Management of the hospitalized child or adolescent with acute severe ulcerative colitis

INTRODUCTION — Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis (UC) and Crohn disease (CD). These disorders have distinct pathologic and clinical characteristics (table 1), but their pathogenesis remains poorly understood. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)

UC disease activity varies substantially among patients, and individual patients may experience variable disease activity over time. Among health care encounters for children with active UC, approximately 5 percent have acute severe colitis [1]. Some of these cases will be the initial manifestation of UC, while others represent exacerbations or "flares" of the chronic disease. The management of these patients is reviewed here. Other aspects of the diagnosis and management of children with UC 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 "Management of mild to moderate ulcerative colitis in children and adolescents".)

DEFINING DISEASE SEVERITY — Disease severity is typically assessed using the pediatric UC activity index (PUCAI) (table 2) (calculator 1) [2]. A PUCAI score of 65 to 85 indicates severe disease. Such patients typically have profuse bloody diarrhea, abdominal distention, or tenderness and often have fever, tachycardia, anemia, hypoalbuminemia, or leukocytosis.

Endoscopic evaluation provides a more accurate assessment of disease activity and should be used for the initial evaluation, periodically thereafter, and any time that the results would alter a medical decision without significantly increasing risk. On sigmoidoscopy, severe disease can be defined as an endoscopic Mayo score of 3 (spontaneous bleeding, ulceration). Further details on the evaluation of disease severity are provided separately. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Disease severity'.)

PRETREATMENT EVALUATION — The goals of the pretreatment evaluation for a child with acute severe colitis are to exclude alternative or coexisting conditions, determine severity of disease, and determine what supportive care is needed. The assessment typically includes:

●Blood tests – Perform a complete blood count with differential white blood cell count; erythrocyte sedimentation rate and/or C-reactive protein; serum albumin; and serum electrolytes, blood urea nitrogen, and creatinine. These tests help to confirm the diagnosis and evaluate for complications including anemia, hypoalbuminemia, and dehydration.

Blood cultures should be performed for patients with fever, radiographic evidence of toxic megacolon, or other signs suggesting bacteremia.

●Stool tests

•Enteric pathogens – Test stool for Clostridioides difficile toxins A and B and for enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli [and for Amoeba if the history suggests possible exposure]) because these infections may mimic or precipitate a flare [3]. Between 5 and 25 percent of children presenting with a flare of UC have underlying C. difficile [3-6]. If concomitant C. difficile is diagnosed in a patient with a UC flare, this pathogen is usually treated, even though the clinician may not be certain whether the C. difficile is the cause of the flare or if it is bacterial colonization. The clinician must then decide whether the appropriate course of action is to treat the C. difficile, escalate immunosuppressive therapy for inflammatory bowel disease (IBD), or both [7,8]. Details of this evaluation to exclude other causes of colitis are discussed separately. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Differential diagnosis'.)

•Fecal calprotectin – Measuring fecal calprotectin is optional; the result is not useful for diagnosing acute severe colitis but may be useful to follow as part of clinical monitoring for recovery [3]. Elevated fecal calprotectin (eg, >200 mcg/g) indicates colonic inflammation, which could be due to UC or infection.

●Tuberculosis screening – Prior to beginning immunosuppressive treatment, patients should be evaluated for tuberculosis risk factors and tested for latent infection using an interferon-gamma release assay, if not already done. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Infection risk'.)

●Imaging — We suggest a plain radiograph at the time of admission for all patients with acute severe colitis to exclude toxic megacolon [3]. A higher level of suspicion should be used for patients on systemic glucocorticoids because these drugs may mask the symptoms of toxic megacolon. Toxic megacolon occurs in approximately 5 percent of patients with severe UC and may be triggered by hypokalemia or opiate use.

Criteria for diagnosing toxic megacolon in children with colitis are acute dilation of the transverse colon (diameter >4 cm in children <10 years old or >5.6 cm in patients ≥10 years, with loss of haustral folds) and systemic symptoms (eg, fever, tachycardia, dehydration, electrolyte disturbance, altered level of consciousness, and hypotension) [3]. Patients with toxic megacolon should be promptly evaluated and followed closely by surgeons. Emergency or urgent colectomy may be indicated, depending on the patient's condition [3]. (See 'Surgery' below and "Toxic megacolon".)

●Limited colonoscopy – A limited colonoscopy (ie, flexible sigmoidoscopy) is appropriate for most patients, both to assess disease severity and to exclude cytomegalovirus (CMV) infection [3,9]. Full colonoscopy usually should be avoided in patients with severe colitis because of risks of perforation. The assessment can be performed either prior to the start of steroid therapy or subsequently, if symptoms do not respond promptly to intravenous (IV) glucocorticoids. Exclusion of CMV is important prior to starting rescue medications such as cyclosporine, tacrolimus, infliximab, or Janus kinase (JAK) inhibitors.

