Journal of Pediatric Gastroenterology & Nutrition:
Severe Colitis in Children
Kugathasan, Subra*; Dubinsky, Marla C†; Keljo, David‡; Moyer, M Susan§; Rufo, Paul A¶; Wyllie, Robert#; Zachos, Mary∥; Hyams, Jeffrey**
*Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; †Department of Pediatrics, Cedars-Sinai Medical center, Los Angeles, California; ‡Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; §Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical center, Cincinnati, Ohio; ¶Combined Program in Gastroenterology and Nutrition, Children's Hospital, Boston, Massachusetts; #Department of Pediatrics, Cleveland Clinic Foundation, Cleveland, Ohio; ∥Division of Gastoenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Canada; and **Department of Pediatrics, Connecticut Children's Medical Center, Hartford, CT University of Connecticut School of Medicine, Farmington, Connecticut
Received March 28, 2005; accepted September 2, 2005.
Address correspondence and reprint requests to Subra Kugathasan, M.D., Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee WI 53226 (e-mail: email@example.com).
The management of the child with severe or fulminant colitis presents a formidable challenge to clinicians. While many of these patients respond to conventional medical therapy, a substantial proportion do not, requiring the clinical team to decide whether to continue medical therapy or move to colectomy. Patients and their families are often reluctant to consider surgical alternatives further increasing the pressure on clinicians to find novel approaches to these extremely ill children.
Recent advances in immunomodulatory and biological therapy of severe colitis have expanded the therapeutic armamentarium; however, it is not clear whether these new approaches are changing the natural history of this condition. Recently, the Crohn's and Colitis Foundation of American (CCFA) convened a consensus panel of pediatric inflammatory bowel disease experts to develop definitions of severe colitis, examine current treatment strategies, and plan clinical trials of emerging drugs. This review reports the findings of this panel and is designed to give the reader a “state of the art” approach to the management of severe colitis in children.
Assessment of Disease Severity
Disease activity is often viewed as either degree of illness (subjective or objective manifestations of disease) or inflammation (the pathologic process) or a combination of both (1). It is known that patients with ulcerative colitis (UC) present with varying degrees of systemic illness not always corresponding with the degree of endoscopic severity. In 1955, Truelove & Witts (2) proposed three degrees of disease severity (Table 1). Although this classification has never been formally validated either in adults or children, it is widely used in trials of adult patients with severe ulcerative colitis (3-7). A modified Truelove and Witts Score, was employed in a pivotal study on the use of cyclosporine in the treatment of acute severe UC in adults (8). The scoring system now known as Lichtiger Symptom score has a maximal score of 21 and a score ≥10 implies severe disease activity (Table 2).
Werlin and Grand (9) proposed a pediatric modification to the Truelove and Witts score 1977 in which children needed to fulfill 4 of 5 of the following criteria to be defined as having severe colitis: 5 or more bloody stools a day, oral temperature of more than 100°F during the first hospital day, tachycardia, anemia (hematocrit of 30 or less) and serum albumin of 3 g/dl or less. The presence of toxic megacolon (dilation of the transverse diameter of the colon in excess of 6 cm) alone was sufficient to warrant a diagnosis of severe colitis.
Other indices have been developed to measure clinical and/or endoscopic activity but have not been validated in multicenter trials either in adult or pediatric patients (10,11). The Mayo Score(10) has been the most widely employed in the more recent UC clinical trials. This index includes both clinical and endoscopic variables (Table 3). The endoscopic score is a modification of the Baron score (11) which classifies the findings found at sigmoidoscopy: grade 1, abnormal mucosa but nonhemorrhagic; grade 2, moderate hemorrhagic and friable mucosa; and grade 3, severe hemorrhagic with spontaneous bleeding. Although endoscopic improvement or even healing is an important outcome for measuring treatment efficacy and change in disease severity, improvement in clinical signs and symptoms remains the primary outcome of therapeutic intervention in UC.
As noted above, to date there are no validated UC activity indices, especially for use in pediatric clinical trails. Discussions surrounding pediatric clinical trial design have led to the suggestion that the modified Truelove and Witts severity index (2,8) (Table 2) be employed in pediatric clinical trials with some additional clinical caveats. Clinical response would be defined as MTWSI <11 with a drop in MTWSI by ≥3 points coming from a reduction in number of stools per day and/or bloody stools per day as compared to Day 0. Remission would be defined as an MTWSI <4 with no visible blood in the stool at the primary endpoint.
