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42 Special considerations in the diagnosis and

management of inflammatory bowei disease in the pediatric age group

ERNEST G. SEIDMAN AND ARLENE CAPLAN

Introduction

The diagnosis and management of inflammatory bowel disease (IBD) in children and adolescents is a challenge to patients and their families as well as to members of the health-care team. There are many similarities in terms of the clinical features and therapeutic options in IBD, irrespective of the patient's age. Thus, much of what has been included in other chapters pertains to IBD in the pediatric age group, and is not repeated here. However, IBD often occurs at a particularly vulnerable period of child- hood and adolescence, with potentially adverse effects on growth, quality of life and psychosocial functioning. This chapter focuses on specific issues in pediatric IBD, dealing with those problems that are unique to children and adolescents, such as growth failure and pubertal delay. It also emphasizes certain clinical dilemmas that are particularly important in this age group, including an approach to dealing with diagnostic uncertainty in the child with recurrent abdominal pain, therapeutics and adherence issues, as well as psychosocial problems.

Epidemiologic aspects

Crohn's disease (CD) and ulcerative colitis (UC) are the most common chronic inflammatory disorders of children and adolescents in North America and most of Europe. An almost 7-fold increase in the incidence of CD was reported among a primarily Caucasian population in Olmsted County, Minnesota, between 1940 and 1993 [1]. Notably, an increasing proportion of new cases was diagnosed in individuals below age 20, reaching 17% by 1990 [1]. This has led to a decrease in the median age at diagnosis. Other data on the incidence of CD among children in Europe,

the United States and Canada support the evidence for an earlier age at diagnosis, rather than a true increase in disease incidence [2]. Another study revealed that the incidence of CD (7-12 per 100 000) and UC (5-6.9 per 100 000) among African-Amer- ican children in the state of Georgia was similar to that observed in the age-matched population overall [3]. The data revealed that IBD is more prevalent among African-American children than previously thought. A recent prospective study in the British Isles yielded similar results, with an incidence of 5.2 cases of childhood IBD per 100000 population [4].

UC was more frequent in children of Asian descent.

In our IBD clinic the incidence of new cases of CD has increased 4-fold over the past two decades; that for UC does not appear to have changed over the same time period.

Distinctive clinical presentations

In general, the symptoms and signs of IBD are dependent upon the sites involved, their extent as well as severity, rather than the age of the patient [5, 6]. However, there are certain clinical presentations that are either unique or more common to the pediatric age group (Table 1). Notorious among these is growth failure, seen in up to half of patients at the time of diagnosis [5-7]. It is important to recognize that this mode of presentation, far more common in CD than UC, may occur in the absence of gastrointestinal complaints. Unfortunately, this may lead to a delay in diagnosis, often entailing one or more years until IBD is suspected. Aff*ected patients usually have delayed puberty accompanying their poor growth. As discussed below, the manage- ment of such patients is a major challenge, in terms of

Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 773-790.

© 2003 Kluwer Academic Publishers. Printed in Great Britain

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Table 1. Particular clinical presentations of IBD in the pediatric age group

Unique Common

Growth failure

Delayed sexual maturation/

puberty

Recurrent abdominal pain Short stature

Recurrent unexplained fever Arthralgias/arthritis Perianal disease Anorexia

Recurrent aphthous mouth ulcers

improving growth as well as the psychosocial impli- cations of short stature and pubertal delay.

Other 'atypical' clinical presentations which should make the physician suspicious of IBD in the pediatric age group are recurrent unexplained fever, arthralgias or arthritis, perianal disease (tags, fissures, abscesses and/or fistulas), aphthous mouth ulcers or perianal skin tags, and unexplained anorexia [5, 8].

Diagnostic approach to tlie child suspected of IBD

The differential diagnosis of CD and UC in the pediatric age group is summarized in Table 2. As in adults, the recognition and diagnosis of IBD is straightforward in children and adolescents when the clinical presentation is unambiguous. Thus, for example, a diagnosis of colitis (UC or CD) is strongly suspected in patients who present with typical symptoms, such as bloody diarrhea, urgency and abdominal discomfort. These clinical findings are then promptly confirmed by standard radiologic, endoscopic and histologic criteria, and an accurate diagnosis is promptly arrived at [5, 6, 9].

On the other hand, a diagnostic challenge arises in children who present with non-specific and indolent intestinal and extraintestinal symptoms that can be characteristic of both IBD and functional bowel disorders. In the face of such diagnostic uncertainty some clinicians may rely on invasive diagnostic testing, which entails at minimum a barium upper gastrointestinal series and small bowel follow- through (UGI and SBFT), as well as a complete colonoscopy with biopsies in order to confirm or exclude IBD.

In adults over the age of 50, performing a colono- scopy in the setting of a functional bowel disorder is perhaps justifiable on the basis of the merits of screening for colonic tumors. On the other hand, it is inappropriate to pursue these investigations among children in the setting where IBD is very unlikely. Generally speaking, children suspected of IBD have not experienced significant health problems prior to onset of their symptoms. There- fore, one should consider the emotional impact of intrusive testing in the patient who very likely has a functional bowel disorder. Given these clinical challenges, clinical investigators have searched for a marker or a combination of non-invasive tests that may enable clinicians to screen for IBD. The diagnostic approach to the child suspected of IBD should depend upon the level of doubt (Table 3).

Infectious causes of chronic diarrhea are usually

sought in this setting (Table 2), requiring stool

cultures and search for ova and parasites. In view of

the fact that children are often exposed to antibiotic

therapy, assay for Clostridium difficile toxin is

frequently indicated. A complete blood count is

usually obtained, with particular attention paid to

the presence of a microcytic anemia and thrombo-

cytosis, commonly seen in IBD. Hypoalbuminemia,

often observed in the presence of a protein-losing

enteropathy, is also frequent, but not specific for

IBD. Elevated levels of circulating markers of acute-

phase reactants, such as the erythrocyte sedimenta-

tion rate (ESR), C-reactive protein, and oroso-

mucoid, are more common in active CD than in UC

[10]. In addition to their lack of specificity for IBD,

these tests may be all normal in up to one-third of

patients [10-12]. The recently developed highly spe-

cific serologic tests can be useful adjunctive aids in

discriminating IBD in its mild forms from functional

bowel disorders [13-16]. Perinuclear anti-neutrophil

cytoplasmic autoantibodies (pANCA) have been

established as an autoimmune marker most charac-

teristic of UC in the pediatric age group. On the other

hand, antibodies to oligomannosidic epitopes of the

yeast Saccharomyces cerevisiae (ASCA) have been

shown to be a reliable marker of CD. Double

positivity (both IgA and IgG) for ASCA was found

to be 100% specific for pediatric CD [15]. The

potential sensitivity of these markers as screening

tests for IBD is maximized when the two assays are

combined. Table 3 summarizes our approach to the

child suspected of IBD, depending on the severity of

symptoms and the level of clinical suspicion.