CMV infection is diagnosed by immunohistochemistry tests on biopsies from areas with active colitis. Polymerase chain reaction (PCR)-based tests on biopsy specimens are not sufficiently specific to diagnose colonic CMV [3], and serum PCR testing is not sufficiently sensitive. Stool culture for CMV has no role in the evaluation because a positive culture may represent either asymptomatic viral shedding or disease. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Gastrointestinal disease'.)

Studies in adults with UC on chronic glucocorticoid treatment suggest that superinfection with CMV is common and is associated with a high rate of steroid resistance (40 to 60 percent) [10]. Case series in adults suggest that treatment with antiviral agents may be effective for patients with UC and CMV superinfection [11,12]. A study in children with refractory severe UC reported that 15 percent had CMV identified using immunohistochemistry tests [13]. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Pretreatment evaluation'.)

MEDICAL TREATMENT — For most children and adolescents with acute severe colitis, management begins with a trial of medical therapy (algorithm 1). Surgery is an important alternative, and clinical outcomes of colectomy are generally very good. However, most patients do not desire surgery (at least at the initial presentation of UC) and medical therapy is often successful in achieving and maintaining remission. In addition, medical stabilization of an acutely ill patient may reduce surgical complications. Patients who have medically unresponsive disease, experience intolerable drug side effects, or are at high risk of developing cancer should be referred for surgery. (See 'Surgery' below.)

Initial therapy — Children with severe disease (pediatric UC activity index [PUCAI] score 65 to 85) typically have profuse bloody diarrhea, abdominal distention or tenderness, and signs of systemic illness (fever, tachycardia, anemia, hypoalbuminemia, leukocytosis). Such patients require urgent hospitalization for supportive care and medical or surgical interventions [3].

Supportive care

●Hydration – We typically provide intravenous (IV) fluids using isotonic fluids at maintenance rates or slightly above. Patients with acute severe colitis are at risk for dehydration because of limited oral intake and increased fluid losses. Dehydration may also increase the risk of syncope or venous thromboembolism (VTE). (See "Treatment of hypovolemia (dehydration) in children in resource-abundant settings", section on 'Intravenous rehydration therapy'.)

●Nutrition – Patients may continue a regular diet if they can tolerate it; bowel rest tends to reduce stool volume but does not affect disease activity [3]. Enteral nutrition also should be stopped if toxic megacolon is suspected. (See 'Pretreatment evaluation' above.)

Patients who have severe pain when they eat or cannot take in adequate calories may require parenteral nutrition until they improve sufficiently to return to enteral feeding or until they proceed to surgery. (See "Parenteral nutrition in infants and children".)

●Anemia and hypoalbuminemia – Patients with acute severe colitis occasionally require replacement of blood and/or albumin. Anemia is usually caused by a combination of chronic and acute blood loss. We typically transfuse blood for patients with symptomatic hemodynamic instability (tachycardia or orthostasis) or hemoglobin <9 g/dL; this hemoglobin threshold is somewhat higher than is used for patients with chronic anemia and will help compensate for ongoing blood loss.

For patients with anemia who are hemodynamically stable and have more subacute bleeding, IV iron replacement is a reasonable alternative. Currently available IV iron formulations have low rates of adverse events; formulations and considerations are discussed separately. (See "Iron deficiency in infants and children <12 years: Treatment", section on 'Intravenous iron therapy'.)

●Pain management – Abdominal pain in inflammatory bowel disease (IBD) has multiple causes and does not always correlate with intestinal inflammation; thus, management requires an individualized approach. Intermittent abdominal pain is common even among patients in clinical remission, possibly due to visceral hypersensitivity, dysmotility, medication-related effects, and anxiety or depression [14]. Severe or escalating abdominal pain should prompt reevaluation for bowel perforation and toxic megacolon.

In patients with active IBD, initial strategies for management of the pain include relaxation techniques, hot packs, or oral acetaminophen [3]. Severe or escalating abdominal pain, or pain out of proportion to disease severity, may be a symptom of bowel perforation and toxic megacolon and should prompt further evaluation. When first-line steps for pain management are not effective, low-dose morphine (0.05 to 0.1 mg/kg, given infrequently) may be used sparingly and with close monitoring in the inpatient setting [3]. Such patients should be monitored closely by clinicians with experience in managing pediatric colitis because of theoretical concerns that these drugs may increase the risk for toxic megacolon. Of note, a systematic review concluded that opioids are not effective for the management of abdominal pain in children, but this review was based on limited evidence and was not focused on children with IBD [15].

Nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided as they may exacerbate disease activity [3]. This was suggested by a retrospective study in adults that found that use of NSAIDs was associated with a 20-fold increase in the risk of IBD onset or exacerbation [16].

●Prevention of thromboembolism – Hospitalized children and adolescents with IBD are at increased risk for VTE. Risk factors include disease activity, history of previous VTE, central venous catheter, older age, parenteral nutrition, and an underlying hypercoagulable condition [17]. Conservative methods of VTE prevention should be used for all hospitalized patients with IBD, including hydration, mobilization, and use of compression stockings or pneumatic devices if appropriate [17]. Selection of patients for thromboprophylaxis (anticoagulation) is discussed separately [18]. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Venous thromboembolism'.)