Epidemiology of Severe Colitis in Children
The prevalence and outcome of initial and subsequent attacks of severe colitis in children from population-based cohorts is unknown. Available information on severe colitis comes from non-population based specialty centers and mainly from studies in adults but few epidemiological studies have been focused on children with ulcerative colitis. The first attack of ulcerative colitis in children tends to be more severe and the disease distribution more extensive than in adults (12,13,14). At least two retrospective studies undertaken between 1962 and 1994 have described the clinical presentation and the course of pediatric UC. In one study, Hyams et al. (12) described a cohort of 171 children (age range 1.5 to 17 years) with ulcerative colitis from two large centers in the northeast United States. Forty-three per cent of these children had pancolitis while the remaining had disease limited to the left side of the colon. Disease activity was classified as moderate to severe in 57% of cases and mild in the remainder using the criteria of Truelove and Witts. The other study from multiple sites in Wisconsin demonstrated that 90% of newly diagnosed children with ulcerative colitis had extensive colitis extending beyond the spelenic flexure (13). It is possible that the more common use of pancolonoscopy in the past decade facilitated increased recognition of more extensive disease. In contrast, distal disease and limited disease is more frequent in adults with ulcerative colitis and fewer have severe symptoms at diagnosis (15). In this study approximately two-thirds of adults with UC have left-sided disease at presentation.
Natural History of Severe Colitis in Children
Long-term natural history studies in a large number of pediatric patients are limited. Early studies (16,17) suggested a need for colectomy ranging from 26% to 50% but specific rates at 1, 5, and 10 year intervals were not well elucidated. Retrospective data from a more recent pediatric study (12) reports that patients who initially present with more mild disease have a lower rate of colectomy (1%) at 1 year after diagnosis as compared to those who present with moderate to severe disease (8%). The 5-year colectomy rate for children presenting with mild disease was 9% compared to 26% for those presenting with moderate to severe disease. Longer follow-up studies are available among adult UC cohorts with colectomy rates of 30% and 44% at 20 and 25 years after diagnosis, respectively (15,18).
The goals of therapy for severe colitis are to quickly control symptoms, provide maintenance therapy to prevent further relapses, and recognize when medical therapy fails and decide on appropriate surgical intervention. There are limited data on the treatment of children with severe colitis. Attempts to establish standard of care of severe colitis in children are based largely on the adult literature, a few poorly controlled or retrospective series in children and anecdotal experience. This is particularly true for medications with a long track record of established use in IBD (corticosteroids, aminosalicylates, 6-mercaptopurine (6-MP) and azathioprine).
It is imperative that infection be excluded as a cause of symptoms, whether in the newly diagnosed or chronic patient. In addition to testing for standard bacterial pathogens (e.g., Salmonella, Shigella, Campylobacter, E. coli etc) and Clostridium difficile, evaluation for cytomegalovirus (CMV) infection may be indicated in selected patients. Recent reports have suggested CMV can be a cause of worsening symptoms in patients with inflammatory bowel disease (19-23). In one prospective evaluation of 64 adult patients admitted to the hospital for active IBD, blood or urine markers of CMV replication were found in 6% (20). Three patients had CMV viremia and one had bipsy proven CMV colitis. While no consensus recommendations are available, it seems prudent to consider CMV infection in heavily immunosuppressed patients with refractory colitis. Demonstration of CMV in bowel tissue or CMV antigenemia should prompt anti-viral therapy.
Role of “Bowel Rest” and Nutritional Support
The concept of “bowel rest” to allow repair of inflamed tissue is instinctively attractive to physicians caring for patients with severe colitis. However, bowel rest has not been found to be beneficial to these patients. Three well-controlled studies (24-26) have shown no benefit of bowel rest as a supplement to corticosteroid therapy in the treatment of severe colitis, including Crohn colitis, in adults. Serum albumin increased in the enteral but not the parenteral nutrition groups in 2 of these studies, suggesting perhaps a nutritional advantage to enteral nutrition (25,27). This was not supported in the third study where total body nitrogen decreased in the enterally fed but not the parenterally fed group (24). Stool frequency was similar in both enteral and parenteral groups in the study in which it was reported (26). Complications of central venous lines such as pneumothorax and sepsis were reported in all of the studies, and one study reported an increased frequency of postoperative infection in the intravenously alimented group (25). The clinical impression that regular diets increase symptoms of pain and diarrhea in patients with severe colitis, though unsupported by data, results in the common practice of restricting oral intake during initial hospitalization. Continued inability to advance the diet can be an indication of medical failure.