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Ernest G. Seidman andArlene Caplan 775

Table 2. Differential diagnosis of disorders resembling IBD in the pediatric age group

CD UC Infectious etiologies

Acute appendicitis + + Mesenteric adenitis + + Enteritis (y(9rs/y?/a enterocolitica, enteropathogeneic E coii, ++ +

Campylobacter jejuni, Salmonella, Shigella, Entamoeba histolytica, Giardia lamblla, Dlentamoeba fragllls, Mycobacterium

tuberculosis, etc.)

Pseudomembraneous or antibiotic-associated colitis + + + + +

Vascular disorders

Hemolytic uremic syndrome, Henoch Schoenlein Purpura, Behcet's + + + + disease, polyarteritis nodosum, systemic lupus erythematosus,

ischemic bowel disease, dermatomyositis

Immunodeficiency disorders (congenital acquired) + + + + Iatrogenic

Radiation, chemotherapy (typhlitis), graft-versus-host disease + + Obstetric and gynecologic causes

Ectopic pregnancy, ovarian cysts, tumors, endometriosis + + Allergic

Eosinophilic gastroenteropathies + + Neuromuscular

Hirschsprung's disease, pseudo-obstruction syndromes + + + Others

Intussusception, Meckel diverticulum, tumors + ++

Table 3. Contrasting diagnostic approaches to the child suspected of IBD

Clinical Index of suspicion high

Upper gastrointestinal and small bowel follow-through barium X-rays Complete colonoscopy with multiple biopsies

Upper endoscopy (if clinically indicated) Rule out microbial causes

Exclude immunodeficiency disorder Exclude autoimmune enteropathy Exclude allergic disorder

Clinical Index of suspicion low Verify normal physical examination Verify normal growth parameters Carry out limited investigations:

CBC: hemoglobin, platelet count, ESR Serum albumin, iron, ferritin Serological assays: pANCA, ASCA

Abdominal ultrasound + Doppler assessment of mucosal vessel density

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Infectious enterocolitis should always be consid- ered in the differential diagnosis of childhood IBD, even in established cases presenting with a clinical relapse. Most acute, infectious causes of diarrhea resolve after a few weeks. Exceptions include pseudomembranous or antibiotic-associated colitis, particularly prevalent in the pediatric age group. Our recent data show that the yield of C. difljcile toxin increases when stool samples are obtained via colonoscopy and sent promptly to the laboratory on ice [9]. Infestation with Giardia lamhlia or Dienta- moeha fragilis, as well as amebic colitis, can also mimic IBD. The latter classically results in discrete, punched-out ulcers with a rolled, edematous margin.

Rectal cultures for gonorrhea and serologic testing for lymphogranuloma venereum should be consid- ered in the setting of sexually active patients. Rare causes of infection, such as cytomegalovirus (CMV), Cryptosporidium, Microsporidia or Strongyloides should be sought in the setting of congenital or acquired immunodeficiency disorders [17].

The standard investigation of the child for whom the index of suspicion for IBD is high includes colonoscopic evaluation of the colon and barium studies of the upper gastrointestinal tract (Table 3).

Radiologic assessments of the colon and terminal ileum are not adequate diagnostic substitutes for colonoscopy [18]. Images on barium studies as well as computerized tomography (CT) scans have been mistakenly diagnosed as IBD in infectious enteritis or colitis [19]. Furthermore, a recent pediatric study showed that colonoscopy was superior to magnetic resonance imaging (MRI) in distinguishing CD involving the colon from UC [20]. MRI was also inaccurate in terms of assessing inflammation severity. The high false-negative rate of technetium- labeled autologous white blood cell scintigraphy precludes its routine use to estabhsh a diagnosis of IBD in children [21]. Thus, colonoscopy with biopsies remains the most accurate tool for determining the type and severity of IBD in children and adolescents [9]. A study in pediatric patients concluded that scintigraphy can be useful when total colonoscopy or ileoscopy could not be performed [22]. Enteroclysis may be necessary when visualiza- tion of the small bowel is incomplete or impaired by dilation or excessive dilution of the barium with liquid stools. Abdominal ultrasound may be used to screen for thickened loops of bowel, and Doppler assessment of intestinal mucosal vessel density has been shown by our group to correlate with activity in CD [23]. As in adult patients a complete colonoscopy

is imperative to obtain tissue confirmation of the diagnosis, and constitutes the most cost-effective strategy to determine the extent and severity of IBD in children [24]. Biopsies should be routinely taken, as histologic features of UC and CD may be uncov- ered even in zones of macroscopically normal mucosa. In about 10% of cases of so-called indeter- minate colitis, endoscopic and histologic findings may be insufficiently distinctive to unequivocally discern UC from Crohn's colitis. In such instances determination of pANCA and ASCA serologic tests can be helpful [14-16, 25].

Rarely, IBD may present during infancy [26]. The clinical presentation resembles that seen in infants with autoimmune enteropathy [27] or immuno- deficiency disorders [17], requiring careful exclusion of these possibilities (Table 3).

Markers of disease activity

It is not uncommon to be faced with pediatric CD patients who manifest few symptoms, yet present with chronic anorexia and growth failure. It is generally not acceptable to such young patients to re-evaluate disease activity by repeating colono- scopic examination [9]. Follow-up endoscopic stu- dies are reasonable in the case of indeterminate colitis, when surgery is contemplated. It is also justifiable in cases refractory to medical manage-

ment, in order to exclude other disorders such as concomitant infections of the upper {Helicobacter pylori) or lower (C difficile, CMV) gastrointestinal tract.

Biologic markers of the acute-phase response, such as the C-reactive protein, ESR, or serum orosomucoid may be elevated in some patients. In addition, an iron-deficiency anemia, hypoalbumine- mia and thrombocytosis may be found. However, these markers are inadequately specific to be utilized to reliably monitor disease activity [12]. Intestinal permeability, measuring 5-h urinary excretion ratio of lactulose/L-rhamnose, was significantly increased in patients with active CD and extensive UC [28].

However, no correlation was found between this permeability marker and the pediatric CD activity index.