Intravenous glucocorticoids — After blood and stool cultures have been obtained, patients should be given IV glucocorticoids. Common practice is to use methylprednisolone 1 to 1.5 mg/kg per day (up to a maximum of 60 mg daily), divided in one or two daily doses [3,19]. There is some evidence that dosing above 1.5 mg/kg per day does not further improve outcomes [20]. Oral 5-aminosalicylate (5-ASA) preparations should be stopped at the time of hospital admission because 5-ASA preparations are usually ineffective in acute severe exacerbations of colitis and are responsible for worsening colitis in approximately 3 percent of patients [3]. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on '5-aminosalicylic acid (5-ASA)'.)

Patients who respond to initial therapy with glucocorticoids subsequently transition to a different therapy for maintenance. (See 'Maintenance therapy' below.)

The evidence supporting the use of IV glucocorticoids in this setting comes from observational studies in which approximately 70 percent of pediatric patients with acute severe UC responded to high-dose glucocorticoids [19,20]. Additional support comes from clinical trials (mostly involving adult patients) and meta-analyses demonstrating that patients treated with glucocorticoids were more likely to achieve remission compared with those in the placebo group or other controls. These data are discussed separately. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Glucocorticoids' and "Management of the hospitalized adult patient with severe ulcerative colitis", section on 'Systemic glucocorticoids'.)

Antibiotics (selected patients) — Antibiotics are indicated in cases of suspected bacteremia, C. difficile or other enteric infection, and toxic megacolon and are continued until blood and stool cultures are negative.

For children who are not suspected to have these conditions, antibiotics are not routinely recommended, due to lack of evidence for benefit on medium- or long-term outcomes. However, some clinicians utilize oral, multidrug antibiotic regimens empirically and/or for colon salvage therapy in corticosteroid-refractory patients with severe colitis. Support for the latter practice comes from a randomized trial (the PRASCO trial) in which the addition of antibiotics (the combination of amoxicillin, vancomycin, metronidazole, and doxycycline/ciprofloxacin) to IV glucocorticoids may reduce disease activity after five days but did not alter rates of response rates at hospital discharge or long-term colectomy [21]. Another study suggested that antibiotics may also be helpful in inducing remission when utilized in conjunction with anti-tumor necrosis factor (anti-TNF) agents [22]. (See "Management of the hospitalized adult patient with severe ulcerative colitis", section on 'Inpatient management'.)

Subsequent steps for steroid-refractory disease

Deciding on medical versus surgical therapy — Steroid-refractory UC is defined as a lack of response after seven days of IV glucocorticoids and is present in approximately 30 to 40 percent of children with acute severe colitis [3,18].

●Timeline – Our approach to children who are not responding to IV glucocorticoids is as follows (algorithm 1):

•Day 3 to 5 – Discuss and reevaluate. If the child has not responded to three to five days of IV glucocorticoids, steroid-refractory disease is likely. These findings should prompt discussion of and preparation for adding a rescue medication (eg, infliximab). We also suggest educating the family about colectomy as a treatment option. Ideally, this should include consultation with a surgeon with expertise in IBD, if the patient and family are ready to learn more about this option.

In such patients, a flexible sigmoidoscopy is usually indicated to assess disease severity, inform treatment decisions, and exclude cytomegalovirus (CMV) infection if not already done. CMV infection should be excluded before escalating medical therapy or surgery because it is associated with steroid-refractory disease and may respond to antiviral treatment. (See 'Pretreatment evaluation' above.)

•Day 5 to 7 – Change therapy for persistent severe colitis. If the child has severe colitis (PUCAI >65) after five to seven days of IV glucocorticoids, proceed to "rescue" medical therapy (biologics or calcineurin inhibitors) or urgent colectomy, using shared decision-making, as described below.

•Day 7 to 10 – Change therapy for partial responders. For children with persistent moderate disease (PUCAI 35 to 64) after 7 to 10 days of IV glucocorticoid therapy, proceed to "rescue" medical therapy or colectomy [3]. This approach is supported by a prospective study in which a PUCAI score <45 on day 3 of IV glucocorticoids was a good predictor of steroid treatment success [19]. Furthermore, a PUCAI score >70 on day 5 of IV glucocorticoids was a strong predictor that steroid treatment would not be successful (specificity and positive predictive value 100 percent).

