Crohn's disease (CD) is an idiopathic chronic inflammatory disorder. The natural course of Crohn's disease is characterized by flare-ups alterned with periods of remission. Controlling intestinal inflammation is crucial for preventing progressive intestinal damage and the appearance of complications.1

The incidence of CD in children and adolescents is approximately 3 cases/100,000 inhabitants (range 1–8/100,000 inhab.) and this has increased in Spain and Europe during the last decade.2 Up to 20% of CD patients are diagnosed before the age of 18 years. There are differences in the form of onset, natural course, and treatment regimens between adults and children. Another key difference is delayed growth, up to 46% of children and adolescents diagnosed with CD had a decrease in their growth rate before the onset of any other symptoms, and only 12% had a normal growth rate at the time of diagnosis.3 This is not only found at diagnosis, it has a variable prevalence during follow-up.4 It is also important to remember that a chronic disease appearing during childhood is associated with considerable psychological morbidity that may influence personal relationships, psychosexual development, scholastic achievements and adherence to treatment.

There are a wide range of therapeutic objectives that need to be achieved in active disease; these include control of inflammation, mucosal healing, modifying disease progression, preventing the adverse effects of treatment and guaranteeing suitable growth and development.5,6 Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids, without their side effects, in achieving mucosal and transmural remission, a situation that determines better prognosis in the following years, lower hospitalization rate and less use of biological drugs.7–11

Calprotectin is a calcium-binding protein with antimicrobial properties. Calprotectin is released from the cytoplasm of activated neutrophils, and the fecal levels increase in bowel inflammation.12 Fecal calprotectin (FC) values have been correlated with endoscopic scores in adults and children with IBD. It is a non-invasive biomarker with high sensitivity and specificity that enables monitoring of inflammatory activity and prediction of clinical relapse.12–17

The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in newly diagnosed CD children and to study the efficacy of this therapeutic approach in improving the degree of intestinal mucosa inflammation using FC as a non-invasive inflammatory biomarker and to assess the effectiveness of concomitant medications. Another efficacy end point of this study was to determine whether early initiation of thiopurine treatment (before 8 weeks after diagnosis) vs. conventional introduction after relapse, improved long-term prognosis.

This was an observational retrospective study that included all patients under 14 years of age with newly diagnosed CD in a single Pediatric Gastroenterology and Nutrition Unit between January 2002 and December 2012, and who received EEN as first line therapy. The diagnosis of CD was based on established clinical, endoscopic, histological and radiological criteria.18 Patients diagnosed with ulcerative colitis, indeterminate colitis, eosinophilic colitis or infectious colitis were excluded.

All patients received a polymeric formula, Modulen IBD® or Resource IBD® (the same product with different name), both prepared the same way by mixing 1700ml water with 400g product to produce 2000ml of formula (1kcal/ml). The prescribed volumes were based on Schofield equation, which predicts resting energy expenditure.19 Feeds were gradually increased to target volumes in 3–5 days and patients were only allowed to drink water during treatment. EEN was given for a 6–8-week period.

The data collected were age, gender, family history of inflammatory bowel disease (IBD), time from diagnosis and concomitant pharmacological treatment. Disease phenotype was determined according to the Paris classification.20 All patients were assessed at the start and end of the EEN period, the variables analyzed were weight, height, body mass index (BMI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, complete blood count (CBC), FC (Calprest®, Eurospital, Italy) and Pediatric Crohn's Disease Activity Index (PCDAI).21,22 Weight and height were measured with the patient barefoot and in underwear. Samples for the determination of fecal calprotectin were collected at home by the patient the day before and were delivered refrigerated to the laboratory for immediate analysis. Clinical remission was defined as PCDAI<10 and response as a change of more than 12.5 points from baseline PCDAI after 6–8 weeks of EEN. Normal FC levels were considered to be those below 50μg/g of feces. Weight, height and BMI z scores were calculated using data from Spanish growth charts.23