Malnutrition is common in patients with severe colitis, particularly when diagnosis and treatment have been delayed. Nutritional support is important in these patients, and it appears that the enteral route can be safely used, and may be preferable because it has fewer complications than the parenteral route. However, if severe nausea and vomiting are present, patients may be unable to take adequate nutrition enterally and parenteral support would be necessary. A combination of both routes can also be used.
Antibiotics in Severe Colitis
Antibiotics were used together with corticosteroids and parenteral nutrition in the original Oxford intensive intravenous regimen that transformed the outlook of severe colitis in adults (28,29). Several subsequent controlled trials have shown no benefit of intravenous antibiotics (tobramycin alone, ciprofloxacin alone or tobramycin in combination with metronidazole) when added to intravenous corticosteroid therapy (3,30,31). Out of five controlled trials of oral antibiotics in ulcerative colitis, only two showed a short term significant benefit of tobramycin or ciprofloxacin (32,33). Two showed a trend towards benefit with vancomycin or rifaximin (34,35). One showed no benefit of a relatively low dose of ciprofloxacin (36). Curiously, the studies of intravenous antibiotics had a placebo response rate of 65-77%, while the studies of oral antibiotics had a placebo response rate of 42-56% with the exception of the negative study, which had a placebo response rate of 72%. This decreased placebo response rate (42-56% compared to 65-77%) may be responsible for the apparent benefit of oral antibiotics. None of the studies showed benefit of antibiotic therapy beyond the acute stage. There are no controlled trials of antibiotics in children with ulcerative colitis or Crohn colitis.
Oral aminosalicylates are useful in induction and maintenance therapy in mild-to-moderate ulcerative colitis and, to a lesser extent, in Crohn colitis (37). There is no evidence that these medications are of clinical benefit in acute severe colitis. There are also no data available to support the use of topical aminosalicylates in this setting of severe colitis. Since most patients with severe flares of colitis have difficulty retaining enemas or suppositories, preparations for rectal application are unlikely to be of benefit. Since aminosalicylates have not been used as sole therapy for attacks of severe colitis, data are lacking on the efficacy of aminosalicylates alone in the setting of severe colitis. Although not supported by controlled data, it may be prudent to stop the use of aminosalicylates in a hospitalized patient with severe colitis who is also receiving high doses of corticosteroids, since paradoxical worsening of severe colitis may occur in a small subset of patients due to aminosalicylate hypersensitivity (38,39).
Therapy with corticosteroids remains the mainstay of medical therapy for attacks of severe colitis caused by both ulcerative colitis and Crohn disease. The use of corticosteroids has significantly reduced mortality rates since these medications were first used (40). In the original study of Truelove and Witts, cortisone was superior to placebo in the treatment of both first attacks as well as relapses of ulcerative colitis (2). Overall, 40% of patients achieved remission on cortisone at a dose of 100 mg per day orally for up to 6 weeks. Cortisone was particularly beneficial in those with first attacks. In addition, the remission rate was higher in mild disease (75%) compared with severe disease (31%). These investigators later published a landmark article detailing an intensive intravenous regimen for the treatment of severe colitis consisting of fluids (at least 3 liters per day), prednisone-21-phosphate (60 mg per day intravenously in divided doses), and total parenteral nutrition, along with nothing by mouth and rectal hydrocortisone (100 mg twice daily) (29). Remission, defined as the absence of bowel symptoms, was achieved in 60% to 73% of patients with severe colitis using this regimen and was maintained for at least 2 years in 38% to 47%. Interestingly, patients who responded did so within 5 days, and failure to respond was a reliable indicator of the need for colectomy. Others have reported similar results using intravenous corticosteroid therapy in severe ulcerative colitis (41,42). To-date, no controlled studies exist showing a benefit from combining topical corticosteroid therapy with intravenous therapy for severe colitis.
