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Enteral Nutrition and Corticosteroids in the Treatment of Acute Crohn's Disease in Children

Heuschkel, Robert B; Menache, Caroline C*; Megerian, J. Thomas*; Baird, Alison E*

Journal of Pediatric Gastroenterology & Nutrition: July 2000 - Volume 31 - Issue 1 - pp 8-15
Original Articles

Background: The optimal treatment of acute Crohn's disease in children remains controversial. In adults, steroid therapy has been shown to be superior to exclusive enteral nutrition. However, enteral nutrition is effective at inducing a remission in many children with acute Crohn's disease. Steroid usage in children has been associated with adverse side effects, particularly with delayed growth and pubertal development.

Methods: Randomized clinical trials comparing exclusive enteral nutrition with corticosteroids were identified. Two independent reviewers extracted data from selected studies. Studies were assessed for heterogeneity and relative risks for remission induction with enteral nutrition were obtained. Sensitivity analyses were performed in partially randomized studies. Estimates were made of the number of studies needed to overturn the current result. Other outcome measures were qualitatively assessed.

Results: In five randomized clinical trials comprising 147 patients, enteral nutrition was as effective as corticosteroids at inducing a remission (RR = 0.95 [95% confidence interval 0.67, 1.34]). Addition of two further nonrandomized trials did not significantly alter the result. A minimum of 10 further studies, equal in size and outcome to the largest reported pediatric trial to date (n = 68, RR = 0.84), would be required to demonstrate a significant benefit of steroid therapy over enteral nutrition.

Conclusions: There is no difference in efficacy between enteral nutrition and corticosteroid therapy in the treatment of acute Crohn's disease in children. Improved growth and development, without the side effects of steroid therapy, make enteral nutrition a better choice for first-line therapy in children with active Crohn's disease.

Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital; and *Harvard School of Public Health, Boston, Massachusetts, U.S.A.

Received October 28, 1999; accepted December 21, 1999.

Address correspondence and reprint requests to Dr. Robert B. Heuschkel, Division of Gastroenterology, Hunnewell Building, Ground Floor, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, U.S.A.

This article accompanies an editorial. Please see Griffiths AM. Enteral nutrition: the neglected primary therapy of active Crohn's disease. J Pediatr Gastroentero Nutr 2000;31:3–5.

The optimal treatment of active Crohn's disease in children remains disputed. Steroid treatment has been shown to be superior to exclusive enteral nutrition in several meta-analyses of adult studies (1–3), although individual centers have reported both short and long-term benefits of exclusive dietary treatment.

Steroid usage in children has been associated with a wide range of adverse effects in children, in particular on bone mineralization (4,5) and on growth and development (6–8). Steroids are an even less attractive first-line therapy, because children with newly diagnosed Crohn's disease already have significantly low bone mineral density (9) and growth delay (10) at diagnosis.

Thus far, it has not been possible to conduct large enough trials to clarify the benefits or otherwise of a nutritional approach. After successes in small observational studies (11,12), placebo-controlled trials of enteral nutrition were never conducted in the pediatric population and are no longer ethically justified. Studies of the natural history of Crohn's disease show a spontaneous remission occurring in between 18% and 42% of cases within 3 to 4 months, whereas a response to exclusive enteral nutrition is reported between in 53% and 80% of cases (1). Nutritional treatment alone therefore has a significant therapeutic effect.

The efficacy of enteral nutrition in active Crohn's disease is therefore best assessed by its comparison with corticosteroid therapy. The latter, with or without the addition of aminosalicylate anti-inflammatory medication, is the otherwise widely accepted conventional treatment.

Previous meta-analyses have focused predominantly on the induction of remission in adults. No comment has been made on the sequelae of steroid treatment or the benefits of dietary treatment in nutritionally and growth-compromised children. The purpose of the current study was to re-examine this issue on behalf of the pediatric population with Crohn's disease. Although the data in this field remain limited, in this analysis we sought to systematically analyze all available information and to define the current state of the evidence.

