ESSENTIALS OF DIAGNOSIS
Intermittent bouts of low-grade fever, diarrhea, and right lower quadrant pain.
Right lower quadrant mass and tenderness.
Perianal disease with abscess, fistulas.
Radiographic or endoscopic evidence of ulceration, stricturing, or fistulas of the small intestine or colon.
One-third of cases of Crohn disease involve the small bowel only, most commonly the terminal ileum (ileitis). Half of all cases involve the small bowel and colon, most often the terminal ileum and adjacent proximal ascending colon (ileocolitis). In 20% of cases, the colon alone is affected. One-third of patients have associated perianal disease (fistulas, fissures, abscesses). Less than 5% of patients have symptomatic involvement of the upper intestinal tract. Unlike ulcerative colitis, Crohn disease is a transmural process that can result in mucosal inflammation and ulceration, stricturing, fistula development, and abscess formation. Cigarette smoking is strongly associated with the development of Crohn disease, resistance to medical therapy, and early disease relapse.
Because of the variable location of involvement and severity of inflammation, Crohn disease may present with a variety of symptoms and signs (eFigure 15–25). In eliciting the history, the clinician should take particular note of fevers, the patient’s general sense of well-being, weight loss, the presence of abdominal pain, the number of liquid bowel movements per day, and prior surgical resections. Physical examination should focus on the patient’s temperature, weight, and nutritional status, the presence of abdominal tenderness or mass, rectal examination, and extraintestinal manifestations. Approximately 20–30% of patients have an indolent, nonprogressive course. The majority will require specific therapies (often biologic agents) to reduce inflammation, improve quality of life, and reduce the risk of surgery and hospitalization. Most commonly, there is one or a combination of the following clinical constellations.
Crohn disease of colon characterized by scattered ulcers with adherent mucopus and intervening normal appearing mucosa. (Used, with permission, from A. Huang.)
1. Chronic inflammatory disease
This is the most common presentation and is often seen in patients with ileitis or ileocolitis (eFigure 15–26). Patients report malaise, weight loss, and loss of energy. In patients with ileitis or ileocolitis, there may be diarrhea, which is usually nonbloody and often intermittent. In patients with colitis involving the rectum or left colon, there may be bloody diarrhea and fecal urgency, which may mimic the symptoms of ulcerative colitis. Cramping or steady right lower quadrant or periumbilical pain is common. Physical examination reveals focal tenderness, usually in the right lower quadrant. A palpable, tender mass that represents thickened or matted loops of inflamed intestine may be present in the lower abdomen.
Crohn involvement of terminal ileum with extensive linear and stellate ulcers. (Used, with permission, from A. Huang.)
2. Intestinal obstruction
Narrowing of the small bowel may occur as a result of inflammation, spasm, or fibrotic stenosis. Patients report postprandial bloating, cramping pains, and loud borborygmi. This may occur in patients with active inflammatory symptoms (as above) or later in the disease from chronic fibrosis without other systemic symptoms or signs of inflammation.
3. Penetrating disease and fistulae
Sinus tracts that penetrate through the bowel, where they may be contained or form fistulas to adjacent structures, develop in a subset of patients. Penetration through the bowel can result in an intra-abdominal or retroperitoneal phlegmon or abscess manifested by fevers, chills, a tender abdominal mass, and leukocytosis. Fistulas between the small intestine and colon commonly are asymptomatic, but can result in diarrhea, weight loss, bacterial overgrowth, and malnutrition. Fistulas to the bladder produce recurrent infections. Fistulas to the vagina result in malodorous drainage and problems with personal hygiene. Fistulas to the skin usually occur at the site of surgical scars.
One-third of patients with either large or small bowel involvement develop perianal disease manifested by large painful skin tags, anal fissures, perianal abscesses, and fistulas.
5. Extraintestinal manifestations
Extraintestinal manifestations may be seen with both Crohn disease and ulcerative colitis. These include arthralgias, arthritis, iritis or uveitis, pyoderma gangrenosum, or erythema nodosum. Oral aphthous lesions are common. There is an increased prevalence of gallstones due to malabsorption of bile salts from the terminal ileum. Nephrolithiasis with urate or calcium oxalate stones may occur.