Our recent approach has been to estimate intest-

inal wall vessel density as a function of disease

activity, using pulsed color Doppler abdominal

sonography [23]. Affected bowel loops are thicker in

the group of pediatric patients with active CD

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Ernest G. Seidman and Arlene Cap Ian 111 (p< 0.001). Vessel density is much more frequently

moderate or high (2-4, and > 5 vessels/cm^, respec- tively) in active, compared to quiescent CD (0-1 vessel/cm^). This method is simple to perform in young patients, is non-invasive and accurately monitors the course of the disease [29]. Doppler sonography is particularly useful in children in order to objectively document response to therapy, without requiring more invasive endoscopic or radiologic studies.

Therapeutic approach to the child with IBD

The major goals in managing IBD at any stage of life are to induce and maintain remission of disease activity and to assure an optimal quality of life. In the pediatric age group it is essential also to ensure normal nutritional status, growth and development.

However, the yet-obscure etiology and pathogenesis of IBD, along with its highly variable severity, extent and clinical course, render it difficult to achieve an optimal outcome in all cases. Medical therapy for IBD has advanced remarkably in recent years [30, 31]. The general approach to treating the child with IBD, as in adults, is based on the severity of symptoms as well as the localization and extent of the disease. Few controlled clinical trials have been carried out in children, although the recent act of the US Congress will rectify that for the future. The doses of the drugs commonly employed in the pediatric IBD population are summarized in Table 4. The special issues related to surgery in pediatric IBD are discussed below.

5-Aminosalicylates

As in adults, children with mild to moderate UC or CD are typically treated with oral sulfasalazine or 5- aminosalicylic acid (5-ASA), either alone or in combination with topical 5-ASA and/or corticoster- oid enemas. Young children often retain and tolerate suppositories or rectal foam better than enemas.

However, patients with refractory distal colitis may require high-dose prednisolone enemas in order to obtain remission off oral corticosteroids (Table 4).

Corticosteroids

Patients with moderate to severe disease are gener- ally managed with corticosteroids, orally or intra- venously, depending upon symptom severity. Steroid use is associated with numerous side-effects, which are intolerable for many pediatric patients. These include exacerbation of acne, facial puffiness (moon face), hirsutism, striae, cataracts, aseptic necrosis of the hip or knee, hypertension, depression, growth i m p a i r m e n t , m y o p a t h y a n d o s t e o p e n i a with compression or pathologic fractures (Table 4). Thus, systemic corticosteroids are generally reserved for more severe disease, and only for a limited time period. Side effects can be reduced to a certain extent by adopting alternate-day dosing of prednisone and avoiding nocturnal doses. Corticosteroids, whether in the form of prednisone or budesonide, have not been shown to be of benefit as maintenance therapy.

Alternate-day, low-dose prednisone has been pro- posed in order to reduce relapses, without inhibiting linear growth [32]. However, confirmation from randomized controlled trials is lacking. Budesonide is a well-absorbed and rapidly catabolized cortico- steroid that has the advantage of causing fewer glucocorticoid-related systemic side-effects. An ileal release preparation has been observed to induce remission in 50-69% of patients with active CD [33].

The addition of antibiotics (metronidazole and ciprofloxacin) has not been shown to improve the remission rate compared to budesonide alone [34].

Thus, budesonide can be employed for distal ileal or ileocecal CD in children and adolescents. Although the side-effect profile is superior, the efficacy rate is inferior to standard prednisone.

Immunomoduiatory drugs

6-Mercaptopurine (6-MP) and its parent drug azathioprine (AZA) are arguably the most effective i m m u n o s u p p r e s s i v e drugs for the l o n g - t e r m management of both CD and UC [35, 36]. They are proven to be effective for steroid-dependent, as well as chronically active or steroid-resistant disease [36].

More recently, an important pediatric trial showed that 6-MP can dramatically reduce the risks of relapse after steroid-induced remission in CD [37].

This study has revised the approach to the long-term

management of CD, supporting the pre-emptive use

of AZA or 6-MP in order to improve the natural

history of the disease, effectively maintaining long-

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Table 4. Commonly employed medications for IBD in the pediatric age group

Drug and dose Potential side-effects Aminosalicylates

Sulfasalazine (40-60 mg/kg per day; t.i.d.); 5-ASA/ mesalamine/

olsalazine (40-70 mg/kg per day; bid. or t.i.d.);

Topical 5-ASA (enema, 2 - 4 g; or suppository; 0.5 to 1 g, both q 1 2 - 2 4 h )

Corticosteroids

Prednisone ( 1 - 2 mg/kg max. 50 mg/day; q.a.m. or divided b.i.d.).

Topical enemas (hydrocortisone; 5 0 - 1 0 0 mg q 1 2 - 2 4 h; or methylprednisolone, 1 0 - 4 0 mg in 3 0 - 6 0 ml NaCI 0.9%, q 1 2 - 2 4 h) Budesonide ( 9 mg/day; q.a.m.)

Antimetabolite therapy

6-Mercaptopurine (1.25-1.5 mg/kg per day).* Azathioprine (2.25-3 mg/kg per day)*

Methotrexate (15 mg/m^ s.c.)

Immunosuppressive therapy

Cyclosporine A and tacrolimus (dose adjusted according to drug levels) Biological therapy

Anti-tumor necrosis factor alpha (infliximab, 5 mg/kg i.v.) Antibiotics

Metronidazole (10-15 mg/kg per day). Ciprofloxacin (restricted to > 16 years; 250-750 mg b.i.d., according to weight)

Headaches, nausea, hypersensitivity reactions (skin), pancreatitis, pericarditis, granulocytopenia, thrombocytopenia Side-effects of topical applications are seldom encountered

Acne, moon facies, striae, growth impairment, hypertension, aseptic necrosis or bone fractures, depression or other mood alterations, sleep disorder, osteopenia, myopathy

Budesonide: less systemic side-effects

Idiosyncratic: pancreatitis, rash, fever. Leukopenia, hepatitis (associated with increased metabolite levels). Nausea Nausea; teratogenicity; hepatotoxicity; myelosuppression;

pulmonary toxicity; anorexia

Nephrotoxicity, headaches, paresthesias, hirsutism, oral thrush.

Diabetes

Serum sickness-like reactions. Lupus-like syndrome. Lymphomas?

Long-term use: peripheral neuropathy. Bone pain; potential for altered bone health

*Dose adjusted according to TPMT genotype and metabolite levels

term remission while preventing steroid dependence or resistance for most cases [38].