Optimal dose or mode of administration of corticosteroids has not been studied in adults or children in any systematic or controlled fashion. The only dose ranging study was by Baron et al. (43) who compared 20, 40, and 60 mg of orally administered prednisolone in patients with mild to moderate ulcerative colitis. The efficacy of the 40 mg and 60 mg dosing regimens were similar and better than the 20 mg dose. Fewer side effects were noted with the 40 mg dose compared to the 60 mg dose. Treatment with higher steroid doses has shown no additional benefit (44). There is limited information on the use of pulsed intravenous corticosteroid therapy compared to conventional oral therapy. In one study of 19 adult patients with moderate to severely active ulcerative colitis, patients were either treated with 0.8 mg/kg/day of oral prednisolone or 500 mg methylprednisolone given intravenously daily for 2-3 days followed by oral prednisolone (0.8 mg/kg/day). At the end of 4 weeks there were similar numbers of patients in remission in both groups, with a trend toward more rapid improvement in the group treated with pulsed initial therapy (45). The clinical impression that continuous corticosteroid infusion is superior to bolus infusion has not been studied in a controlled fashion. Adrenocorticotropic hormone (ACTH), 40 to 120 U appears to be similar to hydrocortisone in efficacy, (46,47) although there may be an increased benefit to ACTH if the patient has not previously been treated with steroids (48,49).
The recommendations for length of corticosteroid therapy prior to proceeding with surgery because of lack of response varies greatly in adult studies and there is currently no consensus. Recently, it has been reported that, after only 3 days of intensive treatment, most patients (85%) with persistent frequent stools (>8/day) or raised C-reactive protein (>4.5 mg/L) will eventually need colectomy (50). Other authors (42,51) suggest responses may be seen after 10-14 days of therapy. Werlin and Grand (52) reported their pediatric experience in a retrospective review of 19 children with severe colitis (14 with ulcerative colitis and 5 with Crohn colitis). Extending medical treatment beyond 12 days substantially increased morbidity and complications in their series. Another group published a series of 11 pediatric patients with severe ulcerative colitis treated medically for longer than 14 days with favorable outcome (53). One of these patients required colectomy during the initial hospitalization and an additional patient underwent colectomy during the follow-up period of several years. These authors concluded that their results did not support the recommendation for colectomy if remission is not achieved within 14 days. Unfortunately this was a small retrospective study and is not adequately powered to support the conclusion.
At the current time it is reasonable to assume that hospitalized patients who do not respond to intravenous corticosteroids over 5-7 days should be viewed as treatment failures and additional medical therapy or colectomy should be considered. We do not recommend prolonging intravenous corticosteroid therapy alone beyond 7-10 days since the risks of complications are high and the likelihood of response decreasingly likely. Although evidence is lacking in pediatric experience, escalation of therapy with additional immunosuppressive agents may be considered in those children when the child/family is not prepared for colectomy and treatment with these agents are not otherwise contraindicated.
Azathioprine and 6-mercaptopurine
Azathioprine, and its metabolite 6-mercaptopurine have been widely and successfully used in Crohn disease and ulcerative colitis, but their acute use is limited in the presence of severe colitis by their delayed onset of action. Although initial studies of intravenous loading doses azathioprine in adults (54) suggested a rapid onset of action in 4 weeks, a subsequent randomized trial (55) did not substantiate a rapid effect, at least in Crohn disease. In those patients where remission is induced with cyclosporine, maintenance of remission can be improved with the overlap of azathioprine or 6-mercaptopurine with cyclosporine (56,57).
Mahadevan et al. (58) retrospectively reviewed postoperative complications associated with the use of azathioprine or 6-MP before colectomy for ulcerative colitis. The complications were classified as early (within 30 days) or late (within 6 months). In addition to immunosuppressive drugs, factors including extent and duration of disease, dose and duration of corticosteroids, Truelove/Witt score and albumin were examined for associations with postoperative complications. Early complications after restorative proctocolectomy for ulcerative colitis were found to be associated with high dose steroids and severe disease but not with the use of AZA or 6-MP.
Cyclosporine and Tacrolimus
CSA was first used in patients with severe UC in 1990 (59), and the first randomized study confirmed the efficacy of this agent for this indication in 1994 (8). CSA is typically started at a dose of 4 mg/kg/day (IV) or 4-10 mg/kg/day (PO) with subsequent doses adjusted to maintain trough levels of 150-300 ng/ml. A recent randomized double-blind comparison of a continuous daily infusion of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis in adults showed equal efficacy (60). Overall side-effects in the two groups were similar, with a trend toward less hypertension in the low dose group. Early studies in subjects with UC utilized IV CSA to achieve disease remission, and then transitioned responding patients to oral preparations for maintenance therapy. However, subsequent studies have demonstrated that oral CSA appears to be equally effective and may expose patients to less risk (61-63). Children responding to cyclosporine demonstrate increased weight, hematocrit, and serum albumin, as well as decreased steroid usage and erythrocyte sedimentation rates (64).
