CATCH 22 syndrome

Robert M. Beattie, FRCPCH

From the Pediatrie Medical Unit, Southampton General Hospital, Tremona Road, Southampton, United Kingdom

ABSTRACT. Crohn's disease in childhood is a chronic relapsing and remitting condition that can significantly impact normal growth and development. This influences choice of both initial and ongoing management. The goal of therapy is to induce and maintain remission with minimal side effects. Enteral nutrition is effective in active disease and will induce disease remission in most cases avoiding corticosteroid use. The high frequency of relapse means additional immunosuppressive therapies are usually required but nutrition remains a key priority as part of the subsequent management strategy. (Journal of Parenteral and Enteral Nutrition 29:8151-8159, 2005)

In all, 10%-15% of Crohn's disease presents in childhood. The disease runs a chronic relapsing course in most cases. Growth and nutrition are key issues in management, with the aim of treatment being to induce and then maintain disease remission with minimal side effects. The treatment priority thus is not only symptom control and quality of life, but also to ensure that disease control is sufficient to facilitate normal growth and pubertal development. Enterai nutrition as the sole therapy is highly effective and will induce disease remission in up to 80% of patients while avoiding the potential toxicity of corticosteroids, thereby making it an important treatment option in this difficult condition. The role of immunosuppressive therapies, including azathioprine, is discussed elsewhere.1

GROWTH FAILURE AND NUTRITIONAL IMPAIRMENT

Growth failure is present in up to 50% of children and adolescents at presentation and up to 90% are underweight.2 Assessment of and attention to growth and nutrition status are therefore fundamental aspects of management. The growth failure is characterized by delayed skeletal maturation and delayed onset of puberty. Disease remission with treatment results in improved growth and nutrition status3 with a reasonable final adult height in most cases, provided that appropriate therapy is offered (particularly during the midpubertal growth spurt).4'5 Impressive increases in height velocity with catch-up are seen, particularly after surgical resection.6'7

The etiology of the growth failure is multifactorial and poorly understood, involving poor nutrition state,3 the systemic consequences of gut inflammation,8'9 disturbances of the growth hormone/insulin-like growth factor axis,10'11 and the side effects of corticosteroids when used.12

ENTERAL NUTRITION AS PRIMARY THERAPY

The use of enterai nutrition as treatment for Crohn's disease was first reported in adult series.13'14 In 1981, Kirschner reported 7 children with moderately active Crohn's disease and significant growth retardation that responded well to aggressive nutrition supplementation, with improved well-being and an increase in height velocity. In 1983, O'Morain reported 15 children treated for 4 weeks with elemental diet followed by 4 weeks of food reintroduction. During the study period, all of the children improved, with 6 patients crossing into a higher centile channel for weight and 3 for height.16 By the middle of the 1980s, elemental diet was widely used in the United Kingdom as primary therapy in children with Crohn's disease.

Sanderson compared the peptide-based semi-elemental diet Flexical (Mead Johnson; Indianapolis, IN) with steroids in the treatment of children with small bowel disease and found equal efficacy in both groups, but a better effect on long-term linear growth in the group treated with enterai nutrition. The diet was given for 6 weeks as sole therapy. At the end of the 6-week period, food was reintroduced slowly, 1 new food every 2 days according to a strict protocol.17 Subsequent studies by Thomas9 and Papadopoulou18 confirmed that elemental formula was as effective as steroids. Both studies used the elemental diet E028 (SHS International, Liverpool, United Kingdom). Thomas looked at patients with small and large bowel disease and found no difference in the efficacy of enterai nutrition in either group. Of interest, patients in this study who used steroids had a higher oral calorific intake than those treated with enterai nutrition, but linear growth was better in the latter group. However, outcome data were short-term.