Despite the estabHshed efficacy of AZA and 6-MP in controlled trials, dose-ranging studies have not been carried out. Over the past few years, however, pharmacogenetic advances have led to the develop- ment of new strategies in order to optimize and individualize therapy with AZA and 6-MP, maximiz- ing efficacy, while minimizing toxicity [29, 38]. AZA is an inactive prodrug that undergoes a series of enzymatic reactions via competing pathways, lead- ing to two major metabolites (Fig. 1). One route leads to the production of 6-thioguanine nucleotides (6- TG), shown to be the active metabolite [39]. How- ever, excessive levels of 6-TG are potentially myelo- toxic. In the competing pathway, thiopurine methyl- transferase (TPMT) yields 6-methylmercaptopurine ribonucleotides. The latter metabolites appear to be

therapeutically inactive but potentially hepatotoxic at high levels [29, 39, 40]. Co-dominantly inherited polymorphic alleles confer variable TPMT enzyme activity levels, with about 11% of individuals hetero- zygous and 0.3% homozygous for common TPMT mutations. Such individuals have intermediate and low/absent TPMT activity, respectively. Hetero- zygous patients with intermediate activity generate higher therapeutic 6-TG levels, but are at a greater risk for myelosuppression. The identification of a patient's TPMT genotype or phenotype can thus allow the physician to adjust the dose of the drug accordingly, avoiding early leukopenic events [41].

Patients with subtherapeutic 6-TG levels, due either

to under-dosing, poor compliance or excessive

TPMT activity are more likely to be refractory to

therapy with these drugs [40]. Thus, AZA and 6-MP

are generally well tolerated in pediatric IBD patients

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Ernest G. Seidman and Arlene Caplan 779

DNA RNA 6-Thiouric acid

A i

Xanthine Oxidase

HPRT

^

6-Thioguanin(

nucleotides

AzathioprineHi^ 6-MP ill ^6-MP

^

ExtraceUular domaine

TPMT

IntmceUular domaine

6-Methyl- mercaptopurine

ribonucleotides

Purine synthesis

Figure 1. Pathways in the metabolism of azathioprine and 6-mercaptopurine. Oral azathioprine is rapidly converted to 6-MP by a non-enzymatic process. Initial 6-MP transformations occur along competing catabolic (xanthine oxidase; TPMT: thiopurine methyltransferase) and anabolic (HPRT: hypoxanthine phosphoribosyltransferase) enzymatic pathways. The latter intracellular enzyme (dashed line) transforms the drug into 6-thioguanine nucleotides, which have been shown to be the most important factor associated with treatment efficacy. TPMT converts the drug into 6-methyl-mercaptopurine ribonucleotides. Patients heterozygous for a mutant allele of TPMT will convert a higher proportion of the drug into 6-TG. This translates into a higher success rate, but with an increased risk of myelosuppression.

[42]. Measuring 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/

AZA, as w^ell as for identifying individuals at increased risk for drug-induced toxicity [29, 38,40].

Methotrexate is considered to be in the class of antimetabolite therapies, due to its antagonistic effect on folic acid metabolism [43]. Among adults, almost 40% of steroid-refractory chronically active CD patients have been found to respond to w^eekly injections of methotrexate (25 mg). No similar, controlled trials have been done in the pediatric age group. In pediatrics this therapy has generally been

employed in moderate to severe CD, refractory to corticosteroids [44]. Weekly injections (15 mg/m^

weekly subcutaneously) are effective in pediatric patients who had previously failed therapy with 6- MP. In one published open trial of 14 cases, nine showed symptomatic improvement after 4 weeks of therapy [45]. Hepatotoxicity is a major concern of long-term therapy. A recent study in children with juvenile rheumatoid arthritis showed that liver enzyme elevation more than 40% of the time was associated with an increased risk of fibrosis [46].

Obesity may add to the risk.

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T-lymphocyte immunosuppressive drugs

Cyclosporine A (CsA) is a fungal product whose immunomodulatory effects are achieved by blocking lymphocyte cytokine production, interleukin 2 (IL- 2) in particular. This inhibits the activation and proliferation of T helper cells. The efficacy of intra- venous CsA among patients with severe UC is now well established [47]. Although surgery can often be avoided in the short term, the benefits of CsA must be weighed against the risk of severe complications, including potentially life-threatening opportunistic infections and the theoretical risk of lympho- proliferative disease. In addition, most patients relapse upon CsA withdrawal. Thus, CsA is generally employed as a bridge to the longer-term use of AZA or 6-MP [48]. The latter drugs must be initiated several weeks prior to tapering the dose of CsA.

CsA has also been used in CD, especially in cases with severe perianal or fistulizing disease [49]. As noted for severe UC, it is primarily used as a bridge to therapy with a longer-acting immunomodulatory therapy, usually with 6-MP/AZA or methotrexate.

Intravenous CsA (4 mg/kg per day) was used in an open-label study in 10 children with severe Crohn's colitis refractory to steroids, with a 70% response in the short term [50]. However, 30% relapsed within 6 months, and 6-MP-resistant patients did not respond. CsA may also be effective when given orally, if trough CsA levels between 250-400 ng/ml are achieved. Side-effects of CsA treatment include nephrotoxicity, headaches, paresthesias and infec- tions (Table 4). Until further studies with longer follow-up are conducted, the use of CsA should be restricted to those IBD patients with severe, steroid- resistant disease activity who require a drug with a rapid therapeutic onset. Other biologic therapies, such as anti-tumor necrosis factor (TNF) antibodies, have largely replaced the use of CsA for CD. Another T lymphocyte inhibitory drug, tacrolimus or FK506, is considered to be even more potent than CsA. Scant data are available with this drug in IBD, although case reports suggest a beneficial effect in fistulizing CD. A recent open-label study showed some benefit for oral tacrolimus over the short term for nine of 14 pediatric cases with severe, steroid-refractory colitis [51]. Blood levels were maintained in the 10-15 ng/

ml range, and AZA or 6-MP was added after about 6 weeks. However, four of nine responders eventually required a colectomy. Thus, fewer than 50% of cases achieved long-term remissions.

