Severe Colitis in Children

INTRODUCTION 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).TABLE 1: Truelove and Witts ScoreTABLE 2: Lichtiger Symptom ScoreWerlin 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.TABLE 3: The Mayo ScoreAs 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). TREATMENT 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 benefit of oral of the studies showed benefit of therapy beyond the acute There are no controlled trials of antibiotics in children with ulcerative colitis or Crohn colitis. are in and maintenance therapy in ulcerative colitis to a in Crohn colitis There is no that these medications are of clinical benefit in acute severe colitis. There are also no data available to support the use of in this of severe colitis. most patients with severe of colitis have or for are to be of have not been used as therapy for attacks of severe colitis, data are on the efficacy of alone in the of severe colitis. Although not supported by controlled data, it may be prudent to the use of in a with severe colitis who is also of worsening of severe colitis may in a of patients to with corticosteroids remains the of medical therapy for attacks of severe colitis by both ulcerative colitis and Crohn disease. The use of corticosteroids has rates these medications were first used In the original study of Truelove and was to placebo in the treatment of both first attacks as well as of ulcerative colitis of patients on at a dose of per day for to 6 was particularly beneficial in those with first In the rate was in mild disease compared with severe disease a an intensive intravenous regimen for the treatment of severe colitis of least 3 per per day intravenously in and total parenteral with by and defined as the of bowel symptoms, was in to of patients with severe colitis using this regimen and was for at least 2 years in to patients who 5 and to respond was a of the need for colectomy. have reported similar results using intravenous corticosteroid therapy in severe ulcerative colitis no controlled studies a benefit from corticosteroid therapy with intravenous therapy for severe colitis. dose or of of corticosteroids has not been in adults or children in or controlled The only dose ranging study was by Baron et al. who compared and of in patients with mild to moderate ulcerative colitis. The efficacy of the and were similar and than the 20 side were noted with the dose compared to the with has shown no additional benefit There is limited information on the use of intravenous corticosteroid therapy compared to conventional oral therapy. In one study of adult patients with moderate to active ulcerative colitis, patients were either with of oral or intravenously for by oral At the of 4 there were similar of patients in in both with a trend more improvement in the group with initial therapy The clinical impression that corticosteroid is to has not been in a controlled to appears to be similar to in there may be an increased benefit to if the has not been with The recommendations for of corticosteroid therapy to with because of of response in adult studies and there is no Recently, it has been reported after only 3 of intensive most patients with frequent stools or need colectomy Other may be after of therapy. and Grand reported their pediatric in a retrospective review of children with severe colitis with ulcerative colitis and 5 with Crohn medical treatment beyond increased and complications in their group a series of pediatric patients with severe ulcerative colitis for than with outcome One of these patients colectomy during the initial and an additional colectomy during the follow-up of that their results not support the for colectomy if is not this was a retrospective study and is not to support the At the current it is to that patients who do not respond to intravenous corticosteroids should be viewed as treatment and additional medical therapy or colectomy should be do not intravenous corticosteroid therapy alone beyond the of complications are and the of response Although is in pediatric of therapy with additional may be in those children when the is not for colectomy and treatment with these are not and 6-mercaptopurine and 6-mercaptopurine have been widely and used in Crohn disease and ulcerative colitis, but their acute use is limited in the presence of severe colitis by their of Although initial studies of intravenous in adults suggested a of in 4 a subsequent trial not a at least in Crohn disease. In those patients where is with maintenance of can be with the of or 6-mercaptopurine with cyclosporine et al. postoperative complications with the use of or colectomy for ulcerative colitis. The complications were classified as 30 or 6 In addition to including and of dose and of score and albumin were for with postoperative Early complications after for ulcerative colitis were found to be with dose and severe disease but not with the use of or and was first used in patients with severe UC in and the first study the efficacy of this for this indication in 1994 (8). is at a dose of 4 or with subsequent to of A recent of a of 4 2 intravenous cyclosporine in severe ulcerative colitis in adults showed efficacy in the two groups were with a trend in the low dose Early studies in with UC to disease and patients to oral for maintenance therapy. However, subsequent studies have demonstrated that oral appears to be and may patients to Children to cyclosporine increased and serum as well as decreased and rates In in clinical improvement in of pediatric and adult patients with refractory UC therapy is at and patients are in a range of and parenteral to be in the treatment of refractory UC and can in healing in children and follow-up studies often and mucosa While and to be in most children, reduction or therapy be for significant with and or and and with therapy have been in patients with serum the therapeutic range as and is with a reduction but in have also been reported data from adults that or therapy may be in those patients that have not to of intravenous corticosteroid therapy should not be in patients who have of active severe with serum albumin of or low serum or in those who are known to be to long term maintenance therapy with or patients do not respond five should be for colectomy. In those patients that do respond to or immunomodulatory therapy using 6 or should be in as are has been as therapy for during of in of adult patients with severe ulcerative