Since the 1990s, cheaper and more palatable polymeric (whole protein-based) formulas have been used. We reported 7 children,19 all new patients, treated for 8 weeks with the polymeric formula ALIlO (Nestlé, Vevey, Switzerland). All responded clinically with improvement in inflammatory indices by 2 weeks and full clinical remission by 8 weeks. There were no problems with the subsequent food reintroduction. Improved linear growth was seen in 6/7 prepubertal at start of treatment. Ruuska compared polymeric diet (Nutrison standard; Nutricia Zoetermeer, The Netherlands) with steroids in a randomized-controlled trial and found equal efficacy with both treatments.20 Fell et al reported the successful use of the polymeric formula CT3211 (Nestlé) developed from ALIlO in 29 children.21 Overall, 79% achieved clinical remission (based on PCDAI). This formula has now been marketed as Modulen IBD (Nestlé). There have been subsequent published cohort studies,11'22'23 although no randomized controlled trials of the use of Modulen IBD in either adults or children. However, it has achieved widespread acceptability as a highly effective, cheap, and palatable formula that induces disease remission in childhood Crohn's disease, normalizes systemic inflammatory markers, and promotes weight gain and linear growth as sole therapy.

There have been numerous trials that suggest polymeric formulas are as effective as elemental diets in adult patients,24"26 and there has been a Cochrane review with 9 studies comparing elemental diet (n = 170) with nonelemental diet (n = 128) with no significant difference in outcome. Most recently, Ludvigsson et al compared the elemental feed EO28 with the polymeric feed Nutrison in a group of 33 children with no significant difference in outcome apart from better weight gain in the polymeric feed group, perhaps related to better compliance.28 The possible mechanisms by which enterai nutrition may work are reviewed elsewhere.29

It is of interest that there is an early impact of enterai nutrition on the systemic inflammation and IGF-I system, which precedes any significant change in nutrition parameters with significant improvements by day 3 in inflammatory parameters (ESR, IL6) and by day 7 in PCDAI, IGF-I, and C-reactive protein (CRP).22

PRACTICAL ASPECTS OF ENTERAL NUTRITION

Enterai nutrition (polymeric or elemental) needs to be given for 6-8 weeks as sole therapy. During this period, no other foodstuffs should be taken other than perhaps water and sugar-free gum. Feeds can be flavored. The amount required is determined by the degree of nutrition impairment and recommended nutrient intake. It is likely that the intake will exceed the recommended nutrient intake, particularly if there is a nutrition deficit. Most feeds are between 0.7 kcal/ML and 1 kcal/mL. Feeds can usually be concentrated if volume is a limiting factor for compliance. Modulen IBD (Nestlé) is 1 kcal/mL and can be concentrated up to 1.5 kcal/mL if necessary (personal practice). Feeds vary in their palatability and it may be necessary to initiate therapy by nasogastric tube infusion, particularly if the child is anorexic at presentation. The large volumes are often difficult to tolerate in the first few days and it is sensible to increase feed quantity and strength gradually. Refeeding syndrome can occur and, in the severely nutritionally-impaired child, biochemical monitoring including phosphate should be carried out.30

Frequent follow-up is required to ensure the feed is being taken, volumes are adequate, and weight gain is being achieved. It is essential during therapy that clinically the child feels better and that biochemical parameters of inflammation are improving. It is likely that as the child feels better they will become more active and an increase in feed may be required to satisfy hunger. During this period, close attention must be paid to symptoms, systemic markers of inflammation such as the CRP, and nutrition status in order to help predict relapse early.

At the end of the period on enterai nutrition, food can be reintroduced. This involves a gradual reintroduction of different foods depending upon clinical response. There are various regimes for this and there is no consensus on how quickly food should be reintroduced. However, this issue is clearly patient-dependent. In our view, it would be key to ensure that food was not reintroduced too rapidly and that during that period nutrition support was continued to ensure calorie intake is adequate. It is sensible to start with simple foods such as potato, chicken, and rice and to introduce milk, fiber, and wheat-based products later.

