention strategies.97,98 Surveillance colonoscopies are recommended beginning 8 to 10 years after diagnosis. These guidelines have been applied to pediatrics, but there are no data supporting this approach. Colectomy is required if dysplasia or more aggressive lesions are identified.

Chemoprevention of CRC is an area of intense interest. A meta-analysis of the impact of 5-ASA medications demonstrated a protective effect (OR 0.51; 95% confidence interval 0.37 to 0.69).99Ursodeoxycholic acid has been shown to reduce the risk of CRC in patients who have both UC and PSC.100