Biological therapies

The advent of novel biological therapies has largely been the outcome of experimental animal studies in transgenic or gene knockout models of IBD. These novel agents have been engineered to specifically target integral steps in the cascade that contributes to mucosal inflammation, either by blocking pro- inflammatory cytokines or by administering anti- inflammatory cytokines. Infliximab is a human/

mouse chimeric anti-TNF-oc neutralizing antibody that received approval in both the USA and Canada for IBD. Studies have demonstrated that this anti- body is relatively highly effective for rapidly inducing remission in active, therapy-refractory inflammatory CD. The clinical benefits of a single infusion of 5 mg/

kg are generally observed within 2 weeks, and last for 4-8 weeks in about two-thirds of cases [52]. This treatment is also effective in closing fistulas, particu- larly in the perineum, one of the major challenges in CD therapy [53, 54]. Experience in the pediatric age group is limited, but shows similar trends [55].

Although relatively safe, infusion reactions to anti- T N F therapy have been described. The formation of anti-infliximab antibodies has been reported to give rise to hypersensitivity reactions upon re-adminis- tration in some cases. A recent report described the successful desensitization and therapeutic use of infliximab in such patients despite previous anaphy- lactic reactions [56]. Given the uncertainty of long- term sequelae, particularly the risk for lymphomas, this modality of therapy in children is likely to be restricted to the most severe cases. Other new treat- ments that inhibit TNF-ot are being investigated, including CDP571, a humanized monoclonal anti- T N F antibody, and etanercept, a recombinant TNF receptor fusion protein.

Interleukin 10, a cytokine produced by T helper type 2 cells, is an endogenous anti-inflammatory cytokine that down-regulates the production of proinflammatory cytokines (TNF-oc, IL-lp, etc).

Early studies suggested that the administration of

recombinant human IL-10 was effective in treatment

of active CD when given intravenously [57]. Further

clinical trials are currently under way using this

therapy, as well as with IL-11. In terms of biological

therapies for UC, a recent open-label randomized

study showed that subcutaneous interferon-a-2A

resulted in significant improvement in active left-

sided disease, compared to prednisolone enemas

[58]. One pilot study has been carried out in pediatric

IBD [59].

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Ernest G. Seidman and Arlene Cap Ian 781

Table 5. Known causes of undernutrition and growth failure in pediatric patients mXh IBD

Potential factor Details Inadequate energy/nutrient intake

Malabsorption Increased gut losses

Drug-nutrient interactions

Increased requirements

Disease-induced (cytokines, symptoms). Iatrogenic (unacceptable dietary restrictions) Diminished absorptive surface area. Bacterial overgrowth. Bile salt deficiency Secretory losses: electrolytes, minerals, trace metals. Protein-losing gastroenteropathy.

Bleeding

Corticosteroids (calcium, protein). Sulfasalazine (folate). Cholestyramine (fat, vitamins).

Cyclosporine A (magnesium)

Sepsis, fever. Increased cell turnover. Replace losses: catch-up growth

Antibiotics

As in adults, antibiotic therapy has been most often employed for perianal CD. In one report on 325 pediatric patients, 15% had perianal fistulas, while perirectal abscesses were encountered in 13% [60].

Metronidazole is most often used for this indication as well as for treating colonic CD. However, the long- term use of metronidazole has been associated with peripheral neuropathy [61]. Ciprofloxacin has also been advocated for the therapy of perianal CD [62], as well as primary therapy [63]. However, concerns regarding potential toxicity to cartilage in experi- mental animals have precluded the widespread use of this antibiotic in children under the age of 16, or those less than Tanner stage IV [64]. In our experi- ence perianal disease often recurs after cessation of therapy with antibiotics. The use of AZA or 6-MP thus represents a better long-term strategy in most cases. Severe fistulizing disease is best managed with infliximab, or with surgical drainage and seton placement in cases with perineal sepsis.

Assessment and management of malnutrition

Assessing ttie problem

The potential complications of growth impairment and pubertal delay are unique to pediatric IBD patients (Table 1). Weight loss is an extremely com- mon finding at presentation, occurring in almost 90% of cases. Inadequate energy intake often precedes other symptoms so that, by the time of diagnosis, a majority of pediatric patients are malnourished, with weight falling below the third percentile for age along with arrested growth or a deceleration in its velocity [7, 65, 66]. An excellent

Table 6. Nutritional parameters in pediatric patients with IBD Evaluation of growth/chronic malnutrition

(a) Height percent for age (b) Growth velocity (c) Bone age

(d) Bone density (DEXA adjusted to bone or height age) Evaluation of acute malnutrition

(a) Percent ideal weight for height

(b) Serum albumin (secondary to protein-losing enteropathy) (c) Tricipital skinfold

Micronutrient parameters (a) Iron, TIBC, ferritin

(b) Vitamins: folates, B12, A, D, E (c) Other minerals: Ca, Ph, Mg, Zn (d) Electrolytes (if profuse diarrhea)

(e) Rare deficiencies: vitamin C, K, selenium, copper

estimation of the degree of acute malnutrition is obtained by calculating the percent ideal weight for height [67]. Very often, growth failure ensues after weight for height falls below 90% of ideal predicted.

The causes of malnutrition in children with IBD are summarized in Table 5. By far the most important cause is inadequate intake of calories to meet the energy needs in the growing child. Anorexia is due to a combination of factors, including the abdominal pain and diarrhea brought on by food ingestion, nausea and early satiety, as well as the proinflamma- tory cytokines that have a suppressive effect on appetite.

Growth and other nutritional parameters to be

followed in all pediatric patients with IBD are

summarized in Table 6. Updating percentile curves

for weight and height, as well as height velocity,

should be part of every assessment at least biannualy

[65-67]. Growth failure may be declared in any

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SHORT STATURE

I I

Growth Velocity Normal

Constitutional Delayed Growth

Growth Velocity 1

Abnormal

Bone Age & Puberty Normal

Genetic Short Stature

Bone Age & Puberty Delayed

Weight for Height % Normal

Hormonal Deficiency

1

Weight for Height % Low

IBD'Related Undernutrition

Figure 2. Assessment of the cause of short stature in pediatric IBD patients.

subject with cessation of linear growth over a period of 6 months or by a decrease exceeding one or more standard deviations in height percentile. An easy bedside rule of thumb is that growth velocity generally exceeds 4 cm per year in prepubertal boys and 3.5 cm in girls. Peak height velocity occurs before menarche in female adolescents. Therefore, it is important to recognize and treat malnutrition before it is too late to achieve any catch-up. For many adolescent patients with IBD, impaired growth lead- ing to short stature and the accompanying delayed maturation of secondary sexual characteristics may be more troubling and debilitating than their under- lying disease [5, 7]. Therapy for correcting growth failure is detailed below.