This study shows that EEN produces clinical and biochemical remission and weight recovery in new onset CD patients. Although we did not perform an endoscopy after the EEN, the significant decrease in the FC indicates a clear improvement in the degree of intestinal inflammation.12–15 Though the rate of mucosal healing achieved by EEN in some case reports are similar to that of anti-TNF-α and much higher than steroids9–11,24–26 they suffer from bias, as EEN is more likely to be administered to patients with recent onset or mild to moderate disease, while steroids are more likely to be administered to severe disease, and anti TNF to patients with longer duration uncontrolled disease. However, unlike steroids, EEN has a positive effect on linear growth with an increase in growth rate in the 6 months following the start of treatment and on bone mineral density.27–30

In a recent study with 34 patients,11 58% of the patients treated with EEN achieved endoscopic remission (measured by SES-CD31) and 21% showed transmural remission measured by MR enterography. These authors showed that early endoscopic remission was associated with lower rates of endoscopic relapse, less use of anti-TNF-α and fewer hospitalisations one year after diagnosis. Response was better in those with less time since diagnosis. These same authors showed that induction of remission with steroids instead of EEN increased the risk of failure to respond or loss of response to anti-TNF-α.

The efficacy of EEN was first observed at the beginning of the 1970s, when it was found that the clinical and nutritional status of some patients improved after being treated with elemental formula while awaiting surgical treatment. Although the mechanisms of EEN on intestinal inflammation in CD are not fully understood, there are a number of hypotheses, including modification of the intestinal flora, elimination of the uptake of food antigens, decrease in the intestinal synthesis of inflammatory mediators due to a reduced amount of fat in the diet or the supply of micronutrients to the inflamed gut.32

Analysing the data from more than 25 pediatric studies, the overall efficacy of EEN is found to be 84% (95% CI, 81–87%), although with different enteral formulas, clinical remission criteria and treatment duration. The compliance rate is very high, reaching 90% (95% CI, 88–92%). No differences in the remission rate or compliance have been found in relation to the enteral formula used (polymeric, semi-elemental or elemental), with glutamine supplements or with medium chain triglycerides.33 In our series, only one type of formula was used, specific for CD, enriched with TGF-β, allowing no other food to be taken except water during the EEN period. Partial enteral nutrition (50% of calories in the form of conventional food) has been shown to be less effective than EEN.34 Other approaches, such as allowing up to 20% of daily estimated calories coming from other foods, have not shown lower efficacy.35

Initially it was believed that nutritional treatment was more effective in patients with ileal involvement than in those with disease located exclusively in the colon. There are currently no data to enable a correlation between response to EEN and disease phenotype.36 Moreover, in our series, we found significant differences according to the location although the number of patients with exclusive colonic disease was very small.

Although our study was not designed to address the impact of early thiopurine treatment on the outcome of the disease after induction we did not find differences in terms of maintenance of remission in patients treated early (≤8 weeks) vs. late (>8 weeks), see Table 3, but patients treated earlier needed less steroids during the follow-up (p=0.001). Our results are in concordance to other studies performed in children11,37 and in adults,38,39 and against the results showed by Markovitz et al.40 in a pediatric study. Probably one of the reasons for this discrepancy between pediatric studies may be because none of the patients included in Markovitz’40 study received induction therapy with EEN, and is already known that the achievement of mucosal healing with steroids treatment is unlikely. However, further studies are required before any evidence-based determination can be made as to the most correct use of immunomodulator therapy in pediatric CD.

This study provides valuable information on the efficacy of EEN in pediatric CD. The most important limitations are the small number of patients, which probably underestimates the effect of thiopurines and the retrospective analysis of the data, making it difficult to obtain more robust information.

In conclusion, EEN administered for 6–8 weeks is effective in inducing clinical and biochemical remission, improving anthropometric parameters and decreasing the degree of mucosal inflammation. FC enables monitoring of response to EEN and control of the degree of mucosal inflammation. Patients treated early with thiopurines received less steroids during the follow-up. The EEN period is the key for updating the vaccination schedule and ordering the necessary investigations prior to starting immunosuppression treatment.

The authors have no conflicts of interest to declare.