RELAPSE AFTER ENTERAL NUTRITION

The rate of relapse after enterai nutrition is 50%-90% at 12 months in adult studies.31-34 These rates are difficult to assess in the pediatrie literature, as many of the published reports are of select groups with a short follow-up period, often of

CONTINUED NUTRITION SUPPORT

In 1988, Belli et al reported 8 children with Crohn's disease and severe growth failure whose clinical progress was good with a regimen of elemental diet for 1 out of every 4 months.37 Subsequently, other groups have reported a beneficial effect of intermittent enterai nutrition.38 Wilschanski reported a retrospective cohort of children who elected to continue nutrition support after the induction of disease remission by dietary therapy. These children had better growth and a longer time to first relapse.39

Verma et al have published data from an adult study comparing elemental and polymeric dietary supplementation in a group of steroid-dependent patients. In all, 14 of 27 responded to the treatment, allowing steroids to be withdrawn and remained in remission for the 12 months of follow-up.40 Of the 14 who remained in remission, 7 elected to continue taking the supplement. Six of these remained in remission for a further 12 months, whereas all those who discontinued the supplement relapsed within 6 months.

However, the continued use of nutrition supplements in all patients is controversial. It is necessary to pay careful attention to nutrition status during the management of this chronic condition both during initial treatment and follow-up. Poor nutrition state is a feature at relapse and it is therefore likely that optimizing nutrition will have a protective effect. It may even be that specific micronutrients (eg, fish oils) have a specific immunomodulatory effect, although the evidence is conflicting.

DRUG THERAPY IN CROHN'S DISEASE

The majority of children with Crohn's disease have a relapsing and remitting clinical course. Some children will respond to enterai nutrition alone, but for those who do not and for those who present with severe disease, drug therapy is necessary. The most commonly used medications are corticosteroids, 5-ASA derivatives, and azathioprine (or 6-mercaptopurine). Children with severe disease that does not respond to conventional medications frequently require surgery. Alternative options include more aggressive immunosuppression with agents such as methotrexate, cyclosporin, and tacrolimus or the newer immunomodulatory therapies, such as anti-TNFa antibodies and thalidomide. Antibiotics are used in fulminant colitis, oral, and perianal disease. Children treated by therapies other than enterai nutrition require close attention to nutritional restitution particularly if nutrition is an issue with dietetic input and/or supplements if necessary.

Corticosteroids

Corticosteroids are a powerful immunosuppressant with proven efficacy in the induction of clinical remission. They are widely used in adults and compliance is good. In pediatrie practice, they are often used as second line therapy because of the potential toxicity, but they are frequently used because Crohn's disease in childhood has a relapsing nature. The toxic effects are important, particularly on growth, but also including obesity, striae, susceptibility to infection, mood disturbance, and osteopenia.41

Osteopenia and osteoporosis are significant problems in adults with Crohn's disease, particularly as they get older and in association with steroid treatment.42 Screening for osteoporosis in all patients with inflammatory bowel disease (IBD) is controversial.43'44 Low bone mineral density has been found at diagnosis, notably in those with long-standing symptoms or with a low body mass index (BMI).45 Assessment in children with IBD has shown that low bone mineral density correlates with a low BMI and steroid use.46 Of interest, the children in this study were significantly more likely to have osteopenia, even after adjustment for steroid use. Other groups have reported the association of steroid use and osteopenia in children with IBD.47'41 Pragmatic consensus recommendations advise calcium and vitamin D supplementation during high-dose corticosteroid regimens.48

There have been multiple studies in adults comparing the efficacy of steroids and enterai nutrition, either elemental or polymeric. Fernandez-Banares and Griffiths have published meta-analyses of these. Both principally addressed studies in adults and concluded that steroids were more efficacious than diet in the induction of remission and that results were similar whether elemental or polymeric diets were used. Many of the individual studies quoted were flawed by poor compliance and the results need to be balanced against the potential toxicity of steroid therapy. These meta-analyses have led to a change in adult practice with the widespread acceptance of steroids as primary therapy in Crohn's disease.33'34'36 The pediatrie experience is that enterai nutrition is well tolerated and acceptable to the patient. Compliance as a consequence is good with multidisciplinary and family support, the powerful motivation being to continue with a treatment if it makes you better.