The proper management of short stature in the IBD child requires a precise evaluation of its cause, as summarized in Fig. 2. The clinician must ascertain whether the growth failure is due to inadequate intake of calories as a result of the IBD itself, or due to potential hormonal deficiency (growth hormone,

thyroxin or Cortisol). In the former but not the latter scenario the weight for height percentile will almost invariably be abnormally low.

Therapy of active Crohn's disease

The potential role of nutritional therapy in children with IBD can be subdivided into two categories:

either as primary therapy in order to induce remis- sion in active CD or UC, or as adjunctive therapy to help maintain remission and to enhance growth [68, 69]. Although several randomized controlled trials have suggested that elemental and semi-elemental diets are as effective as steroids, meta-analyses have shown an overall statistical advantage for cortico- steroids [70]. Nevertheless, nutrition is still a logical choice as primary therapy for active CD in selected cases, especially those children and adolescents with marked undernutrition and growth failure [68, 69].

Patients who tend to respond best (75% remission

rate) are those with newly diagnosed CD involving

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Ernest G. Seidman and Arlene Caplan 783 the terminal ileum with or without the cecum or

proximal colon [69]. Individuals with long-standing disease or extensive colitis generally respond less favorably (50% and 35%, respectively). Although steroids more often induce remission, their use is associated with a net loss of mineral bone density, negative nitrogen balance and with impaired linear growth [68]. On the other hand, nutritional therapy enhances growth, induces net anabolism with posi- tive nitrogen balance, and improves bone health.

Another clinical scenario favoring diet as primary therapy is for adolescents with CD who refuse a course of corticosteroids due to concerns for growth, cosmetic or other adverse effects [69].

Drawbacks to the use of nutrition as primary therapy for CD include the relatively high cost, the unpleasant taste and monotony of defined formula diets when employed as sole source of nutrition. The availability of flavor packets has improved the acceptance and oral tolerance of elemental and semi-elemental formulas. Whichever formula is selected, a major objective is to avoid parenteral nutrition, unless the enteral route has failed or is contraindicated. Defined formulas are as effective as, and certainly safer and less costly than, parenteral nutrition. In order to induce remission we generally administer a semi-elemental diet as sole source of nutrition (40-70 kcal/kg ideal body weight per day), for 4 consecutive weeks. The patients drink the formula during the day, along with clear fluids, as tolerated. The balance is administered nocturnally, by nasogastric tube or via a gastrostomy [9].

In addition to inducing remissions for active disease, nutritional therapy has been employed on an intermittent, cyclical manner (4 out of every 16 weeks) in order to sustain growth as well as to maintain remission off" steroids [71, 72]. Patients who received intermittent semi-elemental diet had significantly fewer relapses and markedly improved growth velocity, compared to those treated with low- dose, alternate-day prednisone. In addition to improving symptoms, elemental diets reduce excessive intestinal permeability, reverse the protein-losing enteropathy and decrease intestinal and systemic markers of inflammation [73]. An alternative approach is to employ AZA or 6-MP, as detailed above. Novel defined formulas that include cytokines such as transforming growth factor-p or an enhanced content of antioxidants are currently under investigation, with promising preliminary results.

The mechanisms underlying the beneficial effects of nutritional therapy remain incompletely under-

stood. Several theories have been postulated:

removal of dietary antigens, elimination of pro- inflammatory nutrients such as omega-6 fatty acids and nucleotides, altered eicosanoid production, bowel gut hormones and flora, as well as diminished pancreatic, hepatobiliary and intestinal secretions [68]. Patients with active IBD have increased produc- tion of arachidonic acid metabolites derived from dietary sources of omega-6 fatty acids such as vege- table oils, leading to high levels of proinflammatory eicosanoids such as leukotriene B4, a potent neutro- phil chemoattractant [68]. Fish oils contain eicosa- pentaenoic acid, an unsaturated fatty acid that is metabolized through the cyclo-oxygenase pathway, leading to leukotriene B5, 30 times less potent than its leukotriene B4 counterpart. Studies using fish oil supplements have lent support to the potential role of dietary fatty acids in the pathogenesis as well as therapy of IBD [68]. One study using enteric-coated fish oil was highly effective in reducing relapses in CD, supporting this hypothesis [74]. Another novel approach to the use of neutriceuticals to alter the inflammatory process in IBD was to employ A^-acetyl glucosamine (N-AG) to assist in tissue repair mechanisms. In a pilot study, treatment-resistant pediatric IBD patients were treated with N-AG orally or rectally [75]. There appeared to be some short-term benefit in several cases, including patients with strictures.

Approach to growth failure

The nutritional impact of IBD is particularly severe in the prepubertal patient. Many patients ingest an insuflftcient quantity of calories in order to meet their energy needs, as well as the metabolic costs of growth. Thus, growth failure is a common, serious complication that is unique to the pediatric age group, encountered in up to half of CD and about 10% of UC patients [7, 65, 66]. Normal growth is an important indicator of remission and an outcome parameter of therapeutic efficacy in pediatric IBD.

However, despite 'appropriate medical therapy,' CD

results in permanent short stature in 20-35% of

adults who had the disease prior to their puberty

[76]. There is a time limit for achieving potential

'catch-up' growth because of progressive bone

maturation and eventual epiphyseal fusion. Weight

gain can be achieved in weeks, whereas growth

acceleration requires many months of sustained

treatment. In order to be effective, therefore, therapy

must be initiated well before bone maturation is

(12)

complete. Chronic undernutrition resulting primar- ily from inadequate caloric intake is by far the most important factor. Caloric intake in pediatric IBD is only 54-85% of estimated requirements, and anor- exia often persists despite clinical remission. Inter- vention must be initiated early, consistently and aggressively, assuring adequate nutritional support over a sufficient period of time in order to achieve enhanced growth. When growth is significantly impaired, and the disease remains localized and non-progressive, surgical management may be considered. In general, however, surgery is consid- ered for growth failure only if optimal medical and nutritional therapies have failed. Although gains in weight and height are seen postoperatively [77], final adult height is not different for the group of patients with C D who had surgery during childhood compared to those who did not [78]. TPN can achieve weight gain and reverse growth arrest in CD. How- ever, metabolic and infectious complications, as well as cost considerations, favor the use of enteral nutritional support [7, 79]. The sustained adminis- tration supplementation of a polymeric formula (40- 80 kcal/kg ideal body weight per day) via nocturnal nasogastric or gastrostomy routes effectively reverses growth failure. Compliance with high-cal- orie oral supplements is generally poor over the long term. Our high rate of success in having children and adolescents accept and comply with this form of therapy resides largely in the positive attitude of the nutrition support team, as well as the patients' high motivation [69].

