INTRODUCTION — Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis (UC) and Crohn disease (CD). UC affects the colon and is characterized by inflammation of the mucosal layer. CD can involve any component of the gastrointestinal tract from the oral cavity to the anus and is characterized by transmural inflammation. These disorders have distinct pathologic and clinical characteristics, but their pathogenesis remains poorly understood. The diseases may present at any age, but peak incidence is in adolescents and young adults. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease" and "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)
The diagnostic evaluation of IBD involves five steps. The first two typically are performed by the general pediatrician, while the last three are performed by the pediatric gastroenterologist.
●Clinical suspicion of the illness based upon clinical symptoms, examination, and screening laboratory data
●Exclusion of other illnesses that have a similar presentation
●Differentiation between CD and UC
●Localization of the region of the disease
●Identification of extraintestinal manifestations (eg, sclerosing cholangitis)
Patients with very early-onset IBD (ie, under age six years, and especially those under age two years) may also warrant immunologic evaluation and genetic sequencing for monogenic forms of IBD.
The diagnosis of IBD in children is reviewed here. Other topics that discuss IBD in children are:
●(See "Overview of the management of Crohn disease in children and adolescents".)
●(See "Management of mild to moderate ulcerative colitis in children and adolescents".)
●(See "Management of severe or refractory ulcerative colitis in children and adolescents".)
●(See "Growth failure and pubertal delay in children with inflammatory bowel disease".)
●(See "Important health maintenance issues for children and adolescents with inflammatory bowel disease".)
EPIDEMIOLOGY — The peak incidence of IBD occurs in patients between the ages of 15 and 30 years [1]. Approximately 5 to 10 percent of patients develop their IBD during childhood or adolescence, although the incidence of pediatric IBD appears to be increasing [2-4]. CD and UC are rare under the age of five years but have been reported as early as infancy [5-9]. In Canada, a country with a high incidence of IBD, the incidence is 10 to 20 individuals per 100,000 population in children 10 to 20 years, compared with approximately 2 per 100,000 in those younger than 10 years [10]. Over 50,000 children in the United States have IBD [2]. (See 'Very early-onset inflammatory bowel disease' below.)
Compared with adults, children with IBD are more likely to present with extensive intestinal involvement and have rapid clinical progression [11,12]. Children also are more likely to have a family history of IBD, suggesting a stronger genetic association for IBD presenting during childhood [5,13]. In particular, a small subset of children who develop IBD-like intestinal inflammation before six years of age have a single gene defect that affects immune function or disturbs epithelial barrier function, collectively known as "monogenic IBD" [6,9,14]. (See "Genetic factors in inflammatory bowel disease" and 'Very early-onset inflammatory bowel disease' below.)
Data from a multicenter pediatric IBD registry provide a description of the characteristics of pediatric IBD according to age [5]. The following observations were made:
●The mean age at diagnosis was 10.3 years; 15 percent of patients were diagnosed before age six years (6 percent before three years), 48 percent at 6 to 12 years, and 37 percent at 13 to 17 years.
●Family history (including both first-degree relatives and extended family) was positive for IBD in 29 percent of patients overall and 44 percent of children with UC who were younger than three years.
●Isolated colonic disease, whether CD, UC, or indeterminate colitis, was more common among children younger than eight years than among older children.
Other aspects of the epidemiology of IBD, including demographics, geographic and time trends, and risk factors, are described separately. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease", section on 'Epidemiology'.)
CLINICAL MANIFESTATIONS
Typical presenting symptoms — Patients with IBD typically present in late childhood or adolescence with one or several of the following features:
●Gastrointestinal symptoms – Diarrhea, bloody stools, abdominal pain, or tenesmus.
●Growth – Growth failure (subnormal gains in height or weight, or weight loss), and/or delayed puberty. Growth failure is a common feature, especially in those with Crohn disease (CD). Nonetheless, a substantial number of children are overweight when they present with IBD because overweight and obesity are common in most populations [15,16]. Thus, obesity or lack of growth failure should not preclude a diagnosis of IBD.
●Physical findings – Abdominal tenderness and/or mass (especially in the right lower quadrant), perianal disease (fistulae, anal skin tags, or fissures (picture 1)), or occult blood in stool.
●Systemic symptoms – Fever and fatigue are common at presentation and during flares of disease.
●Extraintestinal manifestations – Oral ulcerations (eg, aphthous stomatitis) (picture 2), clubbing, rash (erythema nodosum or pyoderma gangrenosum), eye inflammation (uveitis), jaundice or hepatomegaly, or arthritis. (See 'Extraintestinal manifestations' below.)
Findings suggesting colitis — Colitis (inflammation of the large intestine) can occur in patients with either UC or CD. Colitis usually presents as a subacute illness characterized by diarrhea that almost always contains blood, fatigue, anemia, and sometimes weight loss. The onset of symptoms may be insidious, with diarrhea that is initially nonbloody and sometimes poor weight gain. Some children have a more fulminant presentation, with severe abdominal pain, frankly bloody diarrhea, tenesmus, fever, leukocytosis, and hypoalbuminemia.