Laboratory values may reflect inflammatory activity or nutritional complications of disease. A complete blood count and serum albumin should be obtained in all patients. Anemia may reflect chronic inflammation, mucosal blood loss, iron deficiency, or vitamin B12 malabsorption secondary to terminal ileal inflammation or resection. Leukocytosis may reflect inflammation or abscess formation or may be secondary to corticosteroid therapy. Hypoalbuminemia may be due to intestinal protein loss, malabsorption, bacterial overgrowth, or chronic inflammation. The sedimentation rate or C-reactive protein level is elevated in many patients during active inflammation; however, one-third have a normal C-reactive protein level. Fecal calprotectin is an excellent noninvasive test. Elevated levels are correlated with active inflammation as demonstrated by ileocolonoscopy or radiologic CT or MR enterography. Stool specimens are sent for examination for routine pathogens and C difficile toxin by microscopy, culture, and toxin assay or by rapid multiplex PCR diagnostic assessment.
C. Special Diagnostic Studies
In most patients, the initial diagnosis of Crohn disease is based on a compatible clinical picture with supporting endoscopic, pathologic, and radiographic findings. Colonoscopy usually is performed first to evaluate the colon and terminal ileum and to obtain mucosal biopsies. Typical endoscopic findings include aphthoid, linear or stellate ulcers, strictures, and segmental involvement with areas of normal-appearing mucosa adjacent to inflamed mucosa. In 10% of cases, it may be difficult to distinguish ulcerative colitis from Crohn disease. Granulomas on biopsy are present in less than 25% of patients but are highly suggestive of Crohn disease. CT or MR enterography is obtained in patients with suspected small bowel involvement. Suggestive findings include ulcerations, strictures (eFigure 15–27), and fistulas; in addition, CT or MR enterography may identify bowel wall thickening and vascularity, mucosal enhancement, and fat stranding. MR enterography, where available, may be preferred due its lack of radiation exposure. Capsule imaging may help establish a diagnosis when clinical suspicion for small bowel involvement is high but radiographs are normal or nondiagnostic. Barium upper gastrointestinal series with small bowel follow through should no longer be performed except where CT or MR enterography is unavailable.
A Crohn ulcer is seen that has resulted in a colonic stricture. (Used, with permission, from A. Huang.)
The presence of a tender abdominal mass with fever and leukocytosis suggests an abscess. Emergent CT of the abdomen is necessary to confirm the diagnosis. Patients should be given broad-spectrum antibiotics. Percutaneous drainage or surgery is usually required.
Small bowel obstruction may develop secondary to active inflammation or chronic fibrotic stricturing and is often acutely precipitated by dietary indiscretion. Patients should be given intravenous fluids with nasogastric suction. Systemic corticosteroids are indicated in patients with symptoms or signs of active inflammation but are unhelpful in patients with inactive, fixed disease. Patients unimproved on medical management require surgical resection of the stenotic area or stricturoplasty.
C. Abdominal and Rectovaginal Fistulas
Many fistulas are asymptomatic and require no specific therapy. Most symptomatic fistulas eventually require surgical therapy; however, medical therapy is effective in a subset of patients and is usually tried first in outpatients who otherwise are stable. Large abscesses associated with fistulas require percutaneous or surgical drainage. After percutaneous drainage, long-term antibiotics are administered in order to reduce recurrent infections until the fistula is closed or surgically resected. Anti-TNF agents may promote closure in up to 60% within 10 weeks; however, relapse occurs in over one-half of patients within 1 year despite continued therapy. Surgical therapy is required for symptomatic fistulas that do not respond to medical therapy. Fistulas that arise above (proximal to) areas of intestinal stricturing commonly require surgical treatment.
Patients with fissures, fistulas, and skin tags commonly have perianal discomfort. Successful treatment of active intestinal disease also may improve perianal disease. Specific treatment of perianal disease can be difficult and is best approached jointly with a surgeon with an expertise in colorectal disorders. Pelvic MRI is the best noninvasive study for evaluating perianal fistulas. Patients should be instructed on proper perianal skin care, including gentle wiping with a premoistened pad (baby wipes) followed by drying with a cool hair dryer, daily cleansing with sitz baths or a water wash, and use of perianal cotton balls or pads to absorb drainage. Oral antibiotics (metronidazole, 250 mg three times daily, or ciprofloxacin, 500 mg twice daily) may promote symptom improvement or healing in patients with fissures or uncomplicated fistulas; however, recurrent symptoms are common. Refractory fissures may benefit from mesalamine suppositories or topical 0.1% tacrolimus ointment. Immunomodulators or anti-TNF agents or both promote short-term symptomatic improvement from anal fistulas in two-thirds of patients and complete closure in up to one-half of patients; however, less than one-third maintain symptomatic remission during long-term maintenance treatment.