A further meta-analysis that included the five pediatrie randomized controlled studies with data from 194 patients was published by Heuschkel et al.49 The authors suggested that enterai nutrition was as effective as steroids in the induction of remission, and these studies included children with disease at all sites. Also, the data suggested that steroid-induced growth suppression could not be prevented by an increase in the intake of calories, and that growth was better in the groups of children treated with enterai nutrition. The data did not address the efficacy of elemental (aminoacid-based) vs polymeric (polypeptide-based) formulas. The published trials directly comparing the efficacy of these types of feed have been too small to determine any significant difference.

It is of interest that, despite the proven clinical efficacy of corticosteroids, when one looks more critically at remission and defines it in terms of clinical, biochemical, endoscopie and histologie criteria, their effects are less convincing.50'51 Although clinical remission is achieved frequently, endoscopie and histologie remission of disease activity is achieved less often and this occurs after enterai nutrition as well.21 In a dis ease which runs a chronic relapsing course, it would seem important to achieve full remission on all parameters with initial therapy, with subsequent therapy aiming to maintain this and thus attain long-term remission. A therapy that improves symptoms but masks low-grade ongoing disease may not affect dis ease progression over the longer term. The real challenge therefore is not just to achieve clinical remission, but to achieve disease control in the long-term.1

CONCLUSION

Enterai nutrition is a simple and effective treatment for Crohn's disease with minimal toxicity that is available for use alone or in combination with other therapies for the management of this chronic relapsing condition with a potentially high morbidity from its chronic relapsing course during childhood and adolescence. Treating children with Crohn's disease remains challenging and requires input from many sources within a multidisciplinary team framework. Further characterization of the mechanism, effect and practical use of nutrition therapy has the potential to herald new approaches to treatment with few side effects.

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Received for publication December 6, 2004.

Accepted for publication February 1, 2005.

Correspondence: Robert M. Beattie, Pediatrie Medical Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. Electronic mail may be sent to mark.beattie@suht. swest.nhs.uk.

Discussion

Dr Meier: Do you think that in severe Crohn's disease with TNF antibodies at the beginning and enterai nutrition you could influence your course of the disease or the length of hospital stay?

Dr Beattie: I think this is difficult. I think that if I switch the question to a slightly different one and talk about azathioprine I would say that in severe Crohn's there are increasingly powerful arguments for putting azathioprine in at diagnosis. I think the difficulty with TNFa is the potential toxicity and although we are supposedly reassured by long-term safety data in adults for it, it is just a worry in children, and I think the worry is that you give a very powerful toxic treatment early on and doing it just delays the natural history of that condition. Once you are on infliximab you tend to get stuck on it and I think that is a cost issue and also an issue in terms of efficacy, the drug becoming less effective with time and because you may need infliximab around the time of puberty to go through the growth spurt, and so if you have introduced it into the child too early on then you don't have that other option later.

Dr Meier: When you look at your nutrition parameters during the Modulen treatment, have you measured other body compositions parameters, like lean body mass, fat mass, or do you have the anthropometrie measurements?

Dr Beattie: We have only done that in the study where we compared inactive and active Crohn's disease from the point of view of measuring lipids and found a significant difference. I think that it is something we have not had facilities all the time to measure but I think Thomas did that when he compared an elemental diet with steroids, and I think that has also been done by Verma in Sheffield.

Dr Roessle: I would be interested to learn whether you have any experience and data on potential deficiencies on specific nutrients in newly diagnosed Crohn's patients and patients getting enterai nutrition. In other terms the Modulen IBD of today is kind of a formula which is moderately rich in protein and also quite enriched in all levels of minerals and micronutrients compared with some specialized formulas which are on the market, and I am particularly thinking of catch up growth, calcium, vitamin D and also essential fatty acids. Would you have any observations to share with us?