By definition, patients with UC have colitis that affects the rectum and extends proximally to a variable degree. CD also may involve the colon, either exclusively (Crohn colitis) or in combination with small intestinal involvement (Crohn ileocolitis). Individuals with IBD presenting at a young age are particularly likely to present with symptoms of colitis: 10 to 15 percent of children and adolescents with IBD present prior to six years of age, and the majority of these children have isolated colonic disease (either UC or Crohn colitis) [5,17,18]. CD tends to be diagnosed in late childhood or adolescence and is the predominant form of IBD diagnosed after eight years of age [5,19].
Other gastrointestinal manifestations — Some patients, particularly those with CD, present with nonspecific gastrointestinal symptoms that may be difficult to distinguish from more common conditions such as functional abdominal pain. The most useful indicators of possible IBD in a child with abdominal pain are: diarrhea, growth failure, pubertal delay, weight loss, rectal bleeding, pallor/fatigue, perianal skin tags (picture 1) (which may be misdiagnosed as hemorrhoids), perianal fistulae or abscesses, a palpable abdominal mass, and a family history of IBD. The abdominal pain associated with CD is often focal and located in the right lower quadrant. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents".)
Growth failure or delay — Growth failure or growth delay is common at presentation, particularly in children with CD. The earliest and most subtle form of growth failure is a decrease in height velocity; this may progress to short stature for age, delayed bone age, and/or pubertal delay. Up to 50 percent of patients with CD have a decrease in height velocity before the onset of any other intestinal symptoms [20]. (See "Growth failure and pubertal delay in children with inflammatory bowel disease".)
Extraintestinal manifestations — Extraintestinal conditions associated with IBD (including nonspecific symptoms such as arthralgias) are identified in approximately 10 percent of patients at presentation and up to 30 percent of patients within the first few years after the IBD is diagnosed [21,22]. These may involve the mouth (picture 2), skin, joints, liver, eye, and (rarely) other organs (table 1A-B).
These disorders are idiosyncratic, appearing in some patients and not others with no clear pattern, although they are more often associated with colonic disease (ie, Crohn colitis or UC). Certain extraintestinal manifestations are more common in CD compared with UC, including oral aphthae (superficial ulcerations, also known as aphthous stomatitis), erythema nodosum, digital clubbing, and arthritis. They do not consistently correlate with the degree of intestinal inflammation. Occasionally, patients present with extraintestinal symptoms (such as aphthous stomatitis, arthritis, or liver disease) before any obvious gastrointestinal symptoms develop [21,23].
Details about these extraintestinal manifestations of IBD are discussed separately. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Extraintestinal manifestations'.)
Laboratory features — The following laboratory features are suggestive of IBD:
Blood tests
●Anemia, increased white blood cell, and platelet count – Approximately 70 percent of patients have anemia at diagnosis of IBD (eg, hemoglobin level <11 g/L) [24,25].
●Elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) – Approximately 65 to 75 percent of patients have an elevated ESR at diagnosis of IBD, and approximately 85 percent have elevated CRP [24,26]. However, estimates vary depending on disease type (CD versus UC), disease severity, and on the cutoff value used to define abnormal ESR or CRP. There are no widely accepted cutoff values for ESR and CRP for identifying patients at risk for IBD, and the normal range for CRP varies among laboratories. In studies evaluating the predictive value of these inflammatory markers, an ESR >20 or >25 mm/hr and CRP >5 or >10 mg/L have been used [26-28]. These markers are somewhat more sensitive for detecting CD than UC, and CRP is more sensitive than ESR [29]. As an example, among children evaluated at a referral center for IBD, CRP was elevated in 100 percent of those with CD and 60 percent of those with UC [26]. In the same study, ESR was elevated in 85 percent of patients with CD and 23 percent of those with UC.
●Depressed albumin level – Approximately 40 percent of patients with IBD have depressed albumin levels at diagnosis (eg, <3.4 g/L) [24].
Normal laboratory tests do not exclude the diagnosis of IBD. In a study of more than 500 children who ultimately were diagnosed with IBD, the ESR, hemoglobin, platelet count, and albumin level were all normal in 19 percent of children with UC and 9 percent of children with CD [24]. Patients with more severe disease were more likely to have abnormal values on these laboratory tests, particularly the ESR. Thus, endoscopic and radiographic evaluation is sometimes appropriate in some patients in whom there is a strong clinical suspicion of IBD, even if initial blood tests are normal. (See 'Endoscopy' below and 'Imaging' below.)
Stool tests
●Gross or occult blood – Bloody stool is a presenting feature in at least 80 percent of patients with UC and 40 percent of those with CD [30,31]. If IBD is suspected but there is no history of gross rectal bleeding, a stool guaiac test may be useful.