Therapeutic aspects: ulcerative colitis

Nutritional support is considered an adjunctive therapy, as there is no evidence that bowel rest or total parenteral nutrition influences the outcome of UC [7, 79]. Patients requiring hospitalization for a relapse should receive parenteral nutrition if their baseline nutritional evaluation reveals that they are malnourished, or if their intake is likely to be curtailed for at least 1 week. Growth failure has been reported in approximately 10% of pediatric patients with UC. Although much less common than in CD, this problem can significantly affect the child's self- esteem, behavior and school performance. Nutri- tional support for growth failure in IBD is discussed above. In our experience a modest improvement of disease activity can be achieved by supplementing the diet with fish oils containing omega-3 fatty acids (9 g/1.73 m^ per day). The magnitude of clinical

benefit is likely contingent upon a concomitant decrease in the ingestion of dietary omega-6 fatty acids (vegetable oils).

Assessment and therapy of micronutrient deficiencies

Patients with IBD often develop micronutrient defi- ciencies, in addition to energy deficits and growth failure, as reviewed above. Among the many poten- tial mineral deficiencies (Table 6), iron is most common, due to the combination of chronic gastro- intestinal blood loss, iron malabsorption and inade- quate dietary intake. The evaluation of iron stores is complicated by the confounding interpretation of low serum iron, transferrin saturation and ferritin levels due to chronic inflammation. Mineral deficien- cies are not uncommonly encountered, and merit monitoring and repletion (Table 6).

Detection and management of bone disease

Prevention of osteoporosis should begin during childhood, a time of rapid growth and increasing bone density. The presence of osteoporosis carries a significantly increased (30%) risk of fracture. In order to prevent osteoporosis one must first identify patients at high risk. Children and adolescents with IBD may have multiple risk factors, including the presence of a chronic inflammatory disorder with the overproduction of inflammatory cytokines that can lead to increased bone resorption. Other risk factors may include undernutrition, a sedentary lifestyle and glucocorticoid therapy. Therefore, bone mineral density (BMD) should be measured as part of the routine work-up of IBD patients in the pediatric age group. Several studies have confirmed that children with IBD are at risk for osteopenia, when compared to healthy age- and sex-matched controls [80, 81].

Bone mineral density (BMD) is best assessed by

dual-energy X-ray absorptiometry (Table 6). Trabe-

cular, rather than cortical bone is predominantly

affected in IBD, as seen in the lumbar spine and

femoral neck. Low BMD is much more prevalent in

children with CD compared to those with UC,

especially among females. In order not to over-

estimate osteoporosis due to growth failure with

delayed bone maturation in IBD, BMD values in

pediatric patients with CD should take into consid-

(13)

Ernest G. Seidman and Arlene Cap Ian 785 eration delayed bone maturation that is often

present. Interpretation of BMD on the basis of bone or height age, rather than chronological age, resulted in a diminution of the overall frequency of abnor- mally low BMD from 44% to 26-30% [80]. The latter prevalence correlates with the results of studies in adult patients. Annual BMD evaluation, corrected for bone or height age, should be part of the manage- ment of IBD in children, particularly in CD, or in patients who have received corticosteroids.

Strategies to prevent and treat osteoporosis include modifying risk factors, such as correcting malnutrition, optimizing intake of calcium and vitamin D, encouraging physical exercise, and limit- ing glucocorticoid therapy, whenever possible.

Several of these goals can be accomplished if nutri- tional therapy is employed for the management of active disease, rather than conventional cortico- steroids [68, 69]. If there is no improvement in BMD, bisphosphonate therapy should be consid- ered. These drugs can help maintain BMD even if corticosteroids are used because of their long skeletal half-life. Repeat dual-energy X-ray absorptiometry should be carried out to confirm adequate response to therapy, since the absorption of these drugs is often problematic. If necessary, bisphosphonates can be administered intravenously.

Psychosocial functioning in pediatric IBD

Although the mortality associated with pediatric IBD is low, the condition still presents a major, lifelong health threat, challenging the psychological resources of both the affected child and the family.

IBD frequently interferes with physical activities, limits social interactions, disrupts education, impairs growth, and delays puberty [5, 82]. Approxi- mately 20% of children have severely disabling disease [5]. In its acute phases IBD can present a serious impediment to daily functioning. Relapses may necessitate hospitalizations, which cause major disruptions in the child's academic, social and family life. The majority of children with CD experience considerable worry, distress and concern about their disease and its effects on school absences, academic achievement and participation in family and social activities away from home [82]. The chronicity of IBD poses persistent demands on children and their families to cope with fluctuating degrees of illness, prolonged use of medications and dietary limita-

tions. The complications of growth failure and delayed puberty in CD add to the psychological stress associated with the disease, particularly as patients approach adolescence [5].

A recent meta-analysis indicated that children with IBD have more psychological disturbances than age-matched groups with other chronic illnesses [83].

Problems of low-self-esteem, anxiety and depression are frequent [84, 85]. Burke et al. [86] reported that about four out of 10 children with CD were either clinically depressed or presented significant depres- sive symptoms soon after diagnosis. Depression is relatively common in children with both CD and UC [87]. While depression is the most common emo- tional problem reported, other difficulties associated with IBD include separation anxiety, fearfulness, social withdrawal, relationship problems, and problems with body image [88, 89]. While a higher incidence of internalizing (self-directed) problems is observed, externalizing (acting-out) problems have also been noted [90].

It is unclear whether depression is associated with the diagnosis of IBD, with the disease process itself, or with its treatment. Burke et al. [86] demonstrated that, in all instances of major depression in pediatric IBD patients, onset followed the diagnosis. The fact that siblings of patients also show an increased incidence of psychiatric disorders raises the possibi- lity that psychopathology in children with CD is due to factors other than the disease itself. These may include genetic predisposition to psychiatric disor- ders, dysfunctional family dynamics or both. There is no evidence for a unique psychological 'profile' for children with IBD. However, in some cases psycho- logical parameters have been useful in distinguishing CD from anorexia nervosa [84, 85].

IBD in children may have considerable conse- quences on the mental health of family members.

Parents frequently have depression, anxiety and somatization [90]. They commonly worry about the effects of the disease on their child's school perfor- mance and on their future. Siblings also express concern about their ill sibling's well-being [91]. They may resent the time their parents devote to their ill sibling.

Therapeutic interventions may also affect psycho- social functioning in the pediatric patient with IBD.