Dr Beattie: The experience of that is that we have a small amount of children who in the early phases of Modulen IBD have dropped their phosphates presumably having a mini although not pathologic refeeding type syndrome. Most Crohn's patients as you know are iron deficient at diagnosis and my experience is that most of them are still iron deficient when they have finished their Modulen, so either tweaking the diet to increase the iron or giving iron supplements at a very low dose is essential. We are able to measure micronutrients on children very easily in Southampton because we are linked with the Institute of Human Nutrition, and in fact it is the unusual patients who would be zinc or selenium deficient, although the interpretation of micronutrients is so influenced by the inflammatory response, I think that presents you with some difficulty. We have had 1 child, and this was a child who took a large amount of Modulen and became sodium deficient symptomatically and had low urinary sodium. We do as a routine thing put our children long-term with Crohn's on multivitamin supplements on the presumption that there must be some persistent micronutrient vitamin deficiencies we are not aware of. We have recently had the facility to do DEXA scanning and I haven't got all the data on that, but I would say I think an interesting observation on enterai nutrition is that we have only got 1 child who has reduced bone mineral density on DEXA scanning and that is a child with very severe ulcerative colitis in fact, although others have seen significantly reduced bone mineral density in childhood IBD. Whenever we do a DEXA scanning we measure the vitamin D so we have not found that as a deficiency.

Dr Sanderson: Can I just make the point that the reason we don't know the long term outcome of growth isn't from one thing. I think the problem arises as of other treatments have come along quite soon after the initial therapy, for instance the high number of patients who were in the steroid group who had surgery 9, 12 months later, that group completely rescued by the surgery because surgery makes children grow very well indeed, and also it is true that other therapies may be used differently in one group vs another, and so it is quite a difficult thing to know the long-term outcome of growth steroids vs enterai feeds simply because of the other treatments that are given, which may not be given equally in both groups.

Dr Beattie: I would agree with that completely. Evolving treatments are particularly relevant as well because certainly now maybe 60% of children will end up on azathioprine whereas it wasn't previously the case. But I think the other thing is the cautious interpretation of growth spurt as well because puberty will be a confounding variable and many of these children were prepubertal and growth delayed, and if we do induce puberty by including disease remission, eg, by surgery, we get super-normal growth. We may have a 14-year-old who we put in a good remission and have super-normal growth for 12 months, but that may not subsequently be sustained. One of the difficult arguments that we put forward in the UK (data presented from Birmingham) is that all you do with enterai nutrition is delay the use of steroids and the growth outcome data, which hasn't been published, is no different longterm.

Dr Paerregaard: You mentioned the issue of concomitant medication during enterai nutrition treatment. Why did you warn against concomitant 5-ASA besides the fact that it doesn't really work, and furthermore what about antibiotics?

Dr Beattie: I think the interesting question about 5-ASA is, should we use them at all? That is one of the anxieties, and certainly the most recent suggestion is that if we use them at all we should use them in very high doses and patient tolerance of high doses of 5-ASA (quite a bulky thing to take), especially when you are on just a liquid diet is fairly poor. The question about antibiotics-and I should have said that-is that when somebody has got a bad perianal disease then apart from the fact that I would probably put them on azathioprine at diagnosis I think they need the metronidazole concomitant with the enterai nutrition.

Dr Paerregaard: But antibiotics is a delicate question because if you presume that enterai nutrition works by modifying the intestinal flora you may either enhance or you may diminish the efficacy of enterai nutrition by giving concomitant antibiotics.

Dr Beattie: The difficulty there in my own experience would be in a child with severe perianal disease; enterai nutrition on its own doesn't work for the perianal disease. But we have had a number of children who have had small bowel disease plus perianal dis ease and the enterai nutrition works for the small bowel disease but I need something more for the perianal disease. I think this is a real difficulty actually because on the one hand you are saying an exclusive enterai feed and you don't allow anything else but on the other hand giving other things.

Dr Meier: Do you think after giving antibiotics, probiotics will help to restore the microflora afterwards or should we give probiotics in Crohn's disease together with enterai nutrition?

Dr Beattie: I don't know the answer to that question. The problem is we don't really know what bacterial switching we make or we may learn that from Dr Lionetti tomorrow and there are a host of different potential probiotics you can use and no convincing evidence coming out for efficacy, and I am very cautious about the use because it might switch things in the wrong direction as much as switch things in the right direction. I would certainly think that if probiotics are added to Modulen, that is a sort of thing I would really like to see a trial on to find out whether it was worth doing.