●Fecal calprotectin – Fecal calprotectin levels are elevated in inflammatory intestinal diseases and may be useful for distinguishing inflammatory gastrointestinal disease including IBD from noninflammatory causes of chronic diarrhea (such as functional abdominal pain) [29,32]. However, the test characteristics vary depending on the prevalence of IBD in the study population. In settings with a high prevalence of IBD, such as a gastroenterology clinic, elevated fecal calprotectin (eg, >200 mcg/g) is useful for identifying patients with a high likelihood of having IBD. In studies from referral centers for pediatric gastroenterology, fecal calprotectin had better performance characteristics for this purpose than ESR, CRP, or hypoalbuminemia [33,34]. By contrast, in settings with a low prevalence of IBD, such as a primary care setting, fecal calprotectin is more useful to rule out IBD (ie, if fecal calprotectin is normal [eg, <50 mcg/g], then IBD is unlikely) [35-38]. Elevated levels of fecal calprotectin are also found in other causes of inflammatory diarrhea including bacterial and viral enteritis, intestinal lymphoma, celiac disease, food allergy, and immunodeficiency [32], and also in the setting of juvenile polyps [39]. Fecal lactoferrin also has been used as a marker for disease activity, but is less well-studied than fecal calprotectin [40,41]. (See "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'General laboratory tests'.)
Fecal calprotectin levels are correlated with disease activity in both CD and UC [42-45]. Therefore, this test can be useful in monitoring response to treatment, but because of limited sensitivity and specificity it should be used in conjunction with other laboratory tests and symptoms to arrive at clinical decisions. The potential benefits of this test also must be weighed against the cost and against the fact that it will not provide a definitive IBD diagnosis.
●Fecal lactoferrin – Fecal lactoferrin has also been utilized to differentiate IBD from non-inflammatory gastrointestinal conditions. Studies have demonstrated comparable sensitivity and specificity to calprotectin. However, this biomarker is less commonly used clinically, perhaps because of fewer publications on its utility [46,47].
●Fecal leukocytes – Compared with fecal calprotectin and lactoferrin, fecal leukocytes have considerably lower specificity and sensitivity for detecting inflammatory diarrhea.
CANDIDATES FOR EVALUATION
Clinical suspicion — IBD should be suspected in a child presenting with one or more of the following clinical features:
●Bloody diarrhea
●Growth failure (subnormal gains in height or weight, or weight loss) or pubertal delay
●Chronic watery diarrhea
●Chronic abdominal pain, especially in the right lower quadrant
●Perianal abscesses, fistulae, and fissures, oral ulcers, or arthritis
●Laboratory abnormalities including anemia, elevated white blood cell and platelet count, elevated erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), depressed albumin level, occult blood in the stool, elevated fecal calprotectin or leukocytes. (See 'Laboratory features' above.)
When to refer — We suggest referral to a pediatric gastroenterologist as soon as IBD is strongly suspected based on marked clinical symptoms (eg, bloody diarrhea) and/or milder symptoms with laboratory abnormalities or a positive family history, as outlined above [48]. The gastroenterologist will be required to perform the endoscopy; the other steps are sometimes performed by the general pediatrician.
DIAGNOSTIC EVALUATION — The diagnosis of IBD is usually established by the combination of clinical features, with or without laboratory abnormalities, coupled with characteristic findings on imaging and endoscopy, including histopathologic analysis. Most patients with suspected IBD should be evaluated with each of the following steps (table 2):
●Stool testing (see 'Stool testing for enteric pathogens' below)
●Small bowel imaging (see 'Imaging' below)
●Upper endoscopy and colonoscopy (see 'Imaging' below)
The order of evaluation depends on the type and severity of presenting features. Patients with isolated mild symptoms may not require completion of each of these steps but should be monitored. Depending on the dominant clinical symptoms, testing to exclude other conditions also may be required. (See 'Differential diagnosis' below.)
Stool testing for enteric pathogens — Patients presenting with diarrhea (especially bloody diarrhea) should be evaluated with a stool culture and tests for C. difficile toxin [49]. Infection with an enteric pathogen can mimic IBD. However, they can also trigger IBD, so the presence of an enteric pathogen does not exclude the possibility of IBD [50]. If enteric pathogens are identified, they should be treated. However, a positive result of C. difficile testing also may be due to colonization rather than infection in children with or without IBD, especially in younger children [51]. Therefore, patients who fail to respond to treatment, or those with symptoms of IBD other than bloody diarrhea, including growth failure, should also be fully evaluated with endoscopy and imaging. If colonoscopy is performed, histopathologic features that suggest chronicity support the diagnosis of IBD rather than an infectious colitis. (See 'Differential diagnosis' below and 'Features of ulcerative colitis' below and "Diagnostic approach to diarrhea in children in resource-rich countries", section on 'Laboratory testing and imaging'.)
Endoscopy — We suggest both colonoscopy and upper endoscopy for patients with suspected IBD, even in the absence of clear lower gastrointestinal symptoms such as bloody diarrhea. The results help to exclude other causes of the symptoms, categorize the IBD as either ulcerative colitis (UC) or Crohn disease (CD) (table 3), and document the disease activity and location to support therapeutic decisions [30,49,52].
The endoscopist should document the macroscopic findings and perform biopsies throughout the gastrointestinal tract to confirm the diagnosis through histopathology (table 3). During colonoscopy, the terminal ileum should be examined if possible, and random biopsies should be taken from the terminal ileum and from each segment of the colon. The specimens should be labeled separately for histopathologic examination to document the location of microscopic abnormalities. (See 'Differentiation between Crohn disease and ulcerative colitis' below.)