Anorectal abscesses should be suspected in patients with severe, constant perianal pain, or perianal pain in association with fever. Superficial abscesses are evident on perianal examination, but deep perirectal abscesses may be detected by digital examination or pelvic CT scan. Depending on the abscess location, surgical drainage may be achieved by incision, or catheter or seton placement. Surgery should be considered for patients with severe, refractory symptoms but is best approached after medical therapy of the Crohn disease has been optimized.
Patients with colonic Crohn disease are at increased risk for developing colon carcinoma; hence, annual screening colonoscopy to detect dysplasia or cancer is recommended for patients with a history of 8 or more years of Crohn colitis. Patients with Crohn disease have an increased risk of lymphoma and of small bowel adenocarcinoma; however, both are rare.
Unlike ulcerative colitis, severe hemorrhage is unusual in Crohn disease.
Malabsorption may arise after extensive surgical resections of the small intestine and from bacterial overgrowth in patients with enterocolonic fistulas, strictures, and stasis resulting in bacterial overgrowth. Serum levels of vitamins A, D, and B12 should be obtained at diagnosis and monitored periodically in patients with ileal inflammation or resection.
Chronic cramping abdominal pain and diarrhea are typical of both irritable bowel syndrome and Crohn disease, but radiographic examinations are normal in the former. Celiac disease may cause diarrhea with malabsorption. Acute fever and right lower quadrant pain may resemble appendicitis or Yersinia enterocolitica enteritis. Intestinal lymphoma causes fever, pain, weight loss, and abnormal small bowel radiographs that may mimic Crohn disease. Patients with undiagnosed AIDS may present with fever and diarrhea. Segmental colitis may be caused by tuberculosis, E histolytica, Chlamydia, or ischemic colitis. C difficile or CMV infection may develop in patients with inflammatory bowel disease, mimicking disease recurrence. In patients from tuberculosis-endemic countries, it can be extremely difficult to distinguish active intestinal tuberculosis from Crohn disease, even with biopsies and PCR analyses. Diverticulitis or appendicitis with abscess formation may be difficult to distinguish acutely from Crohn disease. NSAIDs may exacerbate inflammatory bowel disease and may also cause NSAID-induced colitis characterized by small bowel or colonic ulcers, erosion, or strictures that tend to be most severe in the terminal ileum and right colon.
Treatment of Active Disease
Crohn disease is a chronic lifelong illness characterized by exacerbations and periods of remission. As no specific therapy exists, current treatment is directed toward symptomatic improvement and control of the disease process, in order to improve quality of life and reduce disease progression and complications. Although sustained clinical remission should be the therapeutic goal, this cannot be achieved in all patients. Choice of therapies depends on the disease location and severity, patient age and comorbidities, and patient preference. Early introduction of biologic therapy should be considered strongly in patients with risk factors for aggressive disease, including young age, early need for corticosteroids, perianal disease, stricturing disease, or upper gastrointestinal involvement; laboratory markers of severe inflammation, including low albumin or hemoglobin, or high CRP; or endoscopic findings of deep ulcerations. All patients with Crohn disease should be counseled to discontinue cigarettes.
Patients should eat a well-balanced diet with as few restrictions as possible. Eating smaller but more frequent meals may be helpful. Patients with diarrhea should be encouraged to drink fluids to avoid dehydration. Many patients report that certain foods worsen symptoms, especially fried or greasy foods. Because lactose intolerance is common, a trial off dairy products is warranted if flatulence or diarrhea is a prominent complaint. Patients with obstructive symptoms should be placed on a low-roughage diet, ie, no raw fruits or vegetables, popcorn, nuts, etc. Resection of more than 100 cm of terminal ileum results in fat malabsorption for which a low-fat diet is recommended. Parenteral vitamin B12 (1000 mcg subcutaneously per month) and oral vitamin D supplementation commonly are needed for patients with previous ileal resection or extensive terminal ileal disease.
Supplemental enteral therapy via nasogastric tube may be required for children and adolescents with poor intake and growth retardation.
