INTRODUCTION — There are five principal components of a program for management of Crohn disease (CD) in children and adolescents:
●Medications
●Surgery
●Nutritional rehabilitation and/or nutritional therapy
●Psychosocial support
●Colorectal cancer screening for older patients
Thus, treatment involves a multidisciplinary effort that includes the primary pediatrician or other primary care provider, pediatric gastroenterologist, adjunctive pediatric subspecialists (rheumatologist, ophthalmologist, dermatologist, and endocrinologist), surgeon, nutritionist, psychiatrist, gastrointestinal nurse specialist, pharmacologist, and social worker. For pediatric patients, the focus of this multidisciplinary team is not only on the patient but on the family members and others involved in the patient's care.
This review focuses on the approach to selecting medications for an individual patient and other aspects of management, including exclusive enteral nutrition (EEN). Details about each of the medications are reviewed separately. (See "Medical therapies for Crohn disease in children and adolescents".)
Other aspects of the diagnosis and management of children with CD are discussed in separate topic reviews:
●(See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
●(See "Important health maintenance issues for children and adolescents with inflammatory bowel disease".)
●(See "Growth failure and pubertal delay in children with inflammatory bowel disease".)
GENERAL APPROACH TO TREATMENT
Overview of treatment decisions — Treatment of the ill patient with active CD involves an induction regimen that includes a potent therapy with a rapid onset of action (algorithm 1). If a remission is achieved, the patient can be transitioned to a maintenance regimen using medications that are appropriate for long-term use (table 1). Anti-tumor necrosis factor (anti-TNF) antibodies (eg, infliximab or adalimumab) can be used for both induction and maintenance due to their rapid onset of action. The selection of drugs for induction and maintenance depend on age, disease severity and location, and clinical course. A subset of very young children with inflammatory bowel disease (IBD) may have severe or refractory disease and are more likely to have an identifiable genetic cause of the disease (monogenic IBD). Treatment for those children with monogenic defects often differs from the immunosuppressive treatments below. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)
In the past, clinicians have utilized two primary strategies ("step-up" or "top-down" therapy). These are being replaced by a third strategy: "treat-to-target" therapy.
●"Step-up" therapy – Initiate treatment with a less potent immunosuppressive drug that may be effective in treating this patient's disease activity, and promptly step up therapy to a more potent drug if response is incomplete (usually after three to six months). We use this strategy for patients without risk factors for complicated disease or for those with mild disease activity. (See 'Standard-risk patients' below.)
●"Top-down" therapy – Initiate treatment with a potent immunosuppressant (eg, anti-TNF antibody) early in the course of the disease. We use this strategy for patients with high risks of complicated disease, such as extensive small bowel disease, severe ulcerating colonic disease, growth failure in mid- to late puberty, severe perianal disease, or steroid-unresponsive disease. Increasingly, a top-down strategy is being favored for moderate to severe disease, even without high-risk characteristics, because of the "treat-to-target" concept described below. (See 'Moderate or severe' below.)
●"Treat-to-target" therapy – With this approach, the goal is to achieve mucosal healing rather than resolution of clinical symptoms and laboratory abnormalities. The clinician and patient decide on an initial therapeutic approach for maintenance (eg, subcutaneous methotrexate, 6-mercaptopurine, or infliximab), based on a combination of clinical parameters (disease severity) and patient preference. At some fixed time point in the future (eg, 6 to 12 months after the start of treatment), the patient undergoes a complete reassessment, such as imaging or colonoscopy, as clinically indicated. If the bowel has healed, the patient continues on the current treatment. If the bowel remains inflamed, other therapeutic options are considered.
Treatment goals — The optimal goal for treatment has not been established. Increasingly, a "treat-to-target" approach is used, in which the goal is to achieve mucosal healing (based on objective measures such as serial magnetic resonance imaging [MRI], upper endoscopy, or colonoscopy with biopsies), rather than a goal of resolution of clinical symptoms and laboratory abnormalities (see 'Overview of treatment decisions' above) [1]. This is because endoscopic healing is poorly correlated with clinical symptoms and/or laboratory values. Patients who feel well may still have endoscopic or radiologic evidence of inflammation, and there is some evidence that subclinical inflammation increases the risk for future exacerbations or the development of complications, such as strictures, fistulas, and abscesses [2,3]. The rationale for this aggressive "treat-to-target" approach is that healing the intestinal mucosa may result in better long-term outcomes for pediatric IBD, including fewer complications and surgeries. This potential benefit has not been proven, but, if true, it would balance the costs and burden of the endoscopic and radiographic monitoring procedures. A panel of experts (the STRIDE-II initiative) has developed a list of "preferred targets" in IBD, including clinical remission, biochemical remission, and endoscopic healing [4].
Achieving mucosal healing typically requires long-term immunosuppressive therapy, so the goal of improved mucosal healing must be balanced against the potential risks of the specific medication. Thus, in addition to monitoring closely for drug efficacy, the clinician must monitor for drug toxicities and medication adherence.
Duration of maintenance therapy — For patients with moderate to severe CD who achieve mucosal healing with biologic and/or immunomodulator therapy, the optimal duration of treatment is unclear. However, many such patients will require lifelong therapy with at least one agent.
●Withdrawal of immunomodulator – For those who achieve remission with combination biologic and immunomodulator therapy (eg, infliximab with mercaptopurine), the relative risks and benefits of withdrawing the immunomodulator are unclear and the decision requires detailed discussion and shared decision-making with the patient and family. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Anti-TNF monotherapy versus combination therapy with an immunomodulator'.)
●Withdrawal of biologic agent – For patients who achieve mucosal healing on a biologic agent (with or without an immunomodulator), we generally suggest continuing the biologic agent as long as the medication is effective at controlling the disease and maintaining quality of life and there are no significant adverse effects. Disease relapse rates are high following withdrawal of a biologic agent. As an example, in a study of children with CD who achieved mucosal and histologic healing with anti-TNF therapy, nearly one-half (13 of 24 patients) experienced relapse after changing to an immunomodulator (median follow-up 29 months) [5]. Similar outcomes are seen in studies in adults with CD. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Duration of maintenance therapy'.)
ASSESSMENT OF DISEASE ACTIVITY — The response to therapy is based upon the clinician's evaluation of clinical disease activity and supporting laboratory data, assessed during clinical visits approximately every three to four months. Very stable patients can be assessed twice a year.
Objective assessments, including follow-up magnetic resonance imaging (MRI), upper endoscopy, or colonoscopy, are increasingly used to monitor disease progression and guide treatment decisions; this is known as a treat-to-target approach. (See 'Treatment goals' above.)