We and many other endoscopists prefer to perform endoscopy in children under anesthesiologist-administered propofol or general anesthesia. This approach improves patient comfort and increases the likelihood of a complete endoscopic examination. In a registry of children undergoing colonoscopy for a variety of indications, the short-term complication rate of the procedure was approximately 1 percent [53]. Cardiopulmonary compromise associated with sedation and bleeding from polypectomy accounted for many of the complications in this series. According to this single study, the rate of complications was higher in patients who received intravenous sedation (1.7 percent) than in those who received anesthesia (0.8 percent).
Imaging — In addition to endoscopy, imaging of the UGI tract (focused on the small intestine) is recommended, primarily to distinguish between UC and CD. This is because parts of the UGI tract, generally distal to the duodenum, are not accessible to the endoscope and because certain features of CD, such as stricturing and transmural inflammation, are better assessed by imaging techniques. Radiographic imaging of the small bowel is evolving. The relative advantages and disadvantages of each modality are outlined below [54-56]. Additional information on imaging safety is available at the Image Gently Alliance website and in a separate topic. (See "Radiation-related risks of imaging".)
●Magnetic resonance enterography (MRE) – MRE is the preferred small bowel imaging modality in children, where available. The main advantage of this technique is avoidance of radiation exposure [57]. Diagnostic performance of MRE for detection of active inflammation is high, with a sensitivity of 83 percent and a specificity of 93 percent [58]. The technique also provides information about extraintestinal findings (eg, intraabdominal or perianal fistula or abscess, liver disorders, renal problems, and bone disease) [59-61].
MRE combines oral contrast distension of the bowel with intravenous administration of a gadolinium-based contrast material to detect mucosal bowel lesions and inflammatory activity (image 1) [62]. The patient is prepared with the oral administration of an osmotic agent, such as polyethylene glycol-electrolyte solution (PEG) or mixture of dilute barium and sorbitol (VoLumen, E-Z-EM) to distend the bowel.
This technique requires the patient to drink moderate amounts of contrast and cooperate with breath holding sequences. MRE is generally feasible in children as young as four to five years of age (with assistance of Child Life Services) [63].
●Computed tomography enterography (CTE) – CTE (CT of the abdomen with oral contrast) is a useful second-line option for small bowel imaging. It provides good visualization of the bowel lumen and bowel wall, as well as of extraintestinal complications such as abscess. Because CT can often be done more urgently compared with magnetic resonance imaging, it often is performed for patients with an acute concern, such as clinical suspicion of abscess [64]. It is also useful for small children who cannot stay still for MRE.
The main disadvantage of CTE is radiation exposure. A variety of methods can help minimize the radiation exposure [65]; with use of these methods, CTE now has less radiation exposure than conventional fluoroscopy [66].
●Conventional fluoroscopy – Upper gastrointestinal series with small bowel follow-through (UGI/SBFT) traditionally has been used to evaluate the small bowel for suspected CD, but its use is decreasing [30]. This modality provides good visualization of the small bowel lumen, revealing strictures and fistulas, but does not generally detect small ulcers or erosions and is less able to evaluate for transmural inflammation or abscess than MRE and CTE [54]. It exposes the patient to a moderate amount of radiation, which can be minimized by using pediatric dose-minimizing protocols, such as reducing the number of images of the esophagus and stomach, and limiting imaging to the small intestine [67,68].
The relative merits of fistulography, CT, magnetic resonance imaging, and ultrasonography in evaluating anal fistulas are discussed separately. (See "The role of imaging tests in the evaluation of anal abscesses and fistulas".)
Other modalities
Video capsule endoscopy — Video capsule endoscopy (VCE) is increasingly used in adults for diagnosis and assessment of severity of CD [69]. The role of this procedure in children with suspected IBD is evolving; it is approved by the US Food and Drug Administration for children older than two years [70]. The technique has been effective in identifying small bowel involvement in IBD (picture 3), which may be important for treatment decisions [52,71-75]. In one study, VCE detected a greater extent of CD compared with UGI/SBFT and refined medical management for approximately one-half of the patients with known CD [76]. (See "Endoscopic diagnosis of inflammatory bowel disease in adults" and "Wireless video capsule endoscopy".)
It is unclear if the complication rate is higher in pediatric patients undergoing VCE compared with adults. In a series of 207 capsule endoscopies performed on pediatric patients (age range 8 to 21 years), the risk of symptomatic capsule retention was 5 percent among patients with known IBD (3 of 58 patients) and 38 percent among those with CD and known small bowel abnormalities (3 of 8 patients) [71]. A meta-analysis that included the above study and 14 others reported capsule retention rates of 2.5 percent among patients with CD (9 of 359 procedures), which is similar to retention rates in adults with CD but somewhat higher than for children undergoing VCE for other indications [77]. If small bowel imaging identifies areas of luminal narrowing that might result in a capsule getting stuck in the bowel, a patency capsule study should be performed prior to the VCE, as the passage of a patency capsule makes it less likely that the video capsule will be retained in the bowel [75,78]. If a video capsule is retained in the small bowel, endoscopic or surgical removal of the capsule may be needed [77].