In uncontrolled reports, tacrolimus resulted in clinical improvement in 60-90% of pediatric and adult patients with steroid refractory UC within 6-7 days (65-67). Tacrolimus therapy is initiated at 0.1-0.15 mg/kg/day, and patients are maintained in a target range of 10-15 ng/ml (65-67). Enteral and parenteral tacrolimus dosing appear to be equally efficacious in the treatment of refractory UC (68).
CSA and tacrolimus can result in mucosal healing in children and follow-up studies often reveal endoscopically and histologically normal appearing colonic mucosa (64,66). While CSA and tacrolimus appear to be tolerated in most children, about 25% require dosage reduction or therapy must be discontinued altogether for significant adverse events (69,70). Adverse effects associated with CSA and tacrolimus include: gingival hyperplasia, infections (bacterial or viral), neurotoxicity (seizures, parasthesia, and tremor), coarse facial features, hypertrichosis, elevated liver function tests, and hyperkalemia. These adverse effects associated with CSA therapy have been documented in patients with serum levels within the therapeutic range (63). CSA-induced nephrotoxity (manifest as elevated creatinine and hypertension) is typically reversible with a dosage reduction (63) but CSA causing irreversible reductions in creatinine clearance have also been reported (68).
Current data from adults suggest that CSA or tacrolimus therapy may be considered in those patients that have not responded to 5-7 days of intravenous corticosteroid therapy (61,71). CSA should not be considered in patients who have any evidence of active infection, severe malnutrition (hypoalbuminemia with serum albumin of 2.5 or less, low serum cholesterol) or in those who are known to be intolerant to long term maintenance immunomodulator therapy with azathioprine or 6-mercaptopurine. If patients do not respond within five days, they should be considered for colectomy. In those patients that do respond to CSA or tacrolimus, immunomodulatory therapy using 6 MP or AZA should be phased in as steroids are weaned. Trimethoprim-sulfamethoxazole has been recommended as prophylactic therapy for Pneumocystis carinii pneumonia during periods of triple immunosuppression. Fatal opportunistic infections (Pneumocystis carinnia pneumonia, aspergillus) occurred in 3.5% of 86 adult patients with severe ulcerative colitis treated with CSA (72). Patients with disease activity that recurs while CSA is being weaned should be considered for colectomy (61).
Fleshner et al. (73) retrospectively reviewed the morbidity of subtotal colectomy in patients with severe UC unresponsive to CSA. In the 14 (adult) patients studied there were no deaths. Post-operative complications occurred in 8/14 (57%) of patients, including ileus (22%), deep vein thrombosis (14%), wound infection (14%) and partial dehiscence of the rectal stump (7%). The mean length of postoperative stay was 8.8 days. The authors concluded that CYA treatment may not adversely influence the safety of urgent surgical treatment in severe UC.
While short-term responses to CSA and tacrolimus have been impressive, long-term follow-up studies indicate that disease is likely to return with attempts to wean or discontinue CSA therapy. Response rates at 6 months are about 50-60%, and subsequently fall to 25-40% by 3-5 years (74). Ultimately, 40-70% of patients treated with CSA or tacrolimus will require colectomy within 6 months to 3 years of discontinuing therapy (62,66,71,75). Long-term outcome in patients treated with CSA and tacrolimus therapy appears to be improved when used in conjunction with the immunomodulators such as azathioprine or 6-mercaptopurine (69,71). Data collected from adult studies suggest that patients with younger age, longer disease duration, absence of pancolitis or fever, and higher serum hematocrit or albumin respond more favorably to CSA therapy (76). In contrast, response to CSA or tacrolimus cannot be predicted by the extent, distribution of disease, or age at presentation in pediatric patients.
The successful use of infliximab to treat moderate to severe Crohn's disease has spurred interest in the possible use of this agent to treat severe ulcerative colitis in children and adults (4,77-86). Approximately 200 patients with ulcerative colitis have been reported in uncontrolled series with an overall response rate ranging from 50 to 100%, and remission rates up to 40%. Long term follow up data are limited but in some of these uncontrolled studies prolonged response and remission have been observed (77). It has been suggested that steroid refractory patients (83) and those with more chronic disease (78) are less likely to respond to infliximab. Thus, it should be noted that these uncontrolled studies reflect heterogeneous populations including newly diagnosed disease, relapsed disease, and chronic corticosteroid dependent patients. The first prospective, placebo controlled trial with a total of 43 patients failed to demonstrate efficacy of infliximab compared to placebo (85). Remission rates at 6 weeks after two 5 mg/kg infusions of infliximab or placebo at weeks 0 and 2 were 39% and 30% respectively.