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METHODS

Literature Search

A search of the literature was performed in July 1999 using a MEDLINE search through OVID, Grateful Med, and PubMed from 1966 through July 1999. A search of the Science Citation Index for the first pediatric clinical trial of enteral nutrition versus steroids (13) was also performed. In addition, manual searching for abstracts (1990–1999) was performed from ESPGHAN, NASPGN, and the American Gastroenterology Association (AGA). The reference lists of review articles (14–17) and meta-analyses (1–3) were also scanned for relevant studies. Recent book chapters (18–21) and their bibliographies were reviewed. Contact was made with leaders in the field to ensure no studies had been overlooked. Authors were contacted when necessary to clarify remission criteria and randomization methods.

The search strategy terms included Crohn's disease, enteral nutrition, child (less than 18 years), clinical trial, diet, food (formulated), steroids, and aminosalicylic acids. There were no restrictions on publication type or language to minimize publication bias.

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Inclusion Criteria

The following inclusion criteria were used: pediatric studies (participants aged <18 years); clinical trials (randomized, semirandomized [consecutive allocation], and nonrandomized [equal disease activity and distribution at treatment onset]); minimum 3-week treatment period; treatment of acute Crohn's disease (newly diagnosed or relapsed); and objective assessment of remission with percentage remission reported for each treatment group.

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Exclusion Criteria

The following studies were excluded: observational studies and case series, nutritional supplement studies, studies examining use of enteral nutrition to prolong remission, adult studies that included pediatric patients, and studies in which patients were randomized more than once. Preliminary reports that were later published in full were excluded. The excluded studies (11,12,22–31) and reasons for their exclusion are shown in Table 1.

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Data Extraction

Data, previously agreed to be relevant by all authors, were extracted from each article by two independent observers. Findings were compared and consensus reached among all authors by rereading the manuscripts. All data were extracted on an intention-to-treat basis.

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Statistical Analyses

Steroid therapy induces a remission in 70% to 80% of adults with acute Crohn's disease (32,33), a figure similar to that reported in the pediatric literature. To detect a 20% difference between treatment effects, with a power of 0.8 and an α error of 0.05, requires a minimum of 91 patients per group. If enteral nutrition were any less effective at inducing a remission than approximately 50%, any extra benefits of a dietary therapy may be lost if a clinical remission was achieved in only one in two children. One hundred ninety-three children were included in the overall meta-analysis of seven studies.

Fixed and random effects models (34–36) were used to generate a pooled relative risk (RR) and 95% confidence interval (CI). A commercially available statistics program (STATA 6 Intercool; College Station, TX, U.S.A.) was used throughout. Unlike in previous meta-analyses (1–3) our analysis calculated RRs, not odds ratios (ORs), because several pediatric studies had 100% remission rates, making an OR calculation impossible.

Reported RRs and CIs are presented graphically as horizontal lines. In both figures, only if the 95% CI line does not cross the vertical equivalence line (RR = 1.0) is a statistically significant treatment effect indicated. Values of heterogeneity (Cochrane Q statistic) with associated P values were computed (P < 0.05, for significant heterogeneity). A Galbraith plot was used to visually detect intertrial heterogeneity.

Pooled RR estimates were obtained for the five randomized clinical trials (13,37–40). Further sensitivity analysis was then performed by addition of a partially randomized trial (41) and a nonrandomized trial (42).

We also calculated the number of studies required for a statistically significant result in favor of steroid therapy—that is, achieving an RR with CI below 1.0.

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RESULTS

Of 99 citations retrieved, 19 articles were reviewed in full. Of these articles, five were randomized controlled trials involving 147 children and met the primary criteria for inclusion in the meta-analysis (13,37–40).

Two further trials were included in the analysis, although patients were not truly randomized (41,42). This further increased the power of the study and acted as a form of sensitivity analysis. One hundred ninety-four children (Tables 2 and 3) were therefore included in the two treatment groups. The remaining articles were excluded because they failed to meet the defined criteria (Table 1).

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Baseline Characteristics

In all selected studies, potential confounders were evenly distributed between treatment groups at onset of the trials; age, sex, disease duration, disease distribution (small bowel, ileocecal, colonic), severity of the disease, steroid dosage, and calorie intake by enteral nutrition (Table 2).