Ultrasonography — Ultrasonography is utilized for small bowel imaging of IBD at some centers. The sensitivity and specificity are highly dependent on the experience of the operator but are reported to be between 76 and 92 percent [54,79]. Sonographic features suggesting small bowel involvement include bowel wall thickening and stiffness, and changes in the bowel wall stratification, but intestinal gas frequently obscures the bowel wall [80]. Superficial mucosal abnormalities are not detectable by ultrasound.
Small intestine contrast ultrasonography (SICUS) is a technique in which an oral nonabsorbable anechoic contrast solution (eg, polyethylene glycol 3350) is given by mouth prior to abdominal ultrasonography. One study in pediatric patients reported that SICUS had a sensitivity of 96 percent and specificity of 100 percent for detecting proximal or distal small bowel lesions, with excellent agreement with findings on UGI/SBFT [81]. Like standard ultrasonography, SICUS is highly dependent on the experience of the operator. (See "Transabdominal ultrasonography of the small and large intestine".)
DIAGNOSIS — There are no specific diagnostic criteria for IBD. The diagnosis of IBD is usually established by the combination of clinical features, with or without laboratory abnormalities, coupled with characteristic findings on imaging and endoscopy, including histopathologic analysis. Endoscopy and imaging also help to exclude some other causes of the symptoms, and usually can distinguish between ulcerative colitis (UC) and Crohn disease (CD) (table 3).
DIFFERENTIAL DIAGNOSIS — Considerations in the differential diagnosis depend on dominant clinical features of an individual patient:
Rectal bleeding
In children with rectal bleeding without diarrhea or other symptoms suggestive of IBD, causes of rectal bleeding other than IBD include:
●Anal fissures or hemorrhoids
●Polyps
●Meckel's diverticulum
●Milk protein-induced proctocolitis – Primarily seen in infants
(See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach".)
In children with rectal bleeding in combination with more complex symptoms, considerations include:
●Enteric pathogens – Infectious causes of intestinal inflammation that can mimic UC or CD include Salmonella, Shigella, Yersinia, Campylobacter, Aeromonas, enterohemorrhagic Escherichia coli, Amoeba, Strongyloides, Trichuris trichiura, and C. difficile. In some cases, IBD can be triggered by an enteric infection, particularly C. difficile [50,82]. Therefore, the presence of one of these pathogens does not exclude IBD. Moreover, C. difficile colonization is common, especially in young children, and it may be difficult to distinguish between colonization and infection in some cases [51]. Patients whose rectal bleeding does not resolve after treatment for one of these pathogens should be reevaluated for IBD. (See "Clostridioides difficile infection in children: Treatment and outcome" and 'Stool testing for enteric pathogens' above.)
Cytomegalovirus (CMV) infection can cause colitis. In patients with IBD, superinfection with CMV is associated with a high rate of steroid resistance [83]. Evaluation for CMV disease, using sigmoidoscopic biopsies, is suggested for patients with severe colitis that does not respond promptly to intravenous glucocorticoids (ie, steroid-refractory disease). (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Evaluation for infectious colitis'.)
●Intussusception – Characterized by acute onset of intermittent crampy abdominal pain, often with vomiting and lethargy, and sometimes progressing to rectal bleeding. (See "Intussusception in children".)
●Immunoglobulin A vasculitis (IgAV) – IgAV, also known as Henoch-Schönlein purpura (HSP), also can cause rectal bleeding and abdominal pain. However, almost all patients with IgAV (HSP) also have characteristic purpuric skin lesions. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)
●Familial Mediterranean fever – Case reports describe apparent UC presenting in infants with genetic mutations of familial Mediterranean fever [84]. Presenting symptoms included bloody diarrhea, failure to thrive, anemia and leukocytosis. These reports and epidemiologic studies in populations of adults suggest that the genes responsible for familial Mediterranean fever may have a disease-modifying effect on IBD [85]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)
Growth failure and diarrhea — Children presenting with growth failure and/or nonbloody diarrhea should be evaluated for celiac disease. This can be done by serologic testing. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
Abdominal pain — For patients with diffuse or poorly localized abdominal pain, the differential diagnosis includes functional gastrointestinal disease (including constipation and irritable bowel syndrome [IBS]), which is very common. IBD is generally distinguished from functional abdominal pain by the presence of additional symptoms (including diarrhea, rectal bleeding, and/or growth failure) and laboratory abnormalities. (See "Chronic abdominal pain in children and adolescents: Approach to the evaluation", section on 'Functional disorders'.)
Focal abdominal pain, particularly in the right lower quadrant, is more suspicious for IBD (particularly CD). For patients presenting with right lower quadrant pain, the differential diagnosis includes appendicitis and (very rarely) tuberculosis or lymphoma [86]. In adolescent girls, gynecologic disease must be considered. In patients with an abdominal abscess, the differential diagnosis includes a perforated appendix, vasculitic perforation, or trauma. (See "Causes of acute abdominal pain in children and adolescents".)