A second randomized placebo controlled study examined the utility of infliximab in 45 adult subjects with moderate to severe colitis who were refractory to corticosteroids. The need for colectomy was significantly less in the infliximab treated group (29%) than in the placebo group (67%) (86). Two additional very large randomized placebo controlled trials of infliximab in the treatment of adults with ulcerative colitis have been published in abstract forms (87,88). In both these reports infliximab was superior to placebo in including response and remission at 8 weeks following dosing at 0,2, and 6 weeks (65% to 69%, 34% to 38%, respectively) compared to placebo (29% to 37%, and 6% to 15%, respectively).
Limited experience is also becoming available with other biological agents including daclizumab (89), basiliximab (90), and visilizumab (91). Daclizumab is a humanized monoclonal antibody directed against the IL-2 receptor (CD 25) on antigen-exposed T lymphocytes. Initial pilot data suggested efficacy in 10 patients with chronically active ulcerative colitis (89), but larger scale experience reported failed to demonstrate utility compared to placebo (Dr. Gert Van Assche, personel communication). Basiliximab is a chimeric anti-CD25 which showed efficacy in an open-label trial in 10 patients with steroid-refractory ulcerative colitis (90). Nine of 10 patients achieved clinical remission within 8 weeks, and 7 of these maintained remission to 24 weeks. Visilizumab is a humanized anti-CD3 monoclonal antibody. In a Phase I study of 26 steroid refractory patients with severe ulcerative colitis (91), 61 % had clinical response. Cytokine release syndrome (nausea, chills, arthralgias) was seen as was a transient elevation in Epstein-Barr virus DNA levels.
Additional Treatment Modalities
Several reports have examined the role of heparin in the treatment of severe ulcerative colitis (92-95). Interest in a therapeutic role for heparin therapy arose after anecdotal evidence of paradoxical improvement of disease in patients treated for thrombophlebitis. To date no large scale placebo controlled trial has shown efficacy.
Selective granulocyte and monocyte apheresis has been examined in patients with severe ulcerative colitis (96-100). Initial uncontrolled data suggest benefit as adjunctive therapy in patients receiving high dose corticosteroids or cyclosporine, with a steroid sparing effect noted in the majority of patients. No serious side-effects were noted in patients receiving aphersis therapy.
COMPLICATIONS OF SEVERE UC
Fulminant colitis, with or without toxic megacolon, is a medical emergency. Typical manifestations are high fever, abdominal tenderness and distension and hemorrhage necessitating transfusion. In some patients high dose corticosteroids can mitigate the severity of abdominal tenderness, even in the presence of bowel perforation. Accordingly, serial abdominal radiographs should be performed to look for evidence of colonic dilatation or free air. Toxic megacolon is caused by the sudden progression of inflammation through the bowel wall to the serosal surface and can occur in up to 5% of patients. Abdominal x-rays confirm the presence of megacolon as defined by colonic dilatation at least 6 cm in diameter (101). Clinicians should be aware of potential precipitating factors for toxic megacolon which include C. difficile infection, anti-diarrheal medication (loperamide, opiates), hypokalemia and colonoscopy. Intensive monitoring, fluid support, blood transfusions as needed, parenteral steroids and broad spectrum antibiotics are used (102). The role of cyclosporine and infliximab remain unclear in this subgroup of patients. Signs of perforation and rapid clinical deterioration are indications for emergency colectomy. Patients with evidence of fulminant disease demonstrating peritoneal signs or evidence of systemic toxicity should be considered for emergent sub-total colectomy.
Outcome of Severe Colitis: Predictive Factors
The ability to predict disease course in severely ill patients would be invaluable to the clinician deciding on escalation of medical therapy or moving to colectomy. A recent study of 201 adult patients with ulcerative colitis and 126 healthy matched controls examined the hMLH1 gene, a mismatch repair gene involved in the pathogenesis of hereditary non-polyposis colorectal cancer and which is also located in the linkage susceptibility region to IBD on 3p21(103). A 655 A to G polymorphism was 5 times as likely in UC patients refractory to therapy than non-refractory patients. This study suggests that genetic data may be helpful in predicting disease course and guiding management.