●Shared decision-making – For patients with steroid-refractory disease, options include surgical colectomy or a trial of escalating medical therapy (algorithm 1):

•Surgery – The possibility of surgery should be presented early in the course of acute severe colitis because it is an important alternative to medical therapy for steroid-refractory disease. Moreover, a substantial number of patients who choose escalating medical therapy will ultimately require surgery [3,23]. The main disadvantage of surgery is that it is an invasive procedure with attendant risks. After restoration of bowel continuity, most patients have moderately increased stool frequency. Long-term risks include inflammation in the pouch (pouchitis) and reduced fertility in females. Nonetheless, clinical outcomes of colectomy are generally very good. For some patients who are very ill or who have a history of difficult-to-treat, medically refractory disease, surgery may be considered instead of medical therapy at this stage. Surgeons with experience in IBD should be consulted early in the hospital course, particularly if there is a poor initial response to IV corticosteroids. (See 'Surgery' below.)

•Escalating medical therapy – For patients who are reluctant to undergo colectomy and/or need more time to make the decision about surgery, we offer escalating medical therapy with anti-TNF agents (typically infliximab) or calcineurin inhibitors (cyclosporine or tacrolimus), which are sometimes known as "rescue" or "salvage" therapies (see 'Escalating medical therapy ("rescue")' below). Although these drugs induce remission in approximately 75 percent of children with acute severe colitis, many patients ultimately require colectomy, based on limited data [18,24,25]. The possible benefits of using infliximab, cyclosporine, or tacrolimus must be weighed against the serious risks of these drugs (infection, nephrotoxicity, and neurotoxicity for calcineurin inhibitors, and infection and infusion reactions for infliximab). (See 'Escalating medical therapy ("rescue")' below.)

Escalating medical therapy ("rescue") — If escalating medical therapy is chosen for children with steroid-refractory disease, the main options are anti-TNF agents and calcineurin inhibitors [3]. Suggested dosing and monitoring are outlined in the table (table 3), and clinical evidence is described below.

The majority of centers in the United States utilize infliximab as first-line rescue therapy in acute severe colitis due to ease of use (less frequent infusions and less monitoring required compared with a calcineurin inhibitor). However, observational evidence suggests that calcineurin inhibitors have comparable efficacy. In an observational study from a single center, patients treated with infliximab or a calcineurin inhibitor for six months had similar rates of colectomy (23 versus 27 percent, respectively) and similar declines in clinical measures of disease activity [26]. There is extensive experience with calcineurin inhibitors in both pediatric and adult IBD centers.

Regardless of which of these therapies is chosen, efforts should be made to wean glucocorticoids to reduce the risk of glucocorticoid toxicity or immunosuppression from multiple medications.

Anti-tumor necrosis factor agents

●Infliximab – Infliximab is the most commonly utilized option for patients with steroid-refractory disease [3]. This drug is a chimeric monoclonal antibody against TNF-alpha. It is effective in fistulizing, perianal, and steroid-refractory Crohn disease (CD), but its use in pediatric UC is less defined [27].

Standard induction dosing for infliximab is 5 mg/kg, given at weeks 0, 2, and 6. However, because clearance of infliximab is accelerated in the setting of acute severe colitis, more intensive dosing may be needed. For these patients, most centers initiate treatment with higher dosing (10 mg/kg) and/or shorter dosing intervals (eg, weeks 0, 1, and 4 or even more frequently) [3]. In one retrospective study, intensified infliximab induction (defined as mean induction dose ≥7 mg/kg or interval ≤5 weeks between doses 1 and 3) was associated with increased remission and lower risk for colectomy in children with steroid-refractory UC but not steroid-dependent UC [28]. If intensive dosing is used initially and the patient responds, the dose may be gradually lowered and adjusted toward standard dosing, ideally guided by therapeutic drug monitoring. One retrospective study and meta-analysis in adults suggests that higher doses of infliximab may reduce initial colectomy rates, but long-term outcomes are similar whether standard 5 mg/kg or 10 mg/kg doses are used [29]. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Infliximab'.)

Among children treated with infliximab for steroid-refractory UC, approximately 75 percent have a short-term response to infliximab, but only 30 to 65 percent have sustained response one year later, based on several observational studies [18,24,30]. One of these studies reported that "stepping up" therapy, by either increasing the dose to 10 mg/kg or decreasing the time between infusions, was associated with higher response rates in a subset of nonresponders [30]. Infliximab also appears to modestly reduce the likelihood of colectomy and overall use of glucocorticoids. In a retrospective multicenter study, 45 children treated with infliximab for UC had a cumulative risk of colectomy of 21 percent within one year and 26 percent within two years; the likelihood of requiring concomitant glucocorticoid treatment was 32 percent within one year and 48 percent within two years [31]. The efficacy and safety of infliximab and other anti-TNF agents for UC, including large randomized trials in adults, are discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults".)

●Adalimumab – Adalimumab is approved by the US Food and Drug Administration (FDA) for use in children with moderate to severe pediatric UC, but its role in acute severe colitis is not clear, because of limited clinical evidence in children. Therefore, we generally use infliximab rather than adalimumab for children hospitalized with acute severe UC.