Dr Damiao: I would like to return to the endoscopie and histologie remission issue. I think this is very interesting for all of us who work with patients and we need to know if he or she is in remission or not. Did you have the opportunity to follow up on your patients to check whether those that did not reach endoscopie and histologie remission had more relapses, because if this is true I think we should rethink our evaluation of the patients. Usually we just use the Crohn's disease indexes and it seems that they are not very well for us and we are now entering a new phase in terms of therapeutics.

Dr Beattie: It is not my practice now to do repeat colonoscopies. The problem with following the historical cohorts is that there are many other variables, it is like trying to follow growth, there are too many factors to go in to make your long-term predictions about relapse. In the 20 children with ulcerative colitis, the endoscopie healing was not a predictor of subsequent outcome. But returning to your question I would agree, we have to reassess the mucosa because by reassessing the mucosa we can do what must be a pragmatic presumption which is induce long-term mucosal healing. But what I am saying is that I think spot looking at it as a point in time isn't necessarily scientifically valid, it may be that Modulen heals it better at 8 weeks than steroids because steroids take longer to heal the mucosa but have a more sustained effect. I think the reason I presented the data on calprotectin and also the data from ultrasound is that there are other markers which are much easier to measure, which you can then measure far more frequently and if you do measure it more frequently you learn a little bit more about what is truly happening at the mucosal level.

Dr Damiao: I think this is the point, maybe we should include some special markers calprotectin, ultrasound and even intestinal permeability to the clinical points we have already. I am not saying that we should perform endoscopy in all the patients.

Dr Beattie: I think it is important however to remember that doing that is to inform us in terms of research. At the moment there is no clinical evidence that our practice should be dictated by the result of what happens at the mucosal level. I think what we need to do is to find out from a research point of view what happens to the intestinal inflammation before making presumptions about how that should influence our subsequent management, because I am not sure myself that if you do a repeat colonoscopy at 8 weeks or a calprotectin is still raised at 8 weeks, that means the child needs azathioprine for example.

Dr Wenzel: To talk about the follow up parameters, could you comment on the use of MRI especially with new fast high-resolution sequences and especially with small bowel disease?

Dr Beattie: There are some papers coming out now about MRI and how effective that is. I think if MRI is more sophisticated than ultrasound, which I think it is in terms of what it is able to measure, although with ultrasound Doppler and bowel thickness you have got a considerable amount of information, then that is another noninvasive straightforward low radiation way in which we can study what is actually happening to the intestine in parallel to what is happening clinically. I think it depends on availability; we can probably get an ultrasound easier than we can get a MRI.

Dr Walker-Smith: Coming back to the question of follow-up endoscopy, I quite disagree with you about the importance of follow-up endoscopy because I think it is important in the management decision. You showed 2 malignant deaths out of a cohort of 250 and you talk of outcomes: one of the worst outcomes of inflammatory bowel disease is death from cancer or developing malignant disease. I think we have an absolute obligation as clinicians to try to heal the musosa of the children we care for and certainly if you did an endoscopy and mucosa is worse than it was before or as bad even if the child had improved I though we had an absolute obligation to use azathioprine to heal the mucosa and if you are going to have azathioprine with enterai feeding then you need to follow up, a biopsy may go, but if you are just going to use enterai feeding I think you have an absolute obligation to see if the mucosa heals. Now I think infliximab has really changed the whole way we think because as I read the literature I think the whole emphasis now is moving toward mucosal healing. I think what you are saying is turning away from that.

Dr Beattie: I wouldn't agree it turns away because the worry I have got about 8 weeks is looking at things at a point in time and I think that the primary objective has got to be to heal the mucosa, and the pragmatic presumption we should make is if we heal the mucosa the child will have a long time sustained remission. I haven't yet seen any evidence published to say that it is the case and that doesn't mean it is not the case but it is something we should guard against making the presumption before we have the evidence. This is difficult with infliximab. Infliximab does heal the mucosa, but then it gets bad again and one of the things I think is interesting to learn from the infliximab data, how do we know that if we heal the mucosa then the mucosa has any less chance of becoming severely inflamed again, because that is certainly what is happening with infliximab.

