A retrospective study showing maintenance treatment options for paediatric CD in the first year following diagnosis after induction of remission with EEN: supplemental enteral nutrition is better than nothing!

Crohn’s disease (CD) is characterised by patchy, transmural inflammation, which may affect any part of the gastro-intestinal tract from the mouth to the anus. It is a lifelong condition with periods of remission or relapse. The incidence of paediatric CD is rising, with a mean age at diagnosis in childhood of 11.9 years [1]. Presentation in the paediatric population is often with a variety of symptoms, abdominal pain is usually a prominent feature alongside persistent or recurrent diarrhoea with or without blood. Other symptoms include; nocturnal stooling, tenesmus, lethargy, anorexia and nausea as well as growth delay, delayed puberty and malnutrition [2]. Due to the diverse range of symptoms diagnosis can often be delayed, with associated issues of poor growth and undernutrition for all patients as well as delayed puberty in the adolescent patient group.

The aims of treatment include relief of symptoms, resumption of normal growth and pubertal development, prevention of relapse and complications as well as improvement in quality of life. The benefits of treatment need to be balanced against potential side effects. Nutritional therapy was first introduced as a treatment for CD in the 1970’s, [3] and since then EEN has been recognised in many centres as a first line treatment for active paediatric CD [4–7]. EEN has been shown to improve nutritional complications at diagnosis including weight loss, improving inflammatory markers and promoting mucosal healing [8].

Heuschkel et al. (2000) demonstrated that EEN was as effective as corticosteroids at inducing remission in children with CD, a finding replicated by an updated meta-analysis in 2007 [7, 8]. EEN also has the benefit of having minimal side effects. Zachos et al. (2007) identified that while corticosteriods are commonly used in the treatment of adults with CD, their use in children has been met with caution due to their adverse effects notably on growth and bone mineral density [9].

After induction of remission in CD a strategic therapy will be chosen for maintenance of remission; most commonly, in the paediatric setting, azathioprine which carries potential toxicity risks and requires significant monitoring [10]. It is now felt that the role of EN may not just be limited to inducing remission but can also be used to maintain remission [11]. Nutritional support is key in maintaining normal growth and decreasing disease complications with minimal side effects from medications. There has however been a limited amount of research undertaken relating to EN as a maintenance treatment for patients with CD with many of the studies having been in adults [12]. The Cochrane report on Enteral Nutrition for Maintenance of Remission in CD only identified two papers which met their criteria for inclusion [13].

This study aimed to assess if MEN post induction of remission with EEN is achievable and if it helps prolong remission up to a year after diagnosis compared to other treatment strategies.

This study summarises the use of MEN in paediatric CD patients from a complete treatment cohort who have all received EEN for induction of remission. The use of MEN at follow up was then compared alongside the use of azathioprine. The results from this study demonstrate that MEN is a useful strategy to help maintain remission. MEN is a favourable option especially in patients not taking azathioprine, but it’s uses are limited due to issues of palatability and ‘taste fatigue’ in a proportion of patients. Compliance can also be an issue potentially discouraging patients from taking future courses of EEN, however there is no specific research which has addressed this.

For many years immunosuppression has been used to maintain remission in the majority of patients with CD [16, 17]. However these drugs have a recognised side effect profile [18]. This study provides further support for the use of nutritional therapy in children with CD both as an induction therapy but more specifically as a maintenance therapy. It has been well documented that EEN is an effective and favourable treatment option for patients diagnosed with CD, however until now there has only been a small amount of research looking at MEN [5, 6, 19].

Hania et al. (2012) have conducted the only randomised controlled trial comparing mercaptopurine (MP) and elemental diet as maintenance treatment for CD [20]. They studied 95 Japanese adult CD patients who were in clinical remission who were split into 3 maintenance groups (one group received MP, the second elemental diet and the third no active treatment). Follow up at 2 years demonstrated significantly higher remission in both patients receiving MP (56.7%) and patients receiving elemental diet (46.9%) compared to the control group (21.2%). Clearly this study has produced very similar results to the current study. Of note Hanai et al. (2012) had a longer follow up period, studied adult patients and used an elemental rather than a polymeric feed. In the study only 2/32 (6%) patients self-inserted an NG tube to receive elemental feeds, the remaining patients took supplemental drinks orally. The high numbers of patients able to drink elemental diet for 2 years is not something we think would be achievable in our clinical practice.