The FDA approval was based on a phase 3 study that showed meaningful rates of response/remission and mucosal healing in 62 pediatric patients compared with external adult controls (a meta-analysis of the placebo arms in several trials in adults with UC). Patients treated with high-dose adalimumab for induction had higher rates of remission at week 8 compared with those on standard dosing [32]. Among those who did respond by week 8, the proportion who were in remission at one year was 45 percent (14 of 31 patients) for those treated with weekly maintenance adalimumab (0.6 mg/kg, maximum dose 40 mg), 29 percent (9 of 31 patients) for those dosed every other week, and 20 percent in the external placebo adult comparison group. Based on these findings, adalimumab is dosed more frequently for children with UC than for those with CD. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Adalimumab'.)

●Combination therapy – Combination therapy with an anti-TNF agent and an immunomodulator (azathioprine, mercaptopurine, or methotrexate) in children with UC is controversial. One randomized trial in adults with steroid-refractory colitis reported improved remission rates for combination treatment with azathioprine and infliximab compared with either agent alone [33]. In addition, combination therapy has been shown to decrease immunogenicity of infliximab and increase infliximab trough levels in patients with IBD. However, there is a lack of specific evidence to support this practice in children with severe and/or refractory UC. Thus, combination therapy can be entertained but only after careful discussion of the benefit:risk ratio (increased efficacy versus potential increased risk of infection and lymphoma) [3].

The potential benefits and risks of combination therapy are extrapolated from data in adults with UC [33] and children with CD, as discussed separately. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Anti-TNF monotherapy versus combination therapy with an immunomodulator'.)

Calcineurin inhibitors — Calcineurin inhibitors (cyclosporine or tacrolimus) are reasonable alternatives to infliximab for patients with refractory disease [3]. These are not maintenance agents. Patients who respond to treatment should be transitioned to a maintenance drug (typically a thiopurine or vedolizumab), ideally within approximately four to six months or proceed to colectomy. (See 'Maintenance therapy' below.)

●Cyclosporine – IV cyclosporine (2 to 4 mg/kg per day) has been used at some centers as an alternative to colectomy because it can achieve high rates of short-term clinical remission in adult patients with steroid-refractory colitis, although the majority of these patients ultimately require colectomy. Oral microemulsion (or "modified") cyclosporine also may be effective [34]. The conversion from IV to oral microemulsion is approximately 1:3 for the total daily dose (divided in two doses for the oral form), but drug levels should be monitored and the dose adjusted further as needed. Only a few small trials have addressed the use of cyclosporine in children with UC, with outcomes similar to those seen in adults [3]. A systematic review of eight retrospective pediatric case series reported a pooled short-term response of 81 percent, but the majority of patients (60 percent) went on to colectomy in the long term [18]. The use of this drug in adults with UC is described separately. There are no pediatric studies directly comparing the efficacy of cyclosporine with infliximab in severe UC. Adult studies show comparable short- and long-term outcomes for these therapies [35,36]. (See "Management of the hospitalized adult patient with severe ulcerative colitis", section on 'Cyclosporine'.)

●Tacrolimus – Small observational studies in children suggest that oral tacrolimus (0.2 mg/kg per day in two divided doses) may have comparable efficacy with IV cyclosporine in treating fulminant UC or Crohn colitis [26,37-39]. An observational study reported short-term clinical improvement in 43 of 46 children treated with oral tacrolimus (93 percent), with a marked reduction in PUCAI score [25]. However, approximately 50 percent of children treated with tacrolimus will still require colectomy within two years.

If calcineurin inhibitors (tacrolimus or cyclosporine) are used, we suggest prophylaxis against Pneumocystis jirovecii pneumonia [3,40]. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Nonresponders — Limited evidence is available to guide treatment decisions for patients who do not respond to the initial attempt at medical rescue therapy with infliximab or a calcineurin inhibitor. The risks and benefits of changing to a different immunosuppressant (sequential medical rescue therapy) must be carefully discussed with the patient and family. Use of sequential medical "rescue" therapy is controversial [3]. For most patients in this category, we suggest surgery, as discussed below (algorithm 1). (See 'Surgery' below.)

●Decision-making – Our practice is:

•We discuss the option of surgery versus medical therapy again with the patient and family. We review the same considerations that were discussed prior to the initial attempt at medical rescue therapy. We explain that we have limited information about the outcomes of sequential medical therapies, but the likelihood of response is probably lower and the risk of serious infection is higher compared with the initial attempt with infliximab or a calcineurin inhibitor. (See 'Deciding on medical versus surgical therapy' above.)

•For most patients who do not respond to the initial attempt at medical rescue therapy (infliximab or calcineurin inhibitor), we suggest surgery. A surgical consultation is obtained, if not already done. (See 'Surgery' below.)

•However, some patients/caregivers may reasonably choose a second attempt at medical rescue therapy over surgical intervention. For these patients, our approach is as follows:

-For those who did not respond to infliximab as the initial therapy, options include a calcineurin inhibitor (as a bridging therapy), tofacitinib, or upadacitinib.

-For those who did not respond to a calcineurin inhibitor as the initial therapy, options include infliximab, tofacitinib, or upadacitinib.