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Heterogeneity Analysis

The data appeared homogeneous, as shown by the identical values obtained from the fixed and random effects models and the nonsignificant Q values (P > 0.05 for all analyses). A Galbraith plot was used (not shown) to assess heterogeneity and confirmed all seven selected studies to be highly homogeneous.

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Meta-Analysis of Five Randomized Clinical Trials

The pooled relative risk was 0.95 (95% CI 0.67–1.34; values identical in fixed and random effects models). Heterogeneity Q statistic was 0.46, with 4 df (P = 0.98;Fig. 1, Table 4).

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Meta-Analysis of Randomized and Nonrandomized Clinical Trials

Two remaining pediatric studies, although nonrandomized, were reviewed to increase the power of this analysis. Although the study participants were not randomized, there was no evidence of selection bias. The analysis was stratified to acknowledge this difference. In the study by Breese et al. (41), 10 consecutive patients had been treated with corticosteroids, and the next 18 patients were randomized to receive cyclosporin A or enteral nutrition. The study of Chafai et al. (42) was a retrospective analysis of patients treated with corticosteroids and enteral nutrition.

Papadopoulou et al. (31) completed a retrospective analysis of very similar treatment groups, yet their study included more than one treatment episode per patient. Repeated entry of the same patient could compound any selection bias, and thus we omitted this study from our analysis (despite its having the highest RR of 1.30 [nonsignificant CI] and favoring enteral nutrition). Nicholls et al. (30) randomized patients to receive either conventional treatment (steroids or enteral nutrition) or cyclosporin A. However, they then selected patients in the conventional treatment group with small bowel disease for treatment with enteral nutrition (n = 10) and those with colonic involvement for steroid therapy (n = 4). Although a 100% remission rate was achieved in both groups, we did not include this study in our final analysis.

Although treatment was clearly allocated in a nonrandom manner by Chafai et al., (42) the allocation was made in the best interests of the patient—that is, selection of the most effective and appropriate treatment for each patient. Although the comparison of outcome is less valid than if treatment allocation is randomized, the similarity of treatment groups in some way minimizes any selection bias.

The pooled relative risk for all seven studies was 0.982 (95% CI 0.73–1.33; values identical in fixed and random effects models). Heterogeneity Q statistic was 0.82 with 6 df (P = 0.991;Fig. 2, Table 3).

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Sensitivity Analysis

The inclusion of semirandomized studies assessed the sensitivity of our inclusion criteria. There was no significant change in RR or CI ranges and homogeneity was maintained (Table 3), confirming the two additional studies to be very similar to the truly randomized series. This calculation was extended to assess how many further studies would be required to reach a statistically significant treatment effect (Table 3). Only after the inclusion of 10 further studies (data not shown) that were identical in size and outcome to the largest reported pediatric study (n = 68) was a significant RR achieved in favor of steroid therapy (RR = 0.86 [95% CI 0.74–0.99]; Q = 0.83, 14 df;P = 1.0).

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Qualitative Analysis

In view of the relatively limited number of children randomized, quantitative analysis of other factors had limited statistical value. We reviewed the available data with particular reference to speed of remission induction, duration of remission, nutritional endpoints, and height velocities. The only significant difference between the two treatment groups was in height velocities achieved at short-term follow-up. Thomas et al. (37) showed the children randomized to enteral nutrition to have a significantly higher mean height velocity standard deviation score (SDS) 6 months after treatment (+0.32 vs. −3.1). This was despite a significantly higher calorie intake in the steroid-treated group, indicating the growth suppressant effects of steroids are not overcome by simply increasing calorie intake.

An identical finding was reported by Sanderson et al. (13), who showed a significantly higher mean height velocity SDS at 3 months in the group randomized to enteral nutrition (+0.2 vs. −2.85). Chafai et al. (42) also confirmed a significantly higher growth velocity in the group receiving elemental diet.

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DISCUSSION

In this analysis of 194 children with acute Crohn's disease, enteral nutrition was as effective as steroids at inducing a clinical remission (RR = 0.98, 95% CI 0.73–1.33).