Clinical assessment — The clinician should monitor clinical symptoms including diarrhea, abdominal pain, anorexia, growth failure, fatigue, extraintestinal symptoms, school attendance, and psychological stress (eg, anxiety and/or depression). The examination evaluates for signs of abdominal, perianal, dermatologic, and rheumatologic illness. Weight and height are measured at each visit, and the interval height velocity is calculated. Height percentiles should also be interpreted in the context of the child's genetic potential, usually estimated based on the midparental height. Screening and assessing children for growth failure is an essential component of medical care and is discussed in detail separately. (See "Growth failure and pubertal delay in children with inflammatory bowel disease".)
For clinical care, disease severity usually is determined by the clinician's global assessment. Note that this assessment is not standardized, although a scoring system may be used to capture some components (see 'Systems for scoring disease activity' below). Moreover, clinical symptoms do not always correlate with the degree of laboratory or endoscopic inflammation [1]. The following are examples of a typical patient in each category but are not prescriptive:
●Mild – Patient has mild, brief episodes of abdominal pain and loose stools (with or without small amounts of visible blood), little or no anemia, and no weight loss or growth delay. There is no abdominal tenderness on examination. Endoscopy and imaging demonstrate either limited disease (eg, terminal ileitis) or mild disease (eg, a few aphthae in the colon). Noncaseating granulomas may be present. Extraintestinal manifestations usually are not present.
●Moderate – Patient has frequent episodes of abdominal pain that interfere with activities and five or more loose stools daily (with or without visible blood). Weight and height gain are less than expected for age or as compared with the patient's previous trajectory. Patients may have fatigue, mild or moderate anemia, elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), and a somewhat tender abdomen on examination. Radiography and endoscopy demonstrate more extensive or severe disease, such as ulcers throughout the colon, extensive ileal involvement, or significant upper gastrointestinal tract involvement. Extraintestinal manifestations of inflammatory bowel disease (IBD) may be present, such as erythema nodosum, arthritis, or uveitis.
●Severe – Patient has frequent abdominal pain and liquid stools, including at night, and feels fatigued. There is marked abdominal tenderness, with guarding or a mass. A history of weight loss is common, and body mass index is often <10th percentile. There is moderate or severe anemia, elevated ESR, elevated CRP, hypoalbuminemia, malnutrition, and definite growth failure. On endoscopy, deep fissuring ulcers and longitudinal ulcers may be seen throughout the ileum and colon. Extensive small bowel disease (Paris classification L4b) may be present (figure 1 and table 2).
The presence of perianal fistulas or extraintestinal manifestations of IBD (eg, arthritis, fever, uveitis, erythema nodosum) increase the severity assessment. Fatigue is a common symptom, both at clinical presentation and in follow-up. Some fatigue may be associated with disease activity since it tends to improve with treatment directed at the IBD in placebo-controlled trials [6]. Other possible causes of fatigue include anemia, emotional distress, and sleep disturbance [6,7]. The clinician should specifically ask about fatigue during routine monitoring of patients with IBD and address the various contributors as part of management.
Laboratory tests
●Routine tests – The laboratory assessment usually includes a complete blood count (CBC), serum albumin, ESR, CRP, and liver aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). There is some evidence that fecal calprotectin levels or other fecal markers of inflammation are correlated with disease activity and can be a useful adjunct to the clinical and laboratory evaluation of the patient [1,8]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Laboratory features'.)
●Conditional tests – Additional testing depends on the clinical course of the patient. In some patients, particularly those with active disease or on prolonged glucocorticoid therapy, we measure ferritin and iron levels, vitamin D, vitamin B12, and zinc levels and assess skeletal health using bone densitometry periodically (table 3). If ALT and AST are elevated, we check gamma-glutamyl transpeptidase (GGTP) to assess for the unusual complication of primary sclerosing cholangitis; some providers monitor GGTP routinely, along with ALT and AST. A low alkaline phosphatase level should prompt assessment of zinc status. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease" and "Vitamin and mineral deficiencies in inflammatory bowel disease", section on 'Laboratory monitoring for nutrient deficiencies'.)
For patients presenting with a flare of colitis, we screen for bacterial causes of colitis, with stool cultures and testing for Clostridioides difficile toxin; for those with refractory colitis, we also evaluate for infection with cytomegalovirus (CMV). (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Stool testing for enteric pathogens'.)
Radiographic and endoscopic evaluation — Because the treatment goal is typically to achieve mucosal healing (the "treat-to-target" approach (see 'Treatment goals' above)), endoscopy and colonoscopy with biopsies should be performed 6 to 12 months after initiation of any therapy to determine whether the therapy was successful. Once mucosal healing is achieved, further evaluation is prompted by signs and symptoms of disease activity and may consist of repeat radiographic and/or endoscopic assessment. Increasingly, repeat imaging (with MRI; specifically, magnetic resonance enterography [MRE]) and reassessment with colonoscopy are being performed even in the absence of clinical symptoms because data from trials suggest that clinical remission is not necessarily accompanied by endoscopic remission [9,10]. Decisions about the intensity of endoscopic and radiographic monitoring are based on theoretical long-term advantages of achieving mucosal healing, balanced against the potential short-term costs and burden of the procedures (see 'Treatment goals' above). In some centers, contrast-enhanced ultrasound is used for follow-up of small bowel CD. This test has the benefit of being less invasive and easier for the patient but provides less information than MRI [11,12]. Indications for and selection among the endoscopic and imaging options are discussed in a separate topic review. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Diagnostic evaluation'.)
For patients with extensive CD of the colon, we begin surveillance colonoscopy approximately 8 to 10 years after the diagnosis of IBD [13]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Surveillance for cancer'.)
Systems for scoring disease activity
●The Pediatric CD Activity Index (PCDAI) — Disease activity may be quantified using the PCDAI; this system is primarily used for clinical trials but also may be useful for routine evaluation of hospitalized patients (table 4). The PCDAI permits the calculation of a numerical score ranging from 0 to 100 based upon a child's well-being, degree of abdominal pain, bowel movements, weight gain, linear growth, physical examination, hematocrit, sedimentation rate, and serum albumin [14,15]. A score of 0 to 10 denotes inactive disease, 11 to 30 mild disease activity, and over 30 moderate to severe disease activity [16]. It is validated for children 3.5 to 19 years of age [14].