Sequential use of immunosuppressive agents may increase the risk of infection, but overall risks are generally acceptable, based primarily on indirect evidence from adults with IBD or children with autoimmune diseases, as well as limited but increasing experience with tofacitinib and upadacitinib in adults and children, outlined below.

●Second-line rescue agents – The main options for alternate medical therapy are Janus kinase (JAK) inhibitors (tofacitinib or upadacitinib). These drugs are approved for use in adults with UC who have not responded to other biologic therapies, but data are limited on their use in children or for acute severe colitis in any age group. In one case series, four of six adults with acute severe colitis who lost their response to infliximab achieved corticosteroid-free clinical remission by week 8 of upadacitinib treatment [41]. Similarly, small case series in hospitalized children with refractory UC of varying severity suggest that tofacitinib may be beneficial [42,43]. The experience with these and other agents in adults is discussed separately. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Janus kinase (JAK) inhibitors'.)

Safety concerns with JAK kinase inhibitors include infection, hyperlipidemia, thrombosis, and cardiac events. Relevant safety information comes from other populations treated with tofacitinib, including children with juvenile idiopathic arthritis. (See "Polyarticular juvenile idiopathic arthritis: Treatment".)

These drugs are not approved by the FDA for children with UC, but they may be appropriate for selected patients based on individual characteristics and if recommended and managed by an expert clinician, as an "off-label" use [44]. A small study in children with steroid-refractory UC suggests that tofacitinib may reduce the likelihood of colectomy [42]. The limited available data on the use of tofacitinib, upadacitinib, and ustekinumab in children with nonsevere UC are summarized separately. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Other options'.)

Experimental interventions include combination oral antibiotics [45], leukocytapheresis, or rapamycin [46], but these strategies are only supported by small retrospective studies and cannot be recommended at this time.

Medical necessity of off-label use of medications — Use of these second- or third-line agents and/or escalation of doses beyond those approved by the FDA may be appropriate and medically necessary for selected children with UC, as discussed separately. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Medical necessity of off-label use of medications in pediatrics'.)

Maintenance therapy — Patients with acute severe colitis generally require long-term maintenance with either an immunomodulator and/or anti-TNF agent. The choice of maintenance therapy for severe or refractory colitis depends on which therapy was successfully used for induction:

●Glucocorticoid responders – Options for maintenance therapy include infliximab, vedolizumab, thiopurine, or other immunomodulator. The glucocorticoids can be gradually withdrawn by transitioning to oral glucocorticoids, followed by a gradual tapering of the dose. If an immunomodulator is used, mesalamine or other 5-ASA can be used as an adjunct therapy. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Maintenance of remission'.)

●Anti-TNF responders – If infliximab or adalimumab was successful for induction, continue this agent for maintenance therapy and gradually taper the glucocorticoids.

●Calcineurin inhibitor responders – If a calcineurin inhibitor (cyclosporine or tacrolimus) was used for induction, transition the therapy to infliximab (if not previously failed), adalimumab, thiopurine, vedolizumab, or tofacitinib or upadacitinib. While one guideline suggests weaning patients from calcineurin inhibitors within four months [3], clinicians may reasonably choose to continue treatment beyond this timeframe in special circumstances, keeping in mind the risks of prolonged therapy.

●Tofacitinib or upadacitinib responders – If tofacitinib or upadacitinib was used for induction, options include continuing it for maintenance therapy or transitioning to vedolizumab (which may have a better safety profile). (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Other options'.)

Vedolizumab is also occasionally used for patients who stop responding to anti-TNF therapies. It tends to have a slower onset of action compared with other biologic agents but an improved safety profile. Most evidence is extrapolated from studies in adults and a few studies in children with moderate UC. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Second-line options'.)

Patients with severe colitis who improve sufficiently to be discharged from the hospital remain at high risk of relapse or developing complications of their IBD or of immunosuppression. Therefore, these patients require close follow-up, with monitoring of history, examination, laboratory studies, and therapeutic drug monitoring as necessary. We typically reevaluate these patients in clinic one to two weeks after hospital discharge. Even patients who respond well to medication may not achieve a full clinical remission until 8 to 16 weeks after the initiation of their maintenance therapy.

SURGERY — When managed with a modern protocol of medical therapies, approximately 5 to 10 percent of children with UC undergo colectomy within one year of diagnosis and approximately 15 percent within three years [23,47-49]. Outcomes are only partially predicted by disease severity at baseline. (See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Prognosis'.)

Candidates

●Emergency colectomy is required for patients with acute severe colitis and uncontrolled hemorrhage or patients with complications such as toxic megacolon or bowel perforation.

●In addition, we suggest colectomy for patients who do not respond to aggressive medical management within two weeks or after failure of medical rescue therapy, such as infliximab or a calcineurin inhibitor (algorithm 1) [3]. However, some nonresponders may reasonably choose a second attempt at medical rescue therapy over surgical intervention, as discussed above. (See 'Nonresponders' above.)