Meta-analyses published in the adult literature (1–3) suggest a clear benefit of steroid therapy over enteral nutrition. These studies in adults with acute Crohn's disease all report an OR of 0.35 (95% CI 0.23–-0.53) for achieving a remission with enteral nutrition. The RR we calculated from data presented by Griffiths et al. (1) is 0.71. The 95% CI (0.56–0.90) remains below equivalence (RR = 1.0), yet closer to the range we present.

It is also of note that in almost all pediatric and adult studies a clinical disease activity index was used (44–47) to define a clinical remission. These indices, by including measures of a patient's clinical well-being, are likely to favor remission in the steroid-treated groups, given the effect steroids have on improvement of overall well-being.

A significant difference between the adult and pediatric studies is the degree of compliance. Up to 40% of adults were withdrawn from nutritional therapy because of intolerance of the diet (1). Not surprisingly this was highest in those taking an elemental or semielemental diet by mouth (18–41%). However, of 98 children included in this meta-analysis, only 8% did not complete the course of enteral nutrition, despite requiring a semielemental diet administered by nasogastric tube. Griffiths et al. report results excluding patients who withdrew from their study because of intolerance to the diet, yet the OR remains significantly in favor of steroid therapy, 0.57 (95% CI 0.35–0.94). Calculation of the pooled RR for the same data, however, fails to reach significance (RR = 0.86, 95% CI 0.68–1.09). This implies that adults who are able to tolerate nutritional therapy are as likely to go into remission as those treated with steroids, a fact also reported in large adult studies (48).

Compliance in excess of 90% is often reported when using enteral nutrition in children (13,30,31,38). Compliance with a prolonged course of exclusive enteral diet is clearly more difficult for an adult. In addition to the inconvenience, the possible benefits for growth and development do not apply.

Recent observational studies with more palatable polymeric diets are confirming excellent compliance in children who take the diet by mouth (49,50). Successful use of enteral nutrition also requires motivated nursing, dietetic, and medical staff to support children and families during therapy. This may well explain some of the better results obtained in pediatric units in which dietary therapy has become more commonplace (31,37,40,49).

A further difference from published adult data is that in most trials of adults, prevalent rather than incident cases are recruited. In our meta-analysis of pediatric trials a large proportion of randomized patients had newly diagnosed disease. Inclusion of patients with more long-standing or intractable disease may introduce a systematic bias into adult studies. Although not proven, patients with more recently diagnosed disease may respond better to nutritional therapy than those with more long-standing disease. This would make enteral nutrition more effective and better tolerated in the pediatric population.

A qualitative review of treatment effects on growth was also performed. Despite the well-described adverse effects that corticosteroids can have on development, growth, and pubertal maturation (51), only two of the randomized studies document the short-term effects of treatment on growth velocities. The randomized studies by Sanderson et al. (13) and Thomas et al. (37) documented significantly improved height velocity in the enterally fed groups at 3 and 6 months, respectively, although pubertal staging was not controlled for specifically.

It was also impossible to quantify the impact of enteral nutrition on different disease sites. In contrast to the widely held belief that enteral feeding is less effective in large bowel disease (13,52), available data from pediatric studies (38,40) suggests large and small bowel disease respond equally well to nutritional therapy. This is confirmed by the larger adult studies (33,53). As in the meta-analyses of about 400 adults with active Crohn's disease, it was also impossible to detect valid differences in speed of remission induction and time to first relapse.

The efficacy of polymeric diets is also still debated. There are insufficient randomized pediatric or adult data comparing elemental with whole protein, polymeric diets. Although the latter are the ideal clinical choice in palatability and cost, there are no comparative studies to confirm this.

Only 32 patients in the world literature have received polymeric diets in randomized trials comparing those diets with elemental diets; however, meta-analyses including studies of semielemental diets have been unable to document significant differences in efficacy between any one of the three types of diet (1,2). Even these analyses are only able to detect large differences in treatment effects. However, along with findings in multiple observational studies in children documenting the efficacy and palatability of polymeric diets (38,49,50), these findings provide some indication of their potential. Further randomized studies comparing polymeric and elemental diets may be justified to contribute to a statistically conclusive answer.