●Endoscopic scoring systems – Endoscopic monitoring of disease activity is increasingly used to assess response to therapy, ideally using a scoring system to quantify the findings. Studies in adults support a standardized method of reporting ileoscopy and colonoscopy, involving the use of the simple endoscopic score for CD (SES-CD). The SES-CD is accurate and easier to use than other endoscopic activity assessments [13,17]. This index has not been formally validated in pediatric patients. A modified version of this scoring system for evaluating upper gastrointestinal findings in children (the UGI SES-CD) has been evaluated in one study in children but is not yet in widespread use [18].
●Patient self-report systems – The US Food and Drug Administration has recommended that patient-reported outcomes (ie, questions answered by the patients themselves rather than their clinicians) be utilized in future drug trials for adult and pediatric IBD [19,20]. For pediatric CD, these include general and disease-specific quality-of-life measures, including PedsQL and the IMPACT-35 quality-of-life scale [21-23].
SELECTION OF MEDICAL TREATMENT — The following sections summarize our suggestions for treatment in a variety of commonly encountered clinical settings. For each medication, the efficacy and potential risks are discussed in a separate topic review. (See "Medical therapies for Crohn disease in children and adolescents".)
Ileocolonic disease — For CD affecting the ileum and/or colon, treatment choices depend on disease severity and response (algorithm 1). Disease severity is based on the clinician's global assessment, which is outlined above (see 'Clinical assessment' above), or on the Pediatric CD Activity Index (PCDAI). (See 'Systems for scoring disease activity' above.)
Mild — For patients with mild disease limited to the terminal ileum and/or colon and no complications, we generally make an initial attempt to induce remission using aminosalicylates, with or without antibiotics (table 1). If there is active ileitis, the choice of aminosalicylate should be a timed-release or pH-sensitive release form of mesalamine (Pentasa or Asacol) and not one of the other aminosalicylates that are released only in the colon. The use of these agents in this population is based on limited data, consisting of clinical experience and open-label observational studies; no randomized clinical trials have exclusively studied the mild disease phenotype. A mild disease course for the first two years after diagnosis appears to be an uncommon phenotype, but when it does occur, most patients continue to have a mild disease course and do not require escalation to immunosuppressive agents [24]. Reasonable alternatives are to induce remission with glucocorticoids (either topical budesonide [enemas] or systemic prednisone, depending on disease location) or with exclusive enteral nutrition (EEN) therapy. Topical glucocorticoids also may be used as adjuncts to other therapies for patients with rectal involvement. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Aminosalicylates' and "Medical therapies for Crohn disease in children and adolescents", section on 'Antibiotics' and 'Exclusive enteral nutrition' below.)
Once remission is induced, the patient is transitioned to maintenance therapy with aminosalicylates alone. Aminosalicylates are less effective but have lower toxicity than immunosuppressive agents. As a result, we generally attempt maintenance with aminosalicylates before considering immunosuppressive therapy for patients with mild disease.
If clinical symptoms recur after induction therapy is discontinued, we may attempt re-induction with another course of enteral nutrition or budesonide. For those who respond, we transition to another maintenance agent, typically an anti-tumor necrosis factor (anti-TNF) agent (infliximab or adalimumab), a thiopurine (mercaptopurine or azathioprine), or, occasionally, subcutaneous methotrexate. Patients with recurrent flares requiring glucocorticoid treatment (eg, two or more flares in a 12-month period) are likely to benefit from one of these therapies to reduce glucocorticoid use [25]. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Maintenance medications'.)
Moderate or severe — For patients with moderate or severe CD, there is considerable variation in practice for induction therapy. Options for induction therapy include:
●Early use of an anti-TNF agent, either infliximab or adalimumab
●Glucocorticoids
●EEN
Prior to beginning immunosuppressive treatment, patients should be evaluated for tuberculosis risk factors and tested for latent infection using tuberculin skin testing or interferon-gamma release assay (IGRA). In addition, immunization status should be carefully reviewed and brought up to date, including measurement of titers for measles, hepatitis B virus (HBV), and varicella serologies (table 5) [26]. It is reasonable to take these steps as soon as IBD is diagnosed because many patients will eventually require immunosuppressive treatment [27]. Administration of live viral vaccines warrant special planning because live vaccines are not recommended for immunosuppressed patients. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Infection risk' and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Immunizations'.)
High-risk patients — For selected patients with risk factors for complicated CD (extensive small bowel disease, severe ulcerating colonic disease, growth failure in mid- to late puberty, severe perianal disease, or steroid-unresponsive disease), we suggest use of infliximab or adalimumab soon after diagnosis (within the first two to three months) rather than induction therapy with glucocorticoids followed by an immunomodulator (algorithm 2). Patients with these characteristics have an increased risk of poor disease outcome, and there is moderate evidence to guide patient selection for this approach [1]. Infliximab or adalimumab usually have rapid onset of action and can be used as the initial induction medication or shortly after induction with corticosteroids. Alternatively, it is reasonable to manage these patients by inducing with EEN or glucocorticoids, followed by maintenance therapy with an immunomodulator, based on patient preference or if infliximab or adalimumab are not available (algorithm 1).
A beneficial effect for early treatment with infliximab or adalimumab in selected patients was suggested by a large, multicenter observational study in children with newly diagnosed inflammatory (nonpenetrating, nonstricturing) CD, in which early treatment was compared with early treatment with an immunomodulator (eg, mercaptopurine) and no immunotherapy [28]. The groups were matched by a "propensity score," which effectively narrowed the comparison to subjects with relatively high risks for complicated disease. After one year, remission was achieved in 85.3 percent of the children treated with an anti-TNF antibody versus 60.3 percent of those treated with an immunomodulator, and 54.4 percent of those managed without immunotherapy. Early treatment with an anti-TNF antibody was also associated with lower use of corticosteroids and a modest improvement in linear growth compared with the other treatment groups.
The choice between infliximab and adalimumab depends on clinician and patient preferences, such as a preference for subcutaneous administration (eg, adalimumab) versus infusions (eg, infliximab). Details about the use of infliximab, adalimumab, and other anti-TNF agents, including dosing, efficacy, safety, and decisions about use in combination with other immunosuppressive medications, are discussed separately. (See "Medical therapies for Crohn disease in children and adolescents", section on 'First-line biologic agents' and "Medical therapies for Crohn disease in children and adolescents", section on 'Anti-TNF monotherapy versus combination therapy with an immunomodulator'.)
Standard-risk patients — In patients with moderate or severe disease but without risk factors for complicated disease, as described above, several strategies are used (algorithm 1):
●Glucocorticoids or EEN – We typically initiate treatment with glucocorticoids to induce remission (algorithm 1). We use oral glucocorticoids for those with moderate disease and intravenous glucocorticoids for more severe disease. Some patients with more severe abdominal symptoms may benefit from a limited course of bowel rest (up to two weeks) while glucocorticoids are initiated, with total parenteral nutrition (TPN) to maintain nutrition [29,30]. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Glucocorticoids'.)