Psychosis induced by corticosteroid therapy is rarely encountered in pediatric CD patients [92]. However, a wide range of intense emotional reactions among children and adolescents is frequently observed.

Parents view their children's behavior as 'out of

(14)

Table 7. Specific surgical Indications in pediatric IBD

Crohn's disease Ulcerative colitis

Intractable symptoms; failure of medical management Hemorrhage

Fulminant colitis with or without toxic megacolon Suspected perforation or abscess

Obstruction of upper and/or lower gastrointestinal tract. Fistulas:

enteroenteral, enterocutaneous, enterovesical, enterovaginal.

Intractable perirectal disease Growth failure despite nutrition support High risk of dysplasia, carcinoma

Prolonged steroid dependence, intolerance to immunosuppressive agents Hemorrhage

Fulminant colitis, with or without toxic megacolon Suspected perforation

Chronically active, unremitting disease

Growth failure despite nutrition support High risk of dysplasia, carcinoma

character', especially when it comes to challenging parental authority and expressing anger or exhibiting aggression. However, it is unclear to what extent these changes are due to the illness as opposed to the effects of systemic corticotherapy.

The children may report feeling 'different inside' or having 'changed forever' as a result of their IBD.

They frequently feel less in control of their emotions and behavior. Some experience bouts of crying, often without apparent reason. Many state that they have become more withdrawn and unsociable; others report that they no longer feel like enjoying them- selves. They may consciously withdraw from recrea- tional activities or social contact because they fear other children will find out that they have a disease and will treat them differently. Others withdraw simply because they feel unable to participate or enjoy themselves. The aversion of being questioned, feelings of embarrassment, or reluctance to be confronted with their disease often makes it difficult for children and adolescents with IBD to return to school after long absences due to their illness. These reactions of shame and embarrassment often contribute to depressive feelings of psychological isolation, fragility and instability.

Problems related to compliance with therapy are notorious in pediatric populations. For many chil- dren, 'forgetting' to take their medications is a way of psychologically denying their disease. For others it may be more conscious, and related to the lack of efficacy, or side-effects of the drug. In addition to the adverse effects of steroids on mood, cognition and behavior, psychological factors in children, parents or the family at large may also contribute to poor compliance and adherence to therapy. Nutritional therapy can also have important effects on psycho-

social functioning. During periods of treatment, patients endure prolonged periods of food-depriva- tion and experience frustration due to disruption of social and family activities. Special formula diets are particularly difficult for children who eat their meals at school. They are often already embarrassed about their disease. Thus, nutrition as primary therapy potentially exacerbates the child's feeling of being different due to the disease itself, and may contribute to his/her sense of alienation. There is the additional consideration that the feeding tube and pump appa- ratus makes the disease more visible, both to patients and to those around them. This can accentuate feelings of self-consciousness and heighten embar- rassment in social situations. Some patients experi- ence the insertion of a nasal gastric tube as intrusive or aggressive on the part of the medical team. The psychological meaning patients attribute to treat- ment procedures, as well as their emotional reactions (e.g. anxiety, fear, and depression), may be more influential than their physical response in determin- ing treatment success. More data on the psycho- logical effects of medical and nutritional therapies are needed to provide a better understanding of the factors affecting compliance with treatment and the relationship to the medical team. Further study in this area would increase understanding of these factors, allowing gastroenterologists to provide higher-quality care and improved t r e a t m e n t strategies for pediatric IBD.

Children with IBD have been reported to have a

significantly impaired quality of life [82]. They fear

everyday childhood activities and are concerned for

their future employment. These children need

sympathetic management, and efforts should be

concentrated on improving their daily psychosocial

(15)

Ernest G. Seidman and Arlene Caplan ISl functioning, enabling them to lead as normal a life as

possible. This can best be achieved by medically controlling their disease activity, achieving normal growth and development through nutritional inter- ventions, and providing psychosocial support to them and their family members.

Surgical considerations

As in adults, the surgical approach to the child with IBD must always bear in mind that unlike UC, CD is not a surgically curable disorder. Surgical interven- tions are thus reserved either for complications of CD, or for symptoms that cannot be managed medically (Table 7). In the latter situation intract- ability of symptoms generally infers a poor prognosis postoperatively, with clinical relapse within 1 year in 50% of cases [93]. On the other hand, young patients operated upon for ileal strictures or local abscesses have a far better prognosis, with a 50% recurrence rate after 5 years. As summarized in Table 7, other surgical indications include recurrent episodes of partial bowel obstruction, or an abscess that fails to respond to conservative measures. Entero-enteric fistulas are not necessarily an indication for surgery.

Although an enterovesical fistula is not an absolute indication for surgery, most patients will require an operation eventually. Perianal CD also calls for a conservative approach. Abscesses should be drained and fistulas laid flat or treated with setons when possible. Although surgical resection has not been shown to influence the natural history of CD, it can lead to dramatic growth acceleration and attainment of normal adult height in some, but not all, cases [77, 78]. The type of intervention depends on the extent and severity of the disease [94].

The principal indications for surgery in UC [95]

include intractable disease (64%), refractory growth failure (14%), toxic megacolon (6%), hemorrhage (4%), perforation (3%) and cancer prophylaxis (2%). Despite the relative success of CsA, tacrolimus and other immunosuppressive agents, it must be borne in mind that colectomy can be a lifesaving procedure in a child with fulminant colitis or toxic megacolon. CsA and tacrolimus are not only short- term solutions, they are associated with considerable morbidity as well as potential mortality, as reviewed above.

The increased risk of developing colon cancer among patients with onset of UC during childhood is well estabhshed [9]. Proctocolectomy has been the

most commonly practiced and accepted operation. If rectal involvement is mild, some surgeons prefer to carry out a colectomy and ileoanal anastomosis in one stage. Meticulous supervision of the conserved rectum is mandatory, as it might be a site for later cancer. Successful ileoanal-endorectal anastomosis after total colectomy and a mucosal proctectomy is often achieved. The rectal mucosa is stripped from its muscular wall, and the ileal mucosa is sutured on.

The creation of a neorectum with an ileal pouch affords decreased stool frequency. This is now the treatment of choice in the pediatric population. An important factor regarding continence is the level at which the ileoanal anastomosis is performed [95, 96].

Colon cancer may also occur in the case of Crohn's colitis [97]. The relative risk depends largely upon the extent, as well as the duration, of the colitis [98].

Screening is usually initiated after about 8 years of clinical presentation for cases of extensive colitis.

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