Dr Triantafyllidis: Do you think that the same scheme of follow up and the combination of ultrasound and calprotectin in feces can also be applied in adults? I am asking this question because in adults we know that some thickness on the terminal ileum does not mean that the patient has active disease, and also in adult patients it does not mean inflammation. What is your opinion on that?

Dr Beattie: The issue about calprotectin, there is good adult data which matches calprotectin to intestinal inflammation. What I was presenting with ultrasound is simply the facts we have got that you can see changes in the bowel thickness. I think it would then require some parallel evaluations to try to find out how informative that was because you can look at the ultrasound thickness but you can also look at the vessel flow, and even if the bowel is still thick and there will be a fibrosis developed you may get information about blood flow to the intestine which is informative as well, but I think it isn't the case that we can extrapolate that presumption yet.

Dr Triantafyllidis: A measurement of blood flow requires I suppose a special training.

Dr Beattie: It requires specific equipment and specific training and to do an ultrasound of the bowel to get this information takes 20 minutes.

Dr Arnaud-Battandier: In your experience are you proposing again Modulen to the patients who relapse, and how many times were you able to propose a treatment with Modulen?

Dr Beattie: I think that it is a relatively small group that is prepared to go for repeated cycles of enterai nutrition. This is one of my motivations to try to think about whether a shorter course will suffice because we have given a number of children a second course for a short duration. I think that, although compliance is very good at the start because when you first present with Crohn's you are very ill and you get much better, compliance with subsequent courses, the patient's ability to tolerate subsequent courses is less.

Dr Arnaud-Battandier: Because the doctors are less motivated to use or is it really the patients?

Dr Beattie: It is a combination of course but we are in a unit where we push enterai nutrition but still find that patients will for subsequent courses often move away from it.

Dr Meier: But after you have done your treatment for 8 weeks and you still have nutrition problems, you switch to oral nutrition?

Dr Beattie: What we do in that group, all our patients, when they come to the inflammatory bowel disease clinic are reviewed by dietitians so you work on another strategy to optimize the nutrition status and that becomes a priority either by supplements or by specific diets.

Dr Meier: But what is the rationale to stop enterai nutrition after 8 weeks, do you think there is no immunomodulation anymore?

Dr Beattie: I think there is not a rationale, 8 weeks is because the data are for 8 weeks, it is not because 8 weeks is the right duration to give it for, and what I am persuaded by is that the systemic inflammatory response gets better within 8 days and I would suspect it would be useful to look at if a 4 week course would be as effective as a 8 week course, but for the moment we treat for 8 weeks.

Dr Sierra: I would like to add my short experience with fecal calprotectin. In the last World Congress in Paris we have presented the relation between the fecal calprotectin with colonoscopic and histologie lesion. In this experience we have included 6 patients with ileocecal Crohn's disease and in the following months we have seen that fecal calprotectin remained high.

Dr Beattie: I think that it is going to be important to follow a quite significant cohort of patients with fecal calprotectin to find out whether we are going to be in a position where we can predict response for a longer term, and we will also find out what the rates of resolution of the inflammation as we might find out a little bit more about duration, it may be that fecal calprotectin as I showed in a small cohort of patients normalizes very rapidly and maybe they would do better with a shorter duration of enterai nutrition whereas it may take more time in others. I think it is a new area that we can find a lot of interesting information from.

Dr Barabino: I would like to make a comment about the question on the use of MRI. We published last year in Pediatrie Radiology our experience about MRI and we found a very good correlation between endoscopie and MRI results and thickness of the wall.

Dr Fell: You mentioned briefly the issue of iron and iron supplementation. In my practice if a child is anemic I try to ignore it because it is difficult to do anything about it apart from dealing with ongoing inflammation. Do you have any recommendation or personal practice with regards to the role of supplementation of parenteral iron or when do you transfuse?