EEN is an appropriate alternative to glucocorticoids, especially for patients with growth failure; this approach is frequently used as an induction regimen in the United Kingdom and in parts of Europe and Canada. (See 'Exclusive enteral nutrition' below.)
If remission is successfully induced by glucocorticoids or EEN, patients may be transitioned to another regimen for maintenance treatment, typically an anti-TNF biologic and/or a thiopurine (mercaptopurine or azathioprine), vedolizumab, ustekinumab (in those who lost response to anti-TNF therapy (see 'Refractory disease' below)), or subcutaneous methotrexate. If thiopurine treatment is planned, patients should be evaluated for thiopurine methyltransferase genotype (TPMT genotype) or phenotype (TPMT activity) to determine a safe starting dose. Clinical practice is trending away from selecting thiopurines because of their apparent association with malignancy risk. Use of subcutaneous methotrexate is limited by lower response rates; side effects of nausea, headache, and fatigue; and route of administration [31]. A plain-language summary to guide treatment decisions is outlined in the table (table 6). (See "Medical therapies for Crohn disease in children and adolescents", section on 'Maintenance medications'.)
●Anti-TNF biologics – Many clinicians, particularly those practicing in North America, choose to bypass one or more of the above steps and go directly to infliximab, adalimumab, or another anti-TNF biologic agent for these standard-risk patients (algorithm 1). The relative risks of these two strategies have not been fully established. Considerations are:
•Potential advantages of using anti-TNF agents are the greater efficacy of these biologic agents compared with thiopurines [10,32]. Also, anti-TNF agents probably carry a lower risk for lymphoma than thiopurines, although absolute prevalence of lymphoma is low with either of these drugs as monotherapy.
•Potential disadvantages of anti-TNF agents are their high cost relative to thiopurines and that early use of infliximab may lead to loss of response due to development of antibodies to infliximab. Patients on anti-TNF agents have an increased risk for pulmonary opportunistic infections, psoriasis, and neurologic and infusion reactions.
●Aminosalicylates – Aminosalicylates may be considered for patients who are strongly opposed to immunosuppression, but it is unclear if these drugs are superior to placebo in preventing relapse. Patients with recurrent flares requiring glucocorticoid treatment (eg, two or more flares in a 12-month period) are likely to benefit from immunosuppressive (immunomodulatory or biologic) therapy to reduce glucocorticoid use [25]. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Aminosalicylates'.)
Fistulizing disease — The transmural, inflammatory nature of CD predisposes to the formation of fistulae, a complication that may dominate the clinical picture in some patients. For complicated or refractory fistulizing/penetrating disease, infliximab or adalimumab is the treatment of choice, sometimes initially combined with bowel rest and TPN for severely ill patients [1]. Treatment with infliximab does not appear to increase the risk for abscess formation. (See "Medical therapies for Crohn disease in children and adolescents", section on 'First-line biologic agents'.)
A thiopurine or methotrexate also may be helpful for fistulizing disease (as maintenance but not induction therapy). Because these are older drugs, there is less evidence for their efficacy for fistulizing disease than for biologic agents [33]. Antibiotics (eg, ciprofloxacin, metronidazole, or azithromycin) are sometimes used for patients with mild or uncomplicated fistulizing disease (especially perianal fistulas), despite limited evidence. Glucocorticoids and aminosalicylates are not beneficial for fistulizing disease. Management of perianal fistulizing disease is discussed below. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Antibiotics' and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Fistulizing disease' and 'Perianal disease' below.)
Abdominal abscess — Abdominal abscesses (with or without fistulae) should be treated with the combination of percutaneous drainage and systemic antibiotics. Percutaneous drainage promotes healing and should be performed for abscesses larger than 2 cm [33]. Patients should not be fed and are supported with TPN, and the drain should be left in place until the output is low (eg, <10 mL/day).
Antibiotics should initially be selected empirically to target both nosocomial and community-acquired organisms. Appropriate intravenous regimens include imipenem, piperacillin-tazobactam, ticarcillin-clavulanate (where available), or the combination of ceftazidime with metronidazole [33]. Once cultures are obtained, the antibiotic spectrum should be narrowed based on sensitivities of cultured organisms.
Patients with persistent or recurrent abscesses are candidates for percutaneous drainage, followed by surgical resection of the affected intestinal segment [33]. There is ongoing controversy about whether a patient with an abdominal abscess can be managed by percutaneous drainage followed by biologic therapy or whether all patients with abdominal abscess should proceed to surgery [33]. (See "Surgical management of Crohn disease", section on 'Immunosuppressive or biologic therapy'.)
Refractory disease — Patients with ongoing symptoms while on the initial maintenance treatment (whether aminosalicylate, immunomodulator, or anti-TNF biologic) should be reevaluated after three to six months. The reevaluation should ideally include endoscopy to permit disease restaging and to provide objective evidence of lack of or loss of response versus other causes of symptoms such as irritable bowel syndrome, as well as consideration given to change of therapy.
Approximately 30 percent of children with CD are refractory to or dependent on steroids despite concomitant use of thiopurines (mercaptopurine or azathioprine) [34], and a few others are intolerant of thiopurines. In this case, the first-line treatment options are infliximab or adalimumab (algorithm 2). Details about the use of infliximab and adalimumab, including dosing, efficacy, safety, and decisions about use in combination with other immunosuppressive medications, are discussed separately. Patients who do not respond to anti-TNF treatment may benefit from dose adjustment of the anti-TNF, reevaluation to see if there is a surgically resectable segment, or change to another treatment. (See "Medical therapies for Crohn disease in children and adolescents", section on 'First-line biologic agents' and "Medical therapies for Crohn disease in children and adolescents", section on 'Anti-TNF monotherapy versus combination therapy with an immunomodulator'.)
Second-line options for patients who do not respond to immunomodulator and anti-TNF treatment include ustekinumab, vedolizumab, or, occasionally, surgical resection of a discrete diseased segment of the bowel. Vedolizumab and ustekinumab are being studied in children and may transition to first-line biologic treatments because of their better safety profile. (See 'Surgery' below and "Medical therapies for Crohn disease in children and adolescents", section on 'Second-line biologic agents'.)
Before beginning immunosuppressive treatment, patients should be evaluated for latent tuberculosis infection and immunizations brought up to date, as discussed above. (See 'Moderate or severe' above.)