3. Total parenteral nutrition
TPN is used short term in patients with active disease and progressive weight loss or those awaiting surgery who have malnutrition but cannot tolerate enteral feedings because of high-grade obstruction, high-output fistulas, severe diarrhea, or abdominal pain. It is required long term in a small subset of patients with extensive intestinal resections resulting in short bowel syndrome with malnutrition.
B. Symptomatic Medications
There are several potential mechanisms by which diarrhea may occur in Crohn disease in addition to active Crohn disease. A rational empiric treatment approach often yields therapeutic improvement that may obviate the need for corticosteroids or immunosuppressive agents. Involvement of the terminal ileum with Crohn disease or prior ileal resection may lead to reduced absorption of bile acids that may induce secretory diarrhea from the colon. This diarrhea commonly responds to cholestyramine 2–4 g, colestipol 5 g, or colesevelam 625 mg one to two times daily before meals to bind the malabsorbed bile salts. Patients with extensive ileal disease (requiring more than 100 cm of ileal resection) have such severe bile salt malabsorption that steatorrhea may arise. Such patients may benefit from a low-fat diet; bile salt-binding agents will exacerbate the diarrhea and should not be given. Patients with Crohn disease are at risk for the development of small intestinal bacterial overgrowth due to enteral fistulas, ileal resection, and impaired motility and may benefit from a course of broad-spectrum antibiotics (see Bacterial Overgrowth, above). Other causes of diarrhea include lactase deficiency and short bowel syndrome (described in other sections). Use of oral antidiarrheal agents may provide benefit in some patients. Loperamide (2–4 mg), diphenoxylate with atropine (one tablet), or tincture of opium (5–15 drops) may be given as needed up to four times daily. Because of the risk of toxic megacolon, these drugs should not be used in patients with active severe colitis.
1. 5-Aminosalicylic acid agents
Sulfasalazine (1.5–3 g orally twice daily) appears effective in improving symptoms and inducing remission in patients with mild Crohn disease involving the colon (not small intestine) and is recommended in current treatment guidelines. Although mesalamine commonly is used in clinical practice as initial therapy for the treatment of mild to moderately active colonic and ileocolonic Crohn disease, meta-analyses of trial data suggest that it is of no value. Current treatment guidelines recommend against the use of mesalamine for Crohn disease to induce or maintain remission.
Approximately one-half of patients with Crohn disease require corticosteroids at some time in their illness. Corticosteroids dramatically suppress the acute clinical symptoms or signs in most patients with both small and large bowel disease; however, they do not alter the natural history of the underlying disease. Therefore, initial therapy with corticosteroid therapy should be followed by treatment with alternative therapies to promote maintenance of remission and to allow complete withdrawal of corticosteroids. Long-term corticosteroids should not be used to maintain remission.
For patients with mild to moderate Crohn disease involving the terminal ileum or ascending colon, initial treatment is recommended with extended-release budesonide preparation (Entocort), 9 mg once daily for 8–16 weeks, which induces remission in 50–70% of patients. If disease remission has been achieved, budesonide is tapered over 2–4 weeks in 3 mg increments, and the patient observed. Patients with disease relapse may be treated again followed by initiation of immunomodulator therapy (azathioprine, mercaptopurine, or methotrexate) to maintain long-term remission. Budesonide has markedly reduced acute and chronic steroid-related adverse effects, including smaller reductions of bone mineral density and thus is preferred to other systemic corticosteroids.
Prednisone or methylprednisolone, 40–60 mg/day, is administered to patients with mild to moderate Crohn disease involving the colon; mild to moderate ileocolonic disease that has not responded to budesonide; or moderate to severe Crohn disease (in any location) in patients in whom the need for biologic therapy remains uncertain. Remission or significant improvement occurs in greater than 80% of patients after 8–16 weeks of therapy. After improvement at 2 weeks, tapering proceeds at 5 mg/wk until a dosage of 20 mg/day is being given. Thereafter, slow tapering by 2.5 mg/wk is recommended. Long-term treatment with immunomodulators (azathioprine, mercaptopurine, methotrexate) is recommended to attempt to provide a steroid-free disease maintenance. Approximately 20% of patients cannot be completely withdrawn from corticosteroids without experiencing a symptomatic flare-up. Use of long-term low corticosteroid doses (2.5–10 mg/day) should be avoided because of associated complications. Patients requiring long-term corticosteroid treatment should be given immunomodulatory drugs or biologic therapies or both in an effort to wean them from corticosteroids.