Dr Beattie: I think this is a real worry and I have wrestled the way we are trying to work out what the solution is because it must be the case if our patients remain iron deficient that they are a little bit down from that in the same way that toddlers can be less active as a consequence of iron deficiency. What we do is we provide information on how to increase the amount of iron in the diet, there is a recent paper in Gut, however, which does suggest that high iron containing diets may precipitate relapse. We have been giving just 5-10 mL once a day of iron syrup, so a very low dose of iron, and quite to my surprise that made a number of our children iron replete although this really is an early stage of our observations, but that is what we do. I think with regard to transfusion there has been such a shift against transfusion but I would still in acute ulcerative colitis transfuse them up if the hemoglobin were

Dr Meier: It seems that in children enterai nutrition is more effective than in adults in acute phases. Is there an explanation for this, is there something new to explain these differences?

Dr Beattie: In children I think one of the things that we should say is enterai nutrition is better in newly diagnosed patients than in chronic cases, and we tend to have our patients for a relatively small window of that total Crohn's life and so I guess that one could speculate that it is because we see the patients soon and so it is more of an inflammatory than a fibrotic picture, and also that we are seeing children in a very vulnerable phase, usually it is adolescence where issues like growth and adolescent development, not having too many spots from steroids, and not getting the wrong body image issues from steroids, are major issues. So I think these are the many factors. It may also be, and I have talked about it with gastroenterologists in the UK, that the pediatricians probably have an easier access to psychology and dietetic support although that would probably vary in different parts of the country because the efficacy of enterai nutrition is very much dependent on the strength of your dietetic input, and our dietitians would phone for example the patients on enterai nutrition each week to see how they are getting on. I do wonder, however, whether adults in their 20s and 30s who may not at that time want the potential toxicity of steroids are offered this as a treatment option, and certainly by doing handover clinics you introduce enterai nutrition as a potential treatment option into an adult clinic.

Dr Triantafyllidis: Coming back to the previous comment concerning the administration of iron, I would like to say that all the experimental studies performed in rat models of experimental colitis support the assumption that iron supplementation is harmful for the colitis.

Dr Beattie: I think that is the powerful argument for not giving high dose iron supplements but whether that still is the case if you give very low doses of iron is different. I think that this is something I wrestled with a lot because if you are leaving your adolescent patients a little bit anemic, a little bit iron deficient, then they are probably functioning sub-optimally as a consequence, and this was really a practice that emerged from adult colleagues in Southampton where they use very low dose iron supplements and is a regimen I have found effective.

Dr Arnaud-Battandier: Among the questions we receive, because many of us will have phone calls asking how to use a product, we have a question about ulcerative colitis and the use of Modulen. Do you have any experience, because if we consider there are some anti-inflammatory properties maybe there is some action?

Dr Beattie: There is a group of Crohn's patients which have been alluded to earlier today which almost have an ulcerative colitic phenotype, they have no small bowel disease, just a severe pancolitis, and therefore they are similar to an ulcerative colitic population. I think that is the group of Crohn's patients who respond less well to enterai nutrition, and Dr Sanderson has shown that data. I have no experience of using enterai nutrition in ulcerative colitis as a sole treatment. There is a huge issue however in ulcerative colitis where you have got a protein losing state and need to optimize nutrition through dietetic and nutrition input, but certainly I don't have any experience and would not advocate enterai nutrition as a therapy for ulcerative colitis. I don't know whether anybody else has got any experience with that.

Dr Meier: We have treated some adult colitis patients with Modulen in a severe state, and they tolerated it quite well, and there was no problem, it was comparable with other enterai nutrient solutions.

Dr Sanderson: When you say they tolerate the Modulen do you mean that they improved with the Modulen?

Dr Meier: We could decrease parenteral nutrition (PN) and the patients felt better because they could drink something, they could take something by mouth, and the quality of life was better during the time when they were receiving PN and got some Modulen in addition.

Dr Beattie: But there was no evidence that it helped the inflammation.

Dr Beattie: That would be using it for a different indication because if you got a very sick child who is receiving PN from whatever cause is the source of colitis, and you are going to try and switch the PN to an enterai route and you then give whatever additional nutrition support is best tolerated, certainly in that instance I have tended to go for elemental feeds which are I think probably better tolerated for that group of children.

Dr Meier: They were adults, not children.

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