Several clinical strategies have been proposed to identify patients more or less likely to respond to medical therapy or those who will require surgery. In particular, information on the likelihood of successful resolution with continuing intravenous corticosteroid therapy beyond 5-7 days in the poorly responding patient would be important.
In a multivariate analysis Carbonnel et al. (104) demonstrated that patients with a duration of acute symptoms more than 6 weeks, deep rectocolonic ulcerations or patients who met Truelove and Witt criteria for severe disease had an 85% chance of medical failure. If deep rectocolonic ulcerations alone are used as a prognostic criteria only 3 of 46 patients with deep ulcerations avoided surgery while 30 of 39 with moderate endoscopic colitis underwent clinical remission (105).
Bloomberg and Jarnerot (106) reported a series of 34 adult patients with severe colitis who did not respond to 10 days of intensive medical therapy. Twelve of 17 given continued treatment did well with a longer treatment regimen and stayed healthy during a five year follow-up.
Approximately 50% of patients refractory to the first 10 days of intensive therapy do not have severe mucosal colitis on colonoscopy and may safely undergo an additional 5-10 days of therapy prior to considering a surgical alternative (104,106). The widespread use of endoscopy has not been adopted because of fear of increasing or initiating colonic distension or frank perforation during the procedure. In published series totaling over 300 adult patients with severe colitis careful colonic mucosal examination was performed with minimal risk (3,104,107,108). Limited flexible sigmoidoscopy with minimal air insufflations can provide important information on the state of the colonic mucosa. Colonoscopy is contraindicated in patients with toxic dilation.
Kumar et al. (109) in a study of 50 consecutive adult patients admitted to the hospital with severe ulcerative colitis demonstrated that pedal edema, transverse colon dilatation (>5 cm), high C-reactive protein, low serum fibrinogen, prolonged prothrombin time, and Trulove and Witts criteria for severe disease all predicted increased likelihood of failure to medical therapy. Lastly, Ho et al. (110) developed a risk index score to predict likely failure of medical therapy for severe colitis, and identified mean stool frequency, colonic dilatation within the first 3 days of therapy, and hypoalbuminemia (<3.0 g/dl) as independent predictors of outcome.
A recent study examined the role of 99mTc-HMPAO white blood cell scintigraphy in evaluating early treatment response and predicting the need for colectomy in 20 consecutive adult patients with severe UC (111). In the group that responded well to therapy, the scintigraphic activity score (SAS) decreased significantly between admission and one week of therapywhile the most of the non-responders had unchanged or even worsening scores. The SAS was considered by the authors to correlate well with histologic disease activity. In this series, 36% of patients who did not have a decrease in SAS score required colectomy within a short period of time.
When children present with severe/fulminant colitis, the risk of needing colectomy remains high. Despite significant advances in the last three decades, severe colitis remains a serious illness requiring dedicated attention and collaboration among medical, radiological and surgical colleagues. For severe UC, Crohn colitis, and indeterminate colitis, initial management is the same. The use of immunosuppressive or biologic therapy has changed the nature of “conventional” treatment and often lengthens the duration of medical therapy prior to surgery. From the existing literature, this changing approach to severe colitis management, seemingly has not affected morbidity. A summary of treatment modalities and the strength of evidence to support the use of such agents in acute severe colitis is shown in Table 4. Corticosteroids are the only drugs that have consistently shown efficacy in severe colitis. The literature suggests that no more than 40 to 60 mg prednisone equivalent is needed but the length of treatment is still not clear. Cyclosporine can be used with some efficacy in severe colitis but the significant side effects associated with its use and the lack of sustained response in the long term decreases its attractiveness as a therapy. The recent evidence of efficacy of infliximab in the setting of moderate to severe colitis is quite promising but will require long-term follow up of these patients to determine if indeed the natural history of the disease has been altered. Emerging biological agents (e.g., visilizumab) have shown some promise in uncontrolled trials. Prospective studies with the introduction of azathioprine/6-mercaptopurine in children with severe colitis are required to determine whether natural history and overall duration of corticosteroid therapy are altered as was noted with the early introduction of 6-mercaptopurine in children with severe Crohn's disease (112). Lastly, only scientifically proven data developed in children will allow us to safely and convincingly move from experience derived from adult studies to pediatric population.
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