Patients with symptoms or signs of severe disease, including high fever, persistent vomiting, evidence of intestinal obstruction, severe weight loss, severe abdominal tenderness, or suspicion of an abscess, should be hospitalized. In patients with a tender, palpable inflammatory abdominal mass, CT scan of the abdomen should be obtained prior to administering corticosteroids to rule out an abscess. If no abscess is identified, parenteral corticosteroids should be administered (as described for ulcerative colitis below).
The three main indications for use of immunomodulators in Crohn disease are (1) after induction therapy with corticosteroids to allow their withdrawal (particularly in patients who are corticosteroid-dependent) and to maintain remission; (2) for the induction of remission, in combination with anti-TNF therapy, in patients with moderate to severe active Crohn disease (discussed in next section); and (3) in combination with biologic agents to reduce the likelihood of neutralizing antibody formation. Immunomodulators do not appear to be effective as monotherapy for induction of remission and are not recommended in guidelines.
Infliximab, adalimumab, and certolizumab are used to induce and maintain remission in patients with moderate to severe Crohn disease, including fistulizing disease, who are corticosteroid-dependent or refractory. They are also used as early therapy (with or without corticosteroids) in patients with moderate to severe disease who are deemed to be at high risk for disease progression and complications. In addition, these agents are used to treat extraintestinal manifestations of Crohn disease (except optic neuritis).
A. ACUTE INDUCTION THERAPY
Anti-TNF therapies are recommended to induce remission in patients with moderate to severe Crohn disease, either as monotherapy or in combination with immunomodulating agents (azathioprine, mercaptopurine, or methotrexate). Up to two-thirds of patients have significant clinical improvement during acute induction therapy; dosing is described above. Data in support of use of early combination therapy come from a large 2010 trial (SONIC) that compared three treatment arms: combination therapy with infliximab and azathioprine versus infliximab alone or azathioprine alone in patients with moderate to severe Crohn disease who had not previously been treated with immunomodulators or anti-TNF agents. After 6 months, clinical remission (57%) and mucosal healing (44%) was significantly higher with combination therapy than with either agent alone. However, post-hoc analyses of SONIC and other trials report that remission rates are similar between combination therapy and anti-TNF monotherapy when adjusted for the trough levels of the anti-TNF agent. Low trough levels are associated with a decreased likelihood of remission and increased risk of developing anti-drug antibodies. Thus, if anti-TNF levels are measured during induction therapy to optimize long-term drug dosing, combination therapy may be unnecessary. Due to the complexity and higher risks of combination therapy, many clinicians prefer to use monotherapy with proactive therapeutic drug monitoring of anti-TNF levels and antibodies. Combination therapy is appropriate for patients who previously developed antibodies to one biologic agent or who are deemed at higher risk for disease progression.
After initial clinical response, symptom relapse occurs in more than 80% of patients within 1 year in the absence of further maintenance therapy. Therefore, scheduled maintenance therapy is usually recommended (eg, infliximab, 5 mg/kg infusion every 8 weeks; or adalimumab, 40 mg subcutaneous injection every 1–2 weeks). With long-term maintenance therapy, approximately two-thirds have continued clinical response and up to one-half have complete symptom remission. Serum anti-TNF trough levels and drug antibody levels may guide therapy in patients who have lost response. Loss of efficacy may be due to low anti-TNF levels, the development of antibodies to the anti-TNF agent, or inflammation that is unresponsive to anti-TNF therapy. Patients with low serum anti-TNF trough levels and absent drug antibodies should receive increased anti-TNF dosing (infliximab 10 mg/kg; adalimumab 80 mg) or decreased dosing intervals (infliximab every 6 weeks; adalimumab every week). Patients with high antibodies to the anti-TNF agent and low anti-TNF trough levels should be switched to another anti-TNF agent. Patients with inadequate response despite adequate anti-TNF trough levels should be changed to an alternative biologic agent, such as vedolizumab or ustekinumab. Some guidelines recommend proactive therapeutic drug monitoring of anti-TNF drug levels and antibodies in all patients during long-term maintenance to optimize drug dosing, decrease risk of antibody formation, and increase long-term remission rates. Concomitant therapy with anti-TNF agents and immunomodulating agents (azathioprine, mercaptopurine, or methotrexate) reduces the risk of development of antibodies to the anti-TNF agent but may increase the risk of complications (non-Hodgkin lymphoma and opportunistic infections). For this reason, consideration should be given to stopping or reducing the dose of the immunomodulating agent after 6–12 months in patients who are in remission, most especially in men younger than age 30 years in whom there is a higher risk of hepatosplenic T-cell lymphoma and in adults older than age 50–60 years in whom there is a higher risk of lymphoma and infectious complications.