Other disease locations — In addition to the above general guidelines for medication choice by disease severity and response to treatment, some medication choices are influenced by disease location.
Oral lesions — Topical prednisolone syrup may be helpful. For lesions on the lips, consider 0.1% triamcinolone applied to the lips. Evaluate for systemic disease and treat accordingly.
Gastroduodenal disease — Treatment is induced with glucocorticoids for other enteric disease locations. However, because aminosalicylates are ineffective in the stomach, patients with medically significant gastroduodenal disease should be treated with mercaptopurine/azathioprine, subcutaneous methotrexate, or anti-TNF biologic therapy for maintenance therapy. Acid blockade for gastritis or esophagitis with proton pump inhibitors (eg, omeprazole or lansoprazole) may be helpful.
Active ileitis — If disease appears to involve the ileum, treatment is similar to that for ileocolonic disease as outlined above and may include glucocorticoids, aminosalicylates, immunomodulators, or anti-TNF antibodies. For these patients, the choice of aminosalicylate should be a timed-release or pH-sensitive release form of mesalamine (Pentasa or Asacol) and not one of the other aminosalicylates that are released only in the colon. Similarly, if budesonide is selected, the formulation should be enteric coated (eg, Entocort) to distribute the drug to the ileum and cecum. Patients whose disease is limited to the ileum and does not respond to medical treatment are good surgical candidates. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Aminosalicylates' and "Medical therapies for Crohn disease in children and adolescents", section on 'Budesonide'.)
Isolated colonic Crohn disease — Colonic CD is generally treated with corticosteroid or nutrition induction, transitioning to immunomodulators or biologics for maintenance, similar to management of ileocolonic CD, as described above (see 'Ileocolonic disease' above). Increasingly in the United States, anti-TNF therapy is the primary medical modality utilized. Some clinicians bypass corticosteroids and utilize anti-TNF for induction and maintenance. In very mild cases of Crohn colitis (eg, very mild inflammation with a few granulomas seen on biopsy), an aminosalicylate such as sulfasalazine may be attempted, but the patient needs to be followed closely to make sure the disease does not progress. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Second-line biologic agents'.)
Proctitis — For patients with prominent rectal CD, rectally administered glucocorticoids or aminosalicylate preparations may be useful as adjunct therapy. Options include mesalamine, hydrocortisone, or budesonide formulated as an enema, foam, or suppository.
Perianal disease — A detailed assessment of the perianal disease is valuable to determine the appropriate therapy and monitor the clinical response [35]. An examination under anesthesia, ultrasonography, and/or pelvic magnetic resonance imaging (MRI) may be necessary for a full evaluation.
Any perianal abscesses should be drained surgically if needed, followed by antibiotics. For perianal fistulas, antibiotics (metronidazole or ciprofloxacin) are generally used as initial therapy, although the evidence supporting their efficacy is limited [35,36]. Mercaptopurine or azathioprine should be added if the perineum does not heal. For complicated or refractory perianal disease, infliximab or some other anti-TNF agent is the treatment of choice and may be particularly valuable for patients with enterocutaneous fistulas. Glucocorticoids should generally be avoided for patients with clinically significant fistulizing disease since they appear to be associated with worse outcomes for this group of patients [35,37]. Perianal setons are commonly utilized to promote drainage, prevent abscess recurrence, and provide pain relief. However, they will keep a fistulous tract open indefinitely until the seton is removed.
The assessment and management of perianal disease is discussed in a consensus statement from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) [35] and in a separate topic review. (See "Perianal Crohn disease".)
NUTRITIONAL THERAPY — Nutritional therapy has three distinct applications in the treatment of CD:
●Exclusive enteral nutrition (EEN) – Providing all nutritional needs through a liquid formula (EEN or primary nutritional therapy) can promote mucosal healing in a patient with active disease and suppress intestinal inflammation, possibly by altering the gut microflora [38-40]. In this context, nutritional therapy is used as an alternative or supplement to antiinflammatory medications. Nutritional therapy may be particularly useful in motivated children and families who wish to avoid corticosteroids. (See 'Exclusive enteral nutrition' below.)
●Supplemental enteral nutrition – Enteral nutrition can also be used as a supplement to increase energy and nutrient intake and promote growth in a patient with growth failure while the patient continues to take food orally. Supplemental enteral nutrition may also maintain remission by suppressing intestinal inflammation. (See "Growth failure and pubertal delay in children with inflammatory bowel disease" and 'Supplemental enteral nutrition' below.)
●Micronutrient deficiencies – Children with CD are at risk for micronutrient deficiencies due to inadequate food intake and malabsorption, including deficiencies of iron, vitamin B12, and zinc. Optimal care includes routine monitoring for these deficiencies and replacement as needed (table 3). Assurance of adequate intake of calcium and vitamin D are particularly important to minimize risks of osteopenia and osteoporosis. (See "Vitamin and mineral deficiencies in inflammatory bowel disease" and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density'.)
Exclusive enteral nutrition
●Technique – EEN requires that the patient stop eating and receive all dietary energy from formula (taken by mouth, nasogastric tube, or gastrostomy) for 8 to 12 weeks. In most centers, the duration of a course of EEN is six to eight weeks. A daily volume of formula is calculated based on estimated energy requirements and adjusted based on serial measurements of weight and height. The method and evidence base for EEN are reviewed in guidelines from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) [41], the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) [42], and the European Crohn's and Colitis Organisation (ECCO) [1]. The NASPGHAN guideline includes practical considerations for implementation of EEN, including calculation of energy needs and methods of nasogastric tube feeding [41].
●Efficacy – EEN appears to suppress inflammation and promote mucosal healing [1,41-46]. Moreover, small randomized trials suggest that EEN improves growth as compared with glucocorticoids [47-49].
EEN appears to be useful for inducing remission but may be less effective than glucocorticoids. Treatment failures in trials of EEN therapy may be partly explained by patient withdrawal from therapy. In the largest meta-analysis of randomized trials, 83 percent of children treated with EEN achieved remission compared with 61 percent of those treated with glucocorticoids, a difference that was not statistically significant (relative risk [RR] 1.35, 95% CI 0.92-1.97) [50]. In adults, EEN was less likely to achieve remission than glucocorticoids (45 percent versus 73 percent, RR 0.65, 95% CI 0.52-0.82). Subgroup analyses showed no significant differences in effectiveness between formulas of different protein composition (elemental versus polymeric). These findings are consistent with an earlier meta-analysis of eight studies conducted prior to 1995, in which the remission rate ranged from 50 to 80 percent after four weeks of EEN [51]. One of the included studies found that EEN induced mucosal healing more often than glucocorticoids, while the two treatments were equally effective in inducing remission [43]. One report suggests that EEN may be less effective in CD that is limited to the colon as compared with ileocolic CD [52].