Extraintestinal symptoms — Extraintestinal symptoms associated with IBD include arthritis, oral aphthae (superficial ulcerations, also known as aphthous stomatitis), skin disease (erythema nodosum and pyoderma gangrenosum), and episcleritis/iritis (table 1A). These manifestations rarely occur in the absence of gastrointestinal symptoms.
Details about these manifestations are discussed separately. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Extraintestinal manifestations'.)
VERY EARLY-ONSET INFLAMMATORY BOWEL DISEASE — IBD that becomes symptomatic or is diagnosed before six years of age is termed "very early-onset IBD" (VEO-IBD). Compared with children whose IBD develops later in life, those with VEO-IBD, and particularly those with onset before two years of age (sometimes termed "infantile IBD"), are more likely to have monogenic IBD and often have a more severe disease course [87,88]. The related gene defects cause an IBD-like disease by altering immune function or disturbing epithelial barrier function.
●Clinical features – Clinical features that raise suspicion for monogenic IBD include (table 4) [6,9,89,90]:
•Young age of onset (eg, younger than six years, particularly younger than age two years)
•Family history of IBD and/or immunodeficiency in multiple family members, particularly with male predominance, or consanguinity
•Recurrent infections or unexplained fever
•Associated features of autoimmunity (eg, arthritis, sclerosing cholangitis, anemia, or endocrine dysfunction)
•Very severe IBD, complex fistulizing disease, and/or resistance to conventional therapies for IBD
•Symptoms or signs suggesting hemophagocytic lymphohistiocytosis (hepatomegaly, fever, cytopenias, high ferritin) (see "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis")
•Lesions of the skin, nails, or hair
•Current or past history of cancer in the patient
•Endoscopic biopsies with tissue eosinophilia, villous flattening (without evidence of celiac disease)
●Causes and evaluation – Infants or young children presenting with these features warrant careful evaluation for monogenic IBD and consultation with an immunologist (algorithm 1) [6,9,14]. Depending on individual patient features, the evaluation may include panel sequencing, exome sequencing, or genome sequencing technologies [90]. Genetic sequencing is recommended for every child with IBD onset under age two years and also suggested for children under age six, particularly if other clinical features listed above are present, as outlined in a position paper from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [90].
Important causes of monogenic IBD include defects in interleukin-10 (IL-10) signaling, atypical severe combined immunodeficiency, common variable immunodeficiency, chronic granulomatous disease and other neutrophil defects, Wiskott-Aldrich syndrome, agammaglobulinemia, hyperimmunoglobulin M syndrome, familial hemophagocytic lymphohistiocytosis, and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) or other autoimmune enteropathy (table 5) [6] (see appropriate topic reviews).
Details and an extensive list of genes that may be involved in VEO-IBD are provided in the ESPGHAN position paper [90]. Some of these genes are now associated with well-described phenotypes (eg, TTC7A deficiency, MIM #243150), while others have a phenotype that has yet to be extensively defined. (See "Genetic factors in inflammatory bowel disease" and "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)
●Management approach – Identification of a specific monogenic immunologic disorder often requires different management strategies. Some of these mutations affect hematopoietic cells (eg, IL10, IL10RA, XIAP, and FOXP3), and affected patients are candidates for hematopoietic stem cell transplantation. As an example, mutations in the IL10RA gene can present with severe intractable enterocolitis, perianal disease, folliculitis, and arthritis [91]. For these very young patients, several gene sequencing panels are available [92,93], and whole-exome or whole-genome sequencing is increasingly playing an important role in identifying novel genetic mutations and immune deficiencies [94,95]. Other genetic syndromes, such as TTC7A deficiency, are not thought to be candidates for stem cell transplantation, but novel methods of drug screening may identify promising treatments for these life-threatening conditions [96]. (See "Gastrointestinal manifestations in primary immunodeficiency".)
DIFFERENTIATION BETWEEN CROHN DISEASE AND ULCERATIVE COLITIS
Classification schemes — Classification of the IBD facilitates clinical decisions, discussions with the family, eligibility for clinical trials, and epidemiologic research. If possible, the disease should be classified as either Crohn disease (CD) or ulcerative colitis (UC) (table 3). This classification usually is accomplished with the combination of endoscopy and imaging of the small bowel. The provider should make every effort to classify the disease using standardized criteria. If the disease type remains uncertain after complete evaluation, it is provisionally termed IBD-unclassified (IBDU), formerly known as "indeterminate colitis" [89].
Guidelines for the classification of IBD in children were developed by a committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition [30] and are summarized in the algorithm (algorithm 2). More recently, the Pediatric IBD Porto Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition published the "PIBD-classes" criteria, a classification scheme that differentiates pediatric IBD into five diagnostic categories: typical UC, atypical UC, IBDU, Crohn colitis (colonic CD), and CD. This granular classification aims to assist the clinician in characterizing the degree of certainty as to whether a patient has CD, UC, or IBDU, based on typical and atypical clinical and laboratory features [89,97,98].
Features of Crohn disease — In a patient with IBD involving the colon, UC is distinguished from CD by a process of elimination.
In a patient with IBD, any of the following features are diagnostic of CD (table 3) [30]:
●Physical examination – Perianal fistulae, abscess, or large (>5mm) skin tags (picture 1).