Anti-integrins may offer a therapeutic option for patients who do not respond to, or who lose response to, anti-TNF agents.
Vedolizumab is used primarily in patients with moderate to severe Crohn disease in whom anti-TNF therapy has failed or is not tolerated. The full clinical effects of vedolizumab may take 14 weeks to be apparent. A 2014 phase III trial studying patients with Crohn disease showed that when response was lost or side effects developed to one anti-TNF therapy, switching to vedolizumab (300 mg intravenously at weeks 0 and 2) resulted in clinical remission in 26.6% of patients at week 10 compared to 12.1% of patients treated with placebo. In another phase III trial, among patients demonstrating initial clinical improvement with vedolizumab induction therapy, 39% of patients treated with long-term vedolizumab (300 mg every 8 weeks) were in remission at 1 year compared with 21.6% of patients given placebo. Vedolizumab may be less effective than anti-TNF or ustekinumab in the treatment of fistulous disease.
6. Anti-IL-12/IL-23 antibody
Ustekinumab is approved by the FDA for treatment of patients with moderate to severe Crohn disease who have not responded to or are intolerant of conventional therapies. In a phase III trial involving 741 patients with Crohn disease in whom anti-TNF therapy failed, clinical response was seen in 34% of patients 6 weeks after a single-dose of intravenous ustekinumab compared to 21.5% with placebo. In a second phase III trial composed of patients in whom conventional therapy with immunomodulators or corticosteroids (but not anti-TNF) had failed, clinical improvement occurred in 55% compared to 28.7% with placebo. Among patients from both induction trials who were enrolled in a chronic maintenance trial (ustekinumab versus placebo subcutaneously every 8 weeks), 53% of those given ustekinumab were in clinical remission at week 44 versus 36% given the placebo.
Over 50% of patients will require at least one surgical procedure. The main indications for surgery are intractability to medical therapy, intra-abdominal abscess, massive bleeding, symptomatic refractory internal or perianal fistulas, and intestinal obstruction. Patients with chronic obstructive symptoms due to a short segment of ileal stenosis are best treated with resection or stricturoplasty (rather than long-term medical therapy), which promotes rapid return of well-being and elimination of corticosteroids. After surgery, endoscopic evidence of recurrence occurs in 60% within 1 year. Endoscopic recurrence precedes clinical recurrence by months to years; clinical recurrence occurs in 20% of patients within 1 year and 80% within 10–15 years. Therapy with metronidazole, 250 mg three times daily for 3 months, or long-term therapy with immunomodulators (mercaptopurine or azathioprine) has only been modestly effective in preventing clinical and endoscopic recurrence after ileocolic resection. In a 2016 controlled trial of 297 patients undergoing ileocolonic resection, endoscopic recurrence occurred in 30% of patients treated with infliximab every 8 weeks compared with 60% treated with placebo. It may be reasonable to initiate empiric infliximab postoperatively for patients at high risk for disease recurrence and to perform endoscopy in low-risk patients 6 months after surgery in order to identify patients with early endoscopic recurrence who may benefit from anti-TNF therapy.
With proper medical and surgical treatment, the majority of patients are able to cope with this chronic disease and its complications and lead productive lives. Few patients die as a direct consequence of the disease.
For expertise in endoscopic procedures or capsule endoscopy.
For follow-up of any patient requiring hospitalization.
Patients with moderate to severe disease for whom therapy with immunomodulators or biologic agents is being considered.
When surgery may be necessary.
An intestinal obstruction is suspected.
An intra-abdominal or perirectal abscess is suspected.
A serious infectious complication is suspected, especially in patients who are immunocompromised due to concomitant use of corticosteroids, immunomodulators, or anti-TNF agents.
Patients with severe symptoms of diarrhea, dehydration, weight loss, or abdominal pain.
Patients with severe or persisting symptoms despite treatment with corticosteroids.
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