Elective colectomy also has a role in the chronic management of UC (eg, in patients who are unresponsive to or cannot be weaned from glucocorticoids, who experience unwanted side effects [eg, growth failure from steroids], or who have surveillance biopsies that suggest a risk for developing cancer) [3,50]. Some patients may choose to undergo colectomy earlier in the disease course. This is discussed separately. (See "Surgical management of ulcerative colitis".)

A small proportion of patients with what appears to be UC will ultimately be diagnosed with Crohn disease (CD), in which case, surgery will not be curative. Even a thorough preoperative evaluation (including review of small bowel imaging and endoscopic, histologic, and serologic data) cannot exclude this possibility. It is likely that a patient with diffuse continuous colitis, no granulomas on biopsy, and no macroscopic small bowel involvement will have UC. Nonetheless, CD may still be diagnosed in 5 to 25 percent of cases [51,52]. Some of these patients who are ultimately diagnosed with CD may need a permanent ileostomy. Patients should be made aware of this possibility.

The presence of anti-Saccharomyces cerevisiae antibodies (ASCA) is somewhat predictive of which patients with an initial diagnosis of UC or indeterminate colitis may develop evidence of CD after colectomy. In one series, the positive predictive value of ASCA immunoglobulin A (IgA) antibodies was 0.17 and the negative predictive value was 0.94; the positive predictive values are less than a family history of CD [51]. Because of these limited predictive values, these tests should not be used as an important factor in making decisions about colectomy. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Differentiation between Crohn disease and ulcerative colitis' and "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Antibody testing'.)

Technique — The most commonly performed procedure is colectomy and rectal mucosectomy with an endorectal ileoanal pull-through, creation of a distal ileal reservoir, and ileorectal anastomosis (called ileal pouch anal anastomosis [IPAA]). In the urgent surgical setting, a subtotal colectomy, terminal ileostomy, and blind rectal stump are created. After the patient recovers, the rectal mucosectomy and ileoanal pull-through with anastomosis procedure is performed.

Addressing medical and psychologic needs prior to surgery is important for the patient and to improve outcomes. Nutritional correction, treatment of infections, and psychological support are crucial. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Psychological screening and support'.)

Additional details on the pre- and postoperative surgical management of UC are provided in a separate topic review. (See "Surgical management of ulcerative colitis".)

Perioperative management of immunosuppressive therapy — Most immunosuppressive drugs can be discontinued just before surgery, with the exception of glucocorticoids, which must be tapered after surgery. If possible, efforts should be made to limit corticosteroid exposure before elective or semi-elective colectomy to optimize healing of wounds and intestinal anastomoses.

Exposure to immunosuppressive drugs in the preoperative period probably does not have adverse effects on outcomes after surgery, although there is some uncertainty on this point [53]. In one study, preoperative exposure to thiopurines or calcineurin inhibitors within 30 days, or infliximab within 90 days, did not significantly affect postoperative outcomes [54,55]. In another study, the use of tacrolimus prior to colectomy reduced disease severity and was not associated with complications [56]. In contrast, whether vedolizumab increases the risk of perioperative complications is controversial. Some studies suggest an increase in peristomal complications, but other meta-analyses have failed to confirm this finding [57]. (See "Surgical management of ulcerative colitis", section on 'Routine preoperative care'.)

Outcomes — Functional outcomes of IPAA for UC are generally good. Patients who undergo this surgery generally have four to eight bowel movements per day, but continence usually can be achieved [58,59]. In one series, 89 percent of patients were continent two years after undergoing IPAA with creation of a J-pouch reservoir [60]. Studies with long-term follow-up describe ongoing improvement in quality of life even many years after surgery, with some continence problems in 10 to 20 percent of patients [59,61-63]. Other complications include reduced fertility in females undergoing the IPAA procedure, and risks for sexual dysfunction in both males and females [53]. These and other surgical considerations are discussed separately. (See "Surgical management of ulcerative colitis".)

The major complication occurring after ileoanal pull-through with pouch formation is inflammation of the pouch ("pouchitis"), which occurs in 10 to 30 percent of patients [59,60]. Clinical symptoms of pouchitis include diarrhea, rectal bleeding, abdominal cramping, and malaise. Broad-spectrum antibiotics (metronidazole) or glucocorticoid enemas usually are effective therapy; in some patients, systemic steroids are required. Chronic pouchitis eventually develops in approximately 10 percent of patients [63]. Maintenance therapy may include oral bacteriotherapy (probiotics). A diagnosis of CD should be considered in patients in whom pouchitis is chronic and refractory to treatment. (See "Pouchitis: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Management of acute and chronic pouchitis".)