A Cochrane review identified two randomised control trials of MEN which met the inclusion criteria [13] and were both adult studies [21, 22]. The study by Verma et al. (2001) had a moderately small sample size (33 adult patients who were steroid dependent) with no details documented as to the route of obtaining remission [21]. Of these 19 patients took elemental supplements and 14 patients took polymeric supplements. The supplements provided 35-50% of patient’s pre-trial calorie intake. Patients were followed up at 1 year and failure was determined as increase in Crohn’s disease activity index (CDAI), inability to withdraw steroids or surgery being required. 18% patients were unable to complete the study due to tolerance issues. 43% patients achieved and maintained remission and had steroids withdrawn. They identified similar remission rates in the polymeric diet group versus the elemental group. This study therefore demonstrates that whole protein sip feeds, which are generally more palatable, were effective at maintaining remission within this patient group.

The more recent study by Takagi et al. (2006) had a larger sample size of 51 and was carried out across two centres [22]. Patients were randomly assigned to 2 groups, the first group (n = 26) received half their nutritional requirements as an elemental diet and the second group (n = 25) had a free unrestricted diet with no nutritional supplementation. Remission had initially been achieved via surgery, 6–8 weeks EEN, IV methyl prednisolone or Infliximab. All patients were commenced on mesalazine and patients already on azathioprine prior to commencing study remained on the medication. They used an elemental diet providing 900-1200 ml and calories daily. 19% used an NG tube during the study period to obtain the elemental diet. 35% patients in the elemental diet group had relapsed by 2 years, compared to 64% in free diet group. While these studies are on adult patients using elemental feed the results are similar to our own.

This study demonstrates similar remission rates to other studies using EEN as an induction treatment at diagnosis of CD. A moderately high proportion of the patients received the EEN via NGT but this rate was similar to previous work by our group [5, 23] as well as others [24]. Our centre has a strong multidisciplinary team (MDT) approach to patients undertaking EEN, with patients following a formalised pathway with regular MDT support. A full clinical review is carried out at 4 and 8 weeks. This has been shown to improve our numbers of patient able to complete 8 week courses of EEN [25]. Currently patients within our population group only managed to progress to MEN if they received EEN orally. Patients undertaking NG feeds for EEN were unable to consume MEN orally. However, patients were offered the same nutritional formulation for MEN as they were given for EEN which raises questions as to whether an alternative, potentially more palatable nutritional drinks for the individual patients could be used for maintenance. As such we now offer patients who have taken EEN by NG tube an alternative type of supplemental feed to try for maintenance therapy. We did not adopt an approach similar to Wilschanski et al. (1996) where they continued NG nutritional support as we felt this would be too difficult for patients to undertake [11]. However with this study and the other supportive data this may now be an option worth further exploration in selected patients.

Contrary to the findings of our study and other published work, Knight et al. (2005) reported that MEN was not associated with a decreased relapse rate with no significant difference found between the group receiving MEN and the control group [26]. Their study focused on paediatric patients and the volumes of feeds to be taken were large at 1000 ml. This was felt to lead to issues with compliance and they documented that volumes consumed were variable.

In our study, the number of patients in remission at 6 months was statistically significant, however at 1 year was not. This could be due to patients stopping supplements due to compliance and taste fatigue. Following on from these results as a centre we feel it is important that support is optimised and a defined patient pathway would be beneficial to enhance compliance rates with MEN; our clinical practice has changed accordingly.

All studies (Table 2) state the volume of supplemental feeds consumed by patients; however it remains unclear from the literature whether this directly affects remission rates when using MEN. Early satiety and taste fatigue can be problematic if volumes are too high, however it is important that volumes are adequate to promote treatment efficacy. Taste fatigue is a commonly reported phenomenon in patients with chronic disease who take oral supplements [28]. This will limit the length of time supplements can be taken for; methods to minimise taste fatigue include looking at polymeric supplements which are often reported to be more palatable [29].

The mechanism of action of EEN or MEN is not fully understood. Several studies have shown that the gut microbiota is changed significantly after a course of EEN and once diet is introduced the gut flora reverts back to a similar state as pre EEN [30, 31]. This raises the question-does MEN maintain the changes to gut microbiota and therefore maintain remission rates for longer? The studies examining this are small but do support the broad concept that MEN does seem to prolong a favourable bacterial profile compared to standard diet.

There are limitations to our study; sample size is moderate and all patients are from a single centre which has a strong track record for supporting patients undergoing EEN. The study is retrospective and non-randomised but has achieved 100% patient ascertainment and follow up over a 2 year period of all new diagnoses of CD. The follow up time is relatively short but with a significant fall off in patients managing to take supplements by this time is likely to be adequate for analysis purposes for this type of study.

In conclusion, this study demonstrates that a sub group of patients can continue nutritional supplements post induction of remission with EEN as a maintenance treatment. This seems a useful strategy in a sub group of patients especially in those who are not commencing azathioprine. To our knowledge this is the first review evaluating MEN and azathioprine as an ongoing treatment option for this group in paediatrics. A randomised controlled trial would be beneficial in helping to clarify these provisional findings further.