The inclusion of seven pediatric trials in the current analysis ensured sufficient power to detect a clinically significant difference between the two therapies. Further sensitivity analyses demonstrate that for steroids to achieve a statistically significant benefit over enteral nutrition, approximately 700 more children with acute Crohn's disease would require randomization. Results obtained from these children would also have to equal the most favorable outcome for steroid therapy reported so far (RR = 0.84) (40), if our current results were to be overruled. The volume of data necessary to overturn the evidence we report here greatly strengthens these findings (RR = 0.98, CI 0.23–0.53). The entire adult literature includes only approximately 400 randomized patients. With an incidence of less than 10 per 100,000 children (54), larger studies are unlikely to be feasible in children.

Besides reaching a statistically significant conclusion, a meta-analysis must assess and quantify interstudy variability for a conclusion to be valid. A best estimate that encompasses this heterogeneity may be much more robust than a result from a large, tightly controlled, one-center study. The seven studies included in this meta-analysis were found to be substantially homogeneous in their outcomes, making the pooled estimate less uncertain and more generalizeable. Although studies tend to become more diverse as researchers try to avoid duplication of work, this field of study has remained limited in its variability in view of the well-defined population and treatment strategies.

An inherent limitation of meta-analysis is the availability of good quality studies. A key factor in this is often the quality of randomization. Lack of allocation concealment and double-blinding can lead to substantially inflated results of evaluations of treatment effects (55).

Double-blinding in studies with enteral nutrition has never been possible, and although five studies stated that patients were randomized, none reported details of their randomization methods. Because most studies have reported no difference between the treatment effect of steroids and enteral nutrition, a publication bias is most unlikely. Studies demonstrating a clear benefit for either therapy are unlikely to have been overlooked. In addition, we selected studies in abstract form to ensure inclusion of all available data. Although this prevented a quality assessment of included trials as performed by some investigators (1,2), a quality score has not always been useful in a final analysis (1,3).

This systematic review provides both a quantitative and qualitative analysis of the data available on the use of enteral nutrition in children with active Crohn's disease.

If new research in this field is to contribute significantly to our practice and not merely support the current evidence, this analysis also provides an idea of the quality and volume of data required to achieve this. Allocation of funds and enrollment of patients, even if randomized, to studies merely supporting current good-quality evidence is inappropriate. In the absence of large, multicenter studies, however, this analysis demonstrates the benefit of small, well-designed randomized trials if the accumulation of quality evidence is to continue.

Corticosteroids clearly remain essential in the management of patients with Crohn's disease. However, despite their proven efficacy and ease of use, this should not preclude the use of an equally efficacious, but less-convenient therapy. The effect of steroids on growth and puberty make their repeated use particularly unsuitable for children approaching their major period of growth. Steroids also remain poor at healing bowel mucosa (56), whereas there are initial observational studies documenting improved mucosal cytokine profiles after enteral nutrition (28,50). Concerns about the long-term risks of malignancy in the face of active bowel inflammation continue (57–59). With more years of Crohn's disease ahead of them than adults, children may benefit more from achieving a better mucosal remission.

We therefore conclude that enteral nutrition is as effective as steroids in achieving a remission in children with active Crohn's disease. It is likely that a palatable, whole-protein polymeric diet is no less efficacious than an elemental, amino acid–based formula. This should make nutritional therapy a much more practical choice for both patient and clinician.

In view of the benefits of dietary therapy on growth, development, and probably the gut mucosa, an enteral diet should be recommended as first-line therapy in all children with active Crohn's disease.

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Acknowledgments:

The authors thanks Michael A. Stoto, Ph.D., Professor and Chair, Department of Epidemiology and Biostatistics, School of Public Health and Health Services, The George Washington University, Washington, DC, for his help with the statistical analysis.

Supported by grant T32-DK07477-16 from the the National Institutes of Health Training Grant in Pediatric Gastroenterology and Nutrition for training in clinical effectiveness (R.H.).

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Keywords:

Child; Crohn's disease; Enteral nutrition; Meta-analysis of publications; Steroids

© 2000 Lippincott Williams & Wilkins, Inc.