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 5^th to 6^th 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 10^th to 12^th 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: Ulcerative colitis in children (The Basics)")

●Beyond the Basics topic (see "Patient education: Ulcerative colitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Disease severity – Acute severe ulcerative colitis (UC) typically presents with profuse bloody diarrhea, abdominal distention, or tenderness, often with fever, tachycardia, anemia, hypoalbuminemia, or leukocytosis. Severe disease is usually defined by a score of >65 on the pediatric UC activity index (PUCAI) (table 2) (calculator 1) [2]. (See 'Defining disease severity' above.)

●Pretreatment evaluation – Children with acute severe colitis require urgent evaluation to diagnose alternative or coexisting conditions and to determine the severity and extent of disease. The evaluation includes stool tests to exclude enteric infections that may mimic or precipitate a flare (especially C. difficile), abdominal radiograph to evaluate for toxic megacolon, and usually a flexible sigmoidoscopy or colonoscopy to assess disease severity and test for cytomegalovirus (CMV) colitis using colonic biopsies. (See 'Pretreatment evaluation' above.)

●Initial therapy

•Supportive care – Patients with severe disease should be urgently admitted to a hospital. Supportive care includes hydration, nutrition, pain management, and, in some cases, blood transfusion or albumin replacement. (See 'Supportive care' above.)

•Glucocorticoids – For patients with acute severe colitis, we recommend initiating treatment with high-dose intravenous (IV) glucocorticoids (Grade 1B). (See 'Intravenous glucocorticoids' above.)

•Antibiotics – Patients with suspected bacteremia, C. difficile infection or toxic megacolon require broad-spectrum antibiotics, which are continued until blood and stool cultures are negative. Some clinicians utilize broad-spectrum antibiotics more liberally, as part of induction therapy. (See 'Antibiotics (selected patients)' above.)

●Steroid-refractory disease – Patients who do not have a clinically meaningful response to a seven-day course of IV glucocorticoids have steroid-refractory disease. Concomitant enteric infections should be carefully excluded if not already done, including stool cultures, C. difficile toxin, and assessment for CMV infection via sigmoidoscopy. (See 'Subsequent steps for steroid-refractory disease' above.)

Treatment options include surgical colectomy or a trial of escalating medical therapy (algorithm 1). These options should be discussed with the patient and caregivers early in the disease course (once it is apparent that the child has not responded adequately to IV glucocorticoids). The choice between surgery versus escalating medical therapy is individualized, depending on the child's condition and history of prior flares, as well as the patient's and family's values and preferences. Key points during shared decision-making with the family are (see 'Deciding on medical versus surgical therapy' above):

•The advantage of surgery is that it removes the diseased colon. The main disadvantage is that it is an invasive procedure with attendant risks (including both procedure-related risks and long-term risks, which include pouchitis and possible reduced fertility in females). However, clinical outcomes of colectomy are generally very good. (See 'Surgery' above.)

•The main options for escalating medical therapy are a trial of an anti-tumor necrosis factor (anti-TNF) agent therapy (typically infliximab) or a calcineurin inhibitor (cyclosporine or tacrolimus) (table 3). Most children achieve short-term remission with these treatments, but less than one-third achieve long-term glucocorticoid-free remission. The main advantage of escalating medical therapy is that it may avoid the need for surgery. However, many patients ultimately require colectomy. In addition, the potential benefits of these medications must be weighed against the risks of these drugs (infection and infusion reactions for infliximab and infection, nephrotoxicity, and neurotoxicity for calcineurin inhibitors). (See 'Escalating medical therapy ("rescue")' above.)

●Escalating medical therapy – For most patients with steroid-refractory disease who opt for escalated medical therapy, we suggest infliximab rather than other agents (Grade 2C). A calcineurin inhibitor (cyclosporine or tacrolimus) is a reasonable alternative. Our preference for infliximab is based on its ease of use (less frequent infusions, less monitoring). Observational data suggest that infliximab and calcineurin inhibitors have comparable efficacy. (See 'Escalating medical therapy ("rescue")' above.)

●Maintenance medical therapy – Patients with acute severe colitis generally require long-term maintenance with either an immunomodulator and/or anti-TNF agent or other biologic agent (eg, tofacitinib, vedolizumab, or upadacitinib). The choice of maintenance therapy for severe or refractory colitis depends on which therapy was successfully used for induction. (See 'Maintenance therapy' above.)

●Surgery

•Emergency colectomy is required for patients with acute severe colitis and uncontrolled hemorrhage or complications such as toxic megacolon or bowel perforation. (See 'Candidates' above.)

•In addition, we suggest colectomy for patients with acute severe UC and no improvement within two weeks of aggressive medical management or after failure of a first attempt at medical rescue therapy (eg, infliximab or a calcineurin inhibitor) (Grade 2C). However, some nonresponders may reasonably choose a second attempt at medical rescue therapy (eg with tofacitinib or upadacitinib) rather than surgical intervention. (See 'Candidates' above and 'Nonresponders' above.)

•Potential complications of colectomy include incontinence, pouchitis, and reduction in fertility among females. (See 'Outcomes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George H Russell, MD, MS, who contributed to earlier versions of this topic review.