The effects of EEN on quality of life and psychological well-being are not well studied. One study found that treatment with EEN was associated with improvements on a standardized measure of quality of life and that this was closely correlated with disease activity [53].
●Patient selection – The option of treatment with EEN should be routinely discussed as an alternative to glucocorticoids for induction of remission in children with CD. This is consistent with North American guidelines [27,41]. European guidelines encourage EEN in preference to glucocorticoids [1,27,41,42]. An important determinant of the decision is the family's and patient's willingness to commit to the EEN regimen, which involves drinking only formula and eating no food for 8 to 12 weeks. Adherence to the treatment protocol is essential for treatment success, and the family and patient should be informed that response to treatment may be gradual. EEN may be particularly appropriate for patients with growth failure and/or those who are steroid-dependent [25]. This suggestion is based on knowledge of the established adverse effects of glucocorticoids, particularly on bone density, and on the evidence that EEN is moderately effective for inducing remission and mucosal healing. For patients with severe disease, EEN might be used in combination with other medical treatments for induction of remission.
EEN is used far less often than glucocorticoids in the United States for treatment of CD. Providers who rarely use EEN generally cite concerns about adherence due to the limited palatability of most formulas and the desire of most North American children to avoid use of a nasogastric tube [54]. EEN is used somewhat more frequently in Canada and much more frequently in Western Europe compared with the United States [1,42,54-56].
●Follow-up – Little evidence is available to guide maintenance treatment for children in whom EEN successfully induces remission. Options include transition to maintenance medical therapy (eg, 5-aminosalicylic acid or mercaptopurine) and/or tapering to partial enteral nutrition (PEN). In one case series, 28 children were transitioned to nocturnal enteral feeds and resumed eating by mouth during the day [57]. These children were less likely to relapse during the subsequent 12 months as compared with a group of children who opted not to use nocturnal feedings (43 percent versus 79 percent relapse, p<0.02). One older study examined intermittent four-week courses of EEN every four months over a year in eight patients with CD and growth failure and found significantly higher weight and height gains, lower disease activity, and decreased prednisone use compared with age-matched controls receiving standard medical therapy [58].
Partial enteral nutrition with specific exclusion diet — One study suggests that the combination of partial enteral nutrition (PEN) with a specific whole foods-based exclusion diet (CD exclusion diet [CDED]) is more easily accepted by patients than EEN and is at least as effective in inducing remission. In a randomized multinational trial of 74 children with CD, children were treated with 12 weeks of either PEN plus CDED (two six-week phases), or EEN for six weeks transitioning to PEN plus a free diet [59]. Those treated with PEN plus the CDED were more likely to complete six weeks of therapy (98 versus 74 percent) and had similar rates of corticosteroid-free remission (80 versus 74 percent). Since this reflects an intention to treat analysis, the performance of the PEN plus the CDED is likely related to better acceptance with fewer dropouts from that group compared with EEN. The CDED used in this study consists of fruits, vegetables, and selected grains and limits exposure to other foods and food additives purported to induce intestinal dysbiosis (including animal fats, dairy, and gluten) [60].
Supplemental enteral nutrition — Enteral nutrition also has been used as a supplement to a regular diet to maintain remission. Although supplemental therapy is less effective than EEN in inducing remission [44], limited data suggest that it can be helpful in maintaining remission [1,57,61,62]. However, the efficacy of this approach has not been established, and many children are unwilling to continue enteral nutrition long term.
Supplemental enteral nutrition also is used to enhance linear growth and nutritional status in children with growth failure. The indications and implementation of this approach are discussed in a separate topic review. (See "Growth failure and pubertal delay in children with inflammatory bowel disease".)
Other dietary changes — Although epidemiologic and biologic research suggests a possible role for dietary factors in the pathogenesis of inflammatory bowel disease (IBD) [63], there is no good evidence for specific dietary regimens other than to eat a healthy, diverse diet. A study in adults with CD compared the specific carbohydrate diet to the Mediterranean diet and found comparable remission rates [64]. Therefore, it is reasonable to recommend the Mediterranean diet to patients who want to use a dietary approach as an adjunct to their medical regimen, especially since the Mediterranean diet is beneficial for heart health and may be easier to comply with than the specific carbohydrate diet.
The recommendation of a healthy diverse diet is supported by the International Organization for the Study of IBD, which advises patients with IBD to consume a balanced diet composed of carbohydrates, fats, and protein and to limit intake of processed food (eg, sulfites) and artificial sweeteners while avoiding trans fatty acids [65]. These recommendations were based on low- or very low-quality evidence. (See "Nutrition and dietary management for adults with inflammatory bowel disease".)
In particular, none of the following dietary approaches has been shown to be beneficial in maintaining remission:
●Fat, fiber, and carbohydrates – Observational evidence in humans and experimental evidence in animals suggest that dietary fats and carbohydrates may affect intestinal inflammation [63]. Soluble fiber is fermented into short-chain fatty acids in the colon, which in turn are thought to reduce colonic inflammation. However, the same fermentation process may produce gas and diarrhea, causing increased symptoms.
•Diets with variable fiber content and carbohydrate composition have been studied in single-blind, randomized trials in adults. Neither diets low in sugar and increased in fiber content [66,67] nor diets with reduced fiber content ("low-residue") altered the clinical course of the subjects as compared with a control group [68].
•There is insufficient evidence to recommend restriction of wheat and gluten [65]. Gluten-related symptoms reported by many patients may be related to co-ingestion of other fermentable carbohydrates (FODMAPs).
•There is insufficient evidence to recommend restriction of meats or poultry [65].
●Carrageenan and emulsifiers – Limited evidence from animal models and a very small randomized trial suggest that carrageenan can exacerbate inflammation [69]. Animal models also support this possibility for carboxymethylcellulose or polysorbate 80 [65].
●Fish oil – Fish oil and other sources of omega-3 (n-3) fatty acids have antiinflammatory effects in animal models of IBD [70]. However, there is insufficient clinical evidence to draw conclusions about the effects of n-3 fatty acids on the clinical outcomes of CD, based on two systematic reviews of the available literature [71,72]. (See "Vitamin and mineral deficiencies in inflammatory bowel disease", section on 'Answers to common clinical questions'.)