colitis with Patients with disease activity that while is should be for colectomy et al. the of colectomy in patients with severe UC to In the patients there were no complications in of patients, including infection and of the The of postoperative was The that treatment may not the of surgical treatment in severe UC. While to and have been follow-up studies that disease is to with to or therapy. rates at 6 are and to by years of patients with or colectomy 6 to 3 years of therapy Long-term outcome in patients with and therapy appears to be when used in with the such as or 6-mercaptopurine from adult studies that patients with disease of pancolitis or and serum or albumin respond more to therapy In contrast, response to or be by the distribution of or at presentation in pediatric patients. The use of to moderate to severe Crohn's disease has in the possible use of this to severe ulcerative colitis in children and adults patients with ulcerative colitis have been reported in series with an response rate ranging from to and rates to term data are limited but in some of these studies response and have been It has been suggested that refractory patients and those with more chronic disease are to respond to it should be noted that these studies including newly diagnosed and chronic corticosteroid patients. The first placebo controlled trial with a total of patients to efficacy of compared to placebo Remission rates at 6 after two 5 of or placebo at and 2 were and 30% A placebo controlled study the of in adult with moderate to severe colitis who were refractory to The need for colectomy was in the group than in the placebo group Two additional large placebo controlled trials of in the treatment of adults with ulcerative colitis have been in In both these reports was to placebo in including response and at following at and 6 to to compared to placebo to and 6% to is also available with other biological including and is a the on data suggested efficacy in 10 patients with active ulcerative colitis but reported to compared to placebo is a which showed efficacy in an trial in 10 patients with ulcerative colitis of 10 patients clinical and of these to is a In a study of refractory patients with severe ulcerative colitis had clinical was as was a in Several reports have the of in the treatment of severe ulcerative colitis in a therapeutic for therapy after anecdotal of improvement of disease in patients for date no large placebo controlled trial has shown and has been in patients with severe ulcerative colitis data benefit as therapy in patients dose corticosteroids or with a noted in the of patients. were noted in patients therapy. UC colitis, with or toxic is a medical manifestations are and and In some patients dose corticosteroids can the severity of even in the presence of bowel should be to for of or megacolon is by the of inflammation the bowel to the and can in to of patients. the presence of megacolon as defined by at least 6 in diameter should be of for toxic megacolon which and blood as parenteral and antibiotics are used The of cyclosporine and in this of patients. of and clinical are for colectomy. Patients with of fulminant disease signs or of systemic should be for colectomy. of Severe The to disease course in ill patients would be to the on of medical therapy or to colectomy. A recent study of adult patients with ulcerative colitis and the a repair in the of and which is also in the to IBD on A A to was 5 as in UC patients refractory to therapy than patients. This study that data may be in disease course and Several clinical have been proposed to patients more or to respond to medical therapy or those who In information on the of with intravenous corticosteroid therapy beyond in the poorly would be In a et al. demonstrated that patients with a of acute symptoms more than 6 or patients who Truelove and criteria for severe disease had an of medical failure. alone are used as a criteria only 3 of patients with while 30 of with moderate endoscopic colitis clinical and reported a series of adult patients with severe colitis who not respond to 10 of intensive medical therapy. of 17 treatment well with a treatment regimen and during a five year 50% of patients refractory to the first 10 of intensive therapy do not have severe colitis on and may safely an additional of therapy to a surgical The use of has not been because of of increasing or or during the In series adult patients with severe colitis was with with can provide important information on the of the is in patients with toxic et al. in a study of adult patients admitted to the hospital with severe ulcerative colitis demonstrated that transverse colon low serum and and Witts criteria for severe disease all increased of to medical therapy. et al. developed a index score to of medical therapy for severe colitis, and stool the first 3 of therapy, and as of A recent study the of blood in treatment response and the need for colectomy in 20 adult patients with severe UC In the group that well to therapy, the activity score decreased between and one of the most of the had or even worsening The was by the to well with disease In this of patients who not have a in score colectomy a short of children present with colitis, the of colectomy remains significant advances in the three severe colitis remains a illness requiring and among and surgical severe Crohn colitis, and colitis, initial management is the The use of or therapy has the of treatment and often the of medical therapy to the literature, this changing approach to severe colitis has not A of treatment and the of to support the use of such in acute severe colitis is shown in are the only that have shown efficacy in severe colitis. The that no more than to is needed but the of treatment is not can be used with some efficacy in severe colitis but the significant side with use and the of response in the long term as a therapy. The recent of efficacy of in the of moderate to severe colitis is but of these patients to if the natural history of the disease has been biological (e.g., have shown some in trials. studies with the of in children with severe colitis are to whether natural history and of corticosteroid therapy are as was noted with the of 6-mercaptopurine in children with severe Crohn's disease only proven data developed in children allow to safely and move from from adult studies to pediatric of the management approaches and the that to support the use of such in acute severe colitis