●Imaging – Either magnetic resonance enterography (MRE) (image 1), upper gastrointestinal series with small bowel follow-through (UGI/SBFT), or computed tomography enterography (CTE) showing definitive small bowel involvement, with mucosal ulceration, cobblestoning, narrowing or obstruction, or enteric fistulae. Note that some magnetic resonance imaging or CT findings (eg "small bowel enhancement," or wall thickening) may be nonspecific "false positives." (See 'Imaging' above.)
●Gross features at colonoscopy – Colonoscopic findings diagnostic of CD include ulceration and stenosis of the ileocecal valve, cobblestoning or linear ulcerations in the ileum, and stricture and fistula formation.
●Histopathologic features – Noncaseating granulomas (picture 4) in a patient with IBD are diagnostic of CD, unless they are adjacent to ruptured crypts. However, mucosal biopsies reveal these lesions in only 25 to 50 percent of patients with CD [30,99,100]. Transmural lymphoid aggregates are also diagnostic, but these can only be identified at colectomy. Although small bowel involvement is more likely in CD, gastritis or duodenitis may be present at the time of diagnosis in patients with either UC or CD [101].
In patients lacking the above diagnostic findings, CD should still be suspected if any of the following suggestive features are present:
●Growth failure
●Right lower quadrant mass
●Imaging studies showing cecal narrowing, bowel rigidity, and bowel wall edema manifested by separation of bowel loops (image 2)
●Colonoscopic findings of small ulcers (aphthous lesions) in the colon or discontinuous colitis with intervening areas of normal mucosa ("skip areas") (picture 5A-C)
Patients with these suggestive features but no diagnostic findings of CD should be provisionally classified as either CD or IBDU, and the suspicious features should be followed closely over time in an effort to establish a definitive diagnosis of CD or UC.
Although UGI tract involvement is a feature of CD but not UC, the finding of a nonspecific gastritis on upper endoscopy does not help to distinguish the two disorders. This was shown in a prospective study in a cohort of patients with CD or UC who underwent upper endoscopy [101]. Both groups had endoscopic and histologic features of gastritis (92 versus 69 percent in CD versus UC, respectively) and duodenitis (33 versus 23 percent in CD versus UC, respectively).
Features of ulcerative colitis — In UC, typical findings on colonoscopy include a diffuse, continuous process starting at the rectum and extending more proximally into the colon (picture 6). Active disease is characterized by diffuse and continuous edema, erythema, induced and spontaneous friability, and ulceration. The distal colon is usually more severely involved than more proximal aspects of the colon. In severe, relatively acute disease, extensive erosions and ulcerations may be present. Patients with longer-standing disease may have "pseudopolyps," which are islands of regenerating mucosa that appear polypoid, surrounded by relatively atrophic tissue.
The histopathological features of UC include mucosal and submucosal inflammation, cryptitis, and crypt abscess formation; distortion of the architecture; basal lymphoid aggregates; and the presence of Paneth cells in the left colon. The last three features listed suggest chronicity, which if present helps to distinguish the disease from an infectious colitis, which tends to be acute. The inflammation is typically diffuse, compared with the patchy patterns often observed in patients with CD. However, early in the course of pediatric ulcerative colitis, atypical histologic features may be seen, including patchy disease and relative rectal sparing [30,102].
The following clinical features are not typical of UC, so they are sometimes called "nonclassic" features. They are found with sufficient frequency in patients with UC that they do not necessarily exclude that diagnosis [30,102]:
●Small anal fissures and skin tags; oral ulcers
●Gross or histologic evidence of gastritis (without aphthae)
●"Backwash" ileitis, defined as ileal erythema or histologic inflammation (but no linear ulceration or granuloma) [103]
●Periappendiceal inflammation, even in a patient without pancolitis ("cecal patch") (picture 7) [104]
●Rectal inflammation that is less severe than in the more proximal colon (relative rectal sparing)
●Patchy distribution of colitis (histopathologically normal colonic mucosa between two areas of colonic inflammation)
Antibody testing — Antibody testing has limited utility for discriminating between UC and CD, and practice guidelines for children and adults are equivocal regarding its use [30,89,105]. The most common antibody tests are perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) and anti-saccharomyces cerevisiae antibodies (ASCA) [106-108]. When combined into panels, the antibody tests have reasonably high sensitivities for detecting IBD (>90 percent in populations with symptoms), but their ability to distinguish between UC and CD is not well validated [109-112]. The sensitivity and specificity of P-ANCA and ASCA tests are similar in adults and children with IBD [106-108,113].
The positive predictive value (PPV) of these tests depends on the prior likelihood of disease. Patients with low levels of symptoms, or patients from populations with a low incidence of IBD, are more likely to have false-positive results [110]. The tests have greater PPV for patients with higher levels of symptoms, but in most cases, these symptoms would be sufficient indication for proceeding with an endoscopic evaluation. Thus, antibody testing for IBD does not generally contribute useful information to management decisions.