●Other elimination diets – Small observational studies with methodologic flaws suggest that the "specific carbohydrate diet" (which excludes refined sugars, dairy products, and complex carbohydrates), either as primary or adjunct therapy, might be associated with improvement in Pediatric CD Activity Index (PCDAI), serum and stool inflammatory markers, and/or mucosal healing [73,74]. In all cases of dietary therapy, counseling by a registered dietician is advised to make sure that the patient is receiving adequate calories and micronutrients.
There is better evidence for the specific exclusion diet (CDED) used in conjunction with partial enteral nutrition to induce remission, as discussed above. (See 'Partial enteral nutrition with specific exclusion diet' above.)
A few other dietary changes may be appropriate in specific clinical situations:
●Lactose intolerance – Lactose intolerance is more prevalent in patients with CD, particularly those with small bowel disease [75]. These individuals, like other patients with lactose intolerance, may get symptomatic relief from reducing dietary lactose. Thus, for patients with symptoms consistent with lactose intolerance, a trial of a lactose-reduced diet is reasonable. In this case, care should be taken to ensure that adequate dietary calcium and vitamin D are provided.
●Strictures – For other patients with CD and strictures, a low-residue diet may be an appropriate step to avoid bowel obstruction. However, it should be recognized that such dietary changes are unlikely to be relevant, except in unusual cases where a stricture is nearly obstructive, and these patients are likely to need other intervention to avoid this complication [76].
●Micronutrient deficiencies – Evaluation and management of vitamin and mineral deficiencies in patients with CD are discussed separately. (See "Vitamin and mineral deficiencies in inflammatory bowel disease".)
SURGERY
●Perioperative considerations – Hospitalized children and adolescents with inflammatory bowel disease (IBD) are at increased risk for thromboembolism. Though less common than in adults with IBD, thromboembolic (TE) events in children with IBD seem to occur during active disease, with risk factors including previous thromboembolism, major surgery, presence of a central venous catheter, older age, use of parenteral nutrition, and an identified hypercoagulable condition. Routine thromboprophylaxis (anticoagulation) for hospitalized children with IBD remains controversial but should be seriously considered for those with potential risk factors for TE. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Venous thromboembolism'.)
Nutrition support (enteral and/or parenteral) should be considered in any IBD patient about to undergo surgery, especially if the patient is malnourished. Preoperative supplemental nutrition reduces postoperative complications, with a trend toward parenteral nutrition being superior to enteral nutrition [77]. (See 'Supplemental enteral nutrition' above.)
●Indications and efficacy – Surgery in CD is reserved primarily for patients who do not respond to medications or who develop complications (abscess, fistula, perforation, hemorrhage, obstruction, or stricture) that can only be treated surgically.
A review of surgery in pediatric patients with CD estimated that 3.4 to 7.9 percent will undergo surgery within one year of diagnosis, 13.8 to 47.2 percent by five years, and 28 to 34.5 percent by 10 years [78]. Thus, although treatment of CD primarily is medical, many patients will require surgery at some point during their clinical course (see "Surgical management of Crohn disease"). Risk factors for initial surgery are highest in subjects with complicated disease behavior (stricturing and penetrating disease), anti-Saccharomyces cerevisiae antibody (ASCA) positivity, hypoalbuminemia, leukocytosis (at diagnosis), and poor growth [79].
Surgery can be particularly effective in patients with a limited region of disease (eg, terminal ileal or ileocecal disease). The type of surgery depends on the location and disease of the individual patient. The most common type of surgery is ileal resection with partial colectomy and reanastomosis of the remaining healthy colon to the healthy ileum [79-82]. Less common surgeries include subtotal or total colectomy with permanent ileostomy, segmental removal of colon with reanastomosis, strictureplasty, or isolated small bowel resection. The benefits of surgery include rapid improvement in an ill patient and catch-up of growth and puberty in a child or adolescent [83,84].
Postoperative complications, including infections, probably are not increased in patients treated with immunomodulators just prior to surgery [85-87]. (See "Surgical management of Crohn disease", section on 'Immunosuppressive or biologic therapy'.)
●Extent of resection – Surgery usually involves laparoscopic resection of the diseased bowel segment and primary end-to-end anastomosis. In some patients with multiple small bowel strictures, strictureplasty (widening of the strictured area in a manner similar to pyloroplasty) may reduce the need for bowel resection. Recurrence rates with strictureplasty and resection are similar [88-90]. In patients with extensive Crohn colitis that is not responsive to medical therapy, full colonic resection and end-ileostomy may be unavoidable.
The aim of surgery is to resect as little bowel as possible since CD recurs in approximately 40 to 50 percent of patients within two to five years and approximately 75 percent of patients with 10 years, and approximately 20 percent of patients will require a second surgery within 10 years postoperatively [81,91].
●Postoperative recurrence – After surgery, clinical recurrence rates range from 20 to 37 percent at one year and from 34 to 86 percent at three years [92-94]. Endoscopic recurrence precedes the return of clinical symptoms [92,95]. The severity of endoscopic lesions can predict the likelihood of recurrent disease and increased risk of future surgery more than clinical symptoms [96]. For these reasons, endoscopic surveillance of the anastomotic area 6 to 12 months after surgery is recommended to identify a preclinical endoscopic recurrence and allow for earlier treatment modification [1,97].
Risk factors for earlier postoperative recurrence include diffuse (ileocolonic) rather than focal disease, complicated disease [92,98,99], and younger age at surgery [94]. Early initiation of medical treatment is recommended to prevent postoperative recurrence of CD [1]. Based on adult studies, postoperative medical treatment was associated with better outcomes compared with delaying treatment until after endoscopic inflammation has already developed [100,101]. The treatment target is endoscopic and histologic remission, which are associated with better long-term outcomes compared with measures of clinical symptoms [102].
A systematic review of studies in adults found that anti-tumor necrosis factor (anti-TNF) agents are the most effective medications at preventing postoperative endoscopic recurrence and suggested that these medications can be started as soon as four weeks after surgery [103]. Thiopurines also have a role in decreasing postoperative recurrence, but their use must be weighed with the small increased risk of hepatosplenic lymphoma [104]. Methotrexate is associated with a lower risk of lymphoma, but there is little evidence to show that methotrexate monotherapy is effective to prevent postoperative recurrence [78]. Aminosalicylates and antibiotics have minimal benefit in reducing the postoperative recurrence rate (from 40 percent untreated to approximately 30 percent if treated with mesalamine or metronidazole) [78,103,105]. (See "Management of Crohn disease after surgical resection".)
IMPORTANT HEALTH MAINTENANCE ISSUES — Comprehensive health care for children and adolescents with CD requires special considerations for each of the following health maintenance issues:
●Monitoring nutritional status
●Bone health
●Infection risk
●Immunizations
●Eye examinations
●Psychological issues
●Transition to adult health care
●Cancer surveillance
Each of these issues is addressed in a separate topic review. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inflammatory bowel disease in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Crohn disease in children (The Basics)")
●Beyond the Basics topic (see "Patient education: Crohn disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Assessment and monitoring of disease severity – Treatment decisions for patients with Crohn disease (CD) require careful assessment and monitoring of disease location and activity. This includes serial clinical assessments of symptoms and supporting laboratory data, ideally quantified using the Pediatric CD Activity Index (PCDAI) (table 4). Objective assessments, including follow-up magnetic resonance imaging (MRI), upper endoscopy with biopsies, and colonoscopy with biopsies, are increasingly used to monitor disease progression and guide treatment decisions; this is known as a treat-to-target approach. (See 'Assessment of disease activity' above and 'Treatment goals' above.)
●Treatment for mild ileocolonic disease – For patients with mild disease of the ileum and/or colon, we suggest an initial attempt to induce remission using aminosalicylates, with or without antibiotics, rather than initial treatment with glucocorticoids (Grade 2C). Aminosalicylates may reduce symptoms in mild cases. However, they are generally ineffective at inducing mucosal healing for many cases of CD. Therefore, close follow-up is needed and, if inflammation persists, use of an immunomodulator or biologic may be needed. (See 'Mild' above.)
●Treatment for moderate or severe ileocolonic disease – For patients with moderate or severe disease of the ileum and/or colon, a variety of treatments are available (table 1) and there is considerable variation in practice. The choice of drugs typically depends on disease severity and response (algorithm 1). Treatment decisions also depend upon the values and preferences of the patient and family. A plain-language summary to guide treatment decisions is outlined in the table (table 6).
•For patients with risk factors for complicated disease (eg, those with extensive small bowel disease, severe ulcerating colonic disease, growth failure in mid- to late puberty, severe perianal disease, or steroid-unresponsive disease), we suggest early treatment with infliximab or adalimumab rather than induction therapy with glucocorticoids (Grade 2C). A combination of glucocorticoids with infliximab or adalimumab also may be used for the induction therapy. (See 'High-risk patients' above.)
•For patients with no risk factors for complicated disease, we suggest induction of remission with either glucocorticoids or exclusive enteral nutrition (EEN; either polymeric or elemental formulas) rather than aminosalicylates or anti-tumor necrosis factor (anti-TNF) agents (Grade 2C). The choice between glucocorticoids and EEN depends primarily on patient preference and whether the clinician has experience with this therapy. Use of an anti-TNF agent is a reasonable alternative; the choice depends in part on the intended maintenance regimen and cost considerations. (See 'Standard-risk patients' above.)
•EEN should be routinely offered as an alternative or adjunct to glucocorticoids or anti-TNF agents for induction of remission in children with CD. EEN may be particularly appropriate for patients with growth failure and/or those who are steroid-dependent. EEN involves drinking only formula and eating no food for 8 to 12 weeks. This approach is moderately effective for inducing remission and mucosal healing and helps to avoid the established adverse effects of glucocorticoids, particularly on bone density. An important determinant of the decision is the family's and patient's willingness to commit to the EEN regimen since this is essential for adherence and treatment success. Preliminary studies suggest that partial enteral nutrition (PEN) with a specific exclusion diet may be as effective and better accepted by patients than EEN. (See 'Exclusive enteral nutrition' above and 'Partial enteral nutrition with specific exclusion diet' above.)
•If patients treated with EEN or glucocorticoids respond to induction therapy, we suggest transitioning to maintenance therapy with a thiopurine (mercaptopurine or azathioprine) or subcutaneous methotrexate rather than aminosalicylates or multiple courses of glucocorticoids (Grade 2C). Before beginning treatment with a thiopurine, patients should be evaluated for the thiopurine methyltransferase genotype (TPMT genotype) or phenotype (TPMT activity) to determine a safe starting dose. Patients treated with these drugs require close monitoring during therapy. Patients who were induced with an anti-TNF agent typically continue on that agent for maintenance. However, the benefits and risks of anti-TNF agents compared with other maintenance agents (thiopurines or methotrexate) are unclear and require further study. (See 'Standard-risk patients' above and 'Overview of treatment decisions' above.)
●Refractory ileocolonic disease – For patients with ileocolonic disease that is refractory to or dependent on glucocorticoids despite maintenance treatment with thiopurines or methotrexate, treatment may be advanced by adding infliximab, adalimumab, or another biologic agent (eg, vedolizumab, ustekinumab), with or without concomitant thiopurine or methotrexate. Surgery may be helpful for patients with disease in a discrete segment of the bowel (algorithm 2). (See 'Refractory disease' above and 'Surgery' above.)
●Other disease locations – Patients with oral lesions, perianal disease, or proctitis may benefit from other treatment strategies. (See 'Other disease locations' above.)
●Considerations for specific therapies – Details about the main medical therapies used for CD are discussed in a separate topic review (see "Medical therapies for Crohn disease in children and adolescents"). Additional considerations include:
•Immunosuppressive therapy – Before beginning treatment with immunosuppressing medications (especially infliximab and other anti-TNF antibodies), patients should be evaluated for tuberculosis risk factors and tested for latent infection using tuberculin skin testing or interferon-gamma release assay (IGRA). In addition, immunization status should be carefully reviewed and brought up to date, including measurement of titers for measles and hepatitis B virus (HBV) serologies and documentation of immunity to varicella (table 5). (See 'Moderate or severe' above and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Immunizations'.)
•Thromboembolism prophylaxis – Hospitalized children and adolescents with inflammatory bowel disease (IBD) are at increased risk for thromboembolism. Thromboembolic (TE) events in children with IBD occur during active disease, with risk factors including previous thromboembolism, major surgery, central venous catheter, older age, and use of parenteral nutrition. All hospitalized patients should be managed with nonpharmacologic interventions to minimize their risk, and those with multiple risk factors may warrant thromboprophylaxis (anticoagulation). (See 'Surgery' above and "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Venous thromboembolism'.)
●General monitoring and health maintenance – Comprehensive health care for children and adolescents with CD requires special considerations for monitoring growth and nutritional status, including for micronutrient deficiencies (table 3), infection risk, psychological issues, and cancer surveillance. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease" and "Growth failure and pubertal delay in children with inflammatory bowel disease".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alan Leichtner, MD, who contributed to earlier versions of this topic review.
16 : Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.
41 : Use of enteral nutrition for the control of intestinal inflammation in pediatric Crohn disease.