A positive ASCA test is weakly associated with CD, and positive P-ANCA is weakly associated with UC:
●ASCA antibodies are found in 40 to 80 percent of individuals with CD, tend to identify patients with disease of the terminal ileum and cecum, and are unusual in patients with UC [114].
●P-ANCA can be detected in 50 to 80 percent of children and adults with ulcerative colitis compared with 10 to 27 percent of adults with CD (in whom only low titers may be present) [106,114-116].
●Patients with CD who have P-ANCA antibodies often exhibit UC-like features, with disease limited to the colon. Thus, the serotype may be more closely associated with colonic disease location than with disease type [30,114,117,118].
The anti-OmpC antibody has been identified as a potential serologic marker of IBD [119]. The OmpC is an outer membrane porin, E. coli protein that is immunoreactive to P-ANCA monoclonal antibodies [120]. In a study of 198 children, anti-OmpC was detected in 25 percent of patients with CD (n = 81), 11 percent of patients with UC (n = 54), and 5 percent of controls (n = 63) [108]. Because anti-OmpC was positive in nine children with IBD who were not detected by ASCA (IgA and IgG) or P-ANCA, the addition of anti-OmpC to these antibody assays increased the sensitivity from 63 to 70 percent but decreased the specificity from 97 to 94 percent.
Antibodies to the bacterial flagellin CBir1 are found in approximately 50 percent of individuals with CD and have been associated with small bowel, internal-penetrating, and fibrostenosing patterns [110,121].
LOCALIZATION — The location of the disease should be determined as accurately as possible, based on a combination of imaging, endoscopic, and histopathologic results. These studies should optimally be performed before significant therapy since this may alter the findings. The location, severity, and other important characteristics are classified using the Paris classification system, which was developed specifically for clinical studies involving pediatric patients with ulcerative colitis (UC) or Crohn disease (CD) [122]. For UC, the disease involvement should be categorized as proctitis (rectal involvement limited to 15 cm or less), left-sided colitis, extensive colitis (extending past the splenic flexure), or pancolitis (extending past the hepatic flexure) (table 6). For CD, localizing disease means identifying whether the mouth, esophagus, stomach, small bowel, colon, or anus are involved (figure 1 and table 7). By defining the affected areas of the gastrointestinal tract, the clinician will be able to better target medical management appropriately.
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 topics (see "Patient education: Crohn disease in children (The Basics)" and "Patient education: Ulcerative colitis in children (The Basics)")
●Beyond the Basics topics (see "Patient education: Ulcerative colitis (Beyond the Basics)" and "Patient education: Crohn disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical presentation – Typical presenting features of inflammatory bowel disease (IBD) in children are loose stools or bloody diarrhea, abdominal pain, fever, weight loss or growth failure, perianal disease, anemia, arthritis, or delayed onset of puberty (table 2). Clinical features supportive of the diagnosis include abdominal tenderness, oral ulcers, or perianal disease. (See 'Typical presenting symptoms' above.)
●Laboratory features – Laboratory testing often reveals anemia, hypoalbuminemia, and/or an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP); however, laboratory studies are normal in a significant number of children with IBD. (See 'Laboratory features' above.)
●Diagnostic evaluation – If the clinical presentation and/or initial laboratory testing support the diagnosis of IBD, further evaluation should include small bowel imaging and colonoscopy (with biopsies taken from the terminal ileum, if possible). Biopsies from the terminal ileum and each segment of the colon should be sent for histopathologic examination. In many centers, upper endoscopy is also routinely performed at the time of the initial colonoscopy and provides further information as to disease type and extent (table 3) [123]. (See 'Endoscopy' above and 'Imaging' above.)
Children who present with IBD before six years of age, especially those younger than two years or with any features of monogenic IBD (table 4), should be carefully evaluated for monogenic IBD, including immunologic evaluation and genetic sequencing. (See 'Very early-onset inflammatory bowel disease' above.)
●Differential diagnosis – In patients presenting with rectal bleeding, laboratory testing should be performed to exclude other illnesses, including stool cultures and C. difficile toxin. If stools are formed (ie, not diarrhea), other causes of rectal bleeding should be explored, including Meckel's diverticulum, polyps, and anal fissures. (See 'Differential diagnosis' above.)
●Crohn disease (CD) versus ulcerative colitis (UC) – In patients with colitis, imaging and endoscopy also are used to differentiate between UC and CD (algorithm 2). Features diagnostic of CD include evidence of small bowel involvement on advanced imaging (image 1); noncaseating granulomas on histopathologic examination; and/or marked perianal disease (table 3). (See 'Differentiation between Crohn disease and ulcerative colitis' above.)
●Extraintestinal manifestations – Extraintestinal manifestations of IBD may involve the skin, mouth, joints, liver, eye, bones, and (rarely) other organs (table 1A). Patients with suspected or confirmed IBD should be screened for these disorders by a focused history and physical examination. (See 'Extraintestinal manifestations' above.)
The most serious liver disease associated with IBD is sclerosing cholangitis, a progressive liver disease that may be complicated by cirrhosis and hepatobiliary cancer. Patients with IBD should undergo laboratory screening for hepatobiliary disease at diagnosis and periodically thereafter. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Sclerosing cholangitis'.)
