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  1. This trial did not actually test IgG testing

    Dear Editor

    I agree that designing an RCT for a dietary treatment is difficult, but some of the factors that have led to this trial being criticised could have been avoided, even within the existing design of the trial.[1] For example, if all those on the 'sham diet' who did not have high levels of IgG to wheat had been asked to avoid wheat, that would have given roughly equal numbers avoiding wheat in both groups, and would have provided a more stringent test of the hypothesis, at least in relation to this key foodstuff.

    It is indeed possible that a small sub-group of IBS patients exists for whom an inflammatory response involving IgG antibodies is part of the mechanism. Unfortunately, the design of the trial does not allow one to distinguish between this possibility as an explanation for the results, and the alternative explanation: that diets avoiding wheat and dairy products, randomly distributed, will help some IBS patients. If there is indeed a sub-group of IBS sufferers for whom IgG testing is relevant, the way to identify them is by a qualitative rather than a quantitative study. For example, one might take blood samples from a group of IBS patients, then put them through a rigorous diagnostic elimination diet using an established protocol. After double-blind placebo-controlled challenges to confirm the foods identified, the results could be compared with IgG levels before the diet. If there is a resaonably good match between the two for some patients, and if those patients remain well while avoiding those foods, it could be concluded that IgG testing had potential predictive value in this sub-group. The inclusion of additional tests and a very detailed history, at the outset of such a trial, might reveal markers that could identify this sub-group in advance.

    The problem with the current trial is that its ambiguities allow it to be used to promote IgG testing to the general public, who are being informed that these results provide unequivocal support for such testing procedures in all IBS patients.[2]

    The letter from Caroccio et al,[3] regarding infants with cow's-milk sensitivity is interesting, especially the finding that the nature of the IgG response varies from one food antigen to another. Their data on IgG against milk antigens need to be viewed in the context of work by other groups, who have not found any consistent pattern of IgG levels to milk proteins in infants with confirmed clinical reactions to milk (whether IgE -mediated or not).[4,5] It is also well known that the IgG response to food in infants is very different from that of older children and adults, as Caroccio et al have confirmed, and the relevance of findings in infants to the screening of adults with IBS is therefore limited.

    References

    1. Whorwell P J, Atkinson W, Sheldon T A. Author's reply [electronic response to Hunter J O. Food elimination in IBS: the case for IgG testing remains doubtful] gutjnl.com 2004 URl direct link to eLetter

    2. See, for example, http://www.allergy-testing.com/index2.html

    3. Carroccio A, Scalici C. Di Prima L, Iacono G. IgG anti-betalactoglobulin in children with IBS symptoms: a valid aid to decide for the elimination [electronic response to Atkinson W, Sheldon T A, Shaath N, Whorwell P J. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl 2004 URL direct link to eLetter

    4. Host A, Husby S, Gjesing B, Larsen J N, Lowenstein H. Prospective estimation of IgG, IgG subclass and IgE antibodies to dietary proteins in infants with cow milk allergy. Levels of antibodies to whole milk protein, BLG and ovalbumin in relation to repeated milk challenge and clinical course of cow milk allergy. Allergy 1992;47:218-229.

    5. Hidvegi E, Cserhati E, Kereki E, Savilahti E, Arato A. Serum immunoglobulin E, IgA, and IgG antibodies to different cow's milk proteins in children with cow's milk allergy: association with prognosis and clinical manifestations. Pediatr Allergy Immunol 2002;13:255-261.

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  2. IgG anti-betalactoglobulin in children with IBS symptoms: a valid aid to decide for the elimination

    Dear Editor

    We applaud the very elegant study by Atkinson and colleagues, who demonstrated that the assay of IgG antibodies to food may have an important role in helping patients and clinicians identify candidate foods for elimination, with consequent significant improvement of irritable bowel syndrome (IBS) symptoms.[1] For more than 10 years we have assayed IgG anti- betalactoglobulin in children to help us in the diagnosis of cow’s milk allergy (CMA) and our experience shows that this assay has a sensitivity between 83% and 96%.[2] Furthermore, despite the evidence that IgG food antibodies can be present in healthy subjects,[3] we found that CMA patients had a higher antibodies level than healthy controls and, choosing an internal laboratory cut-off, the specificity of the assay ranged between 81% and 97%.[2] Furthermore, in children with vomiting, regurgitation or other symptoms indicating a suspect gastro-esophageal reflux (GER), the IgG anti-betalactoglobulin assay can be an important help to distinguish between patients with CMA and patients with GER not due to CMA.[4,5]

    Stimulated by Atkinson and colleagues results, we reviewed our data collected during the past 10 years and focused on children who suffered from symptoms suggestive of IBS diagnosis. A total of 450 patients (201 males; age range 6 months-14 years, median 1 year) with symptoms and laboratory results indicating a suspected IBS diagnosis were included. All patients were consuming cow’s milk and derivatives and in all cases the IgG anti-betalactoglobulin assay was performed at the moment of the first observation at the hospital, using a commercial kit as previously described.[2] The CMA diagnosis was based on: a) disappearance of symptoms when on a cow’s milk-free diet; and b) reappearance of symptoms following a cow’s milk challenge. The challenges were performed according to a double-blind placebo-controlled method previously described.[6] Other diagnoses were excluded according to standard diagnostic criteria and investigation.

    In total, 296 patients suffered from CMA, whereas 154 suffered from IBS not associated to CMA. IgG anti-betalactoglobulin was elevated in 236 of the 296 patients (80%) with proven CMA and in 22 of the 154 (15%) who did not improve on a cow’s milk-free diet (IBS not associated to CMA). Accordingly, the sensitivity and the specificity of the assay in CMA diagnosis for patients with IBS-like clinical presentation were 80% and 85% respectively. We also noted a progressive decrease in the assay sensitivity with increasing age: maximum was 95% for children aged less than 1 year, minimum 50% for children between 6 and 14 years. A further discordant observation was the frequent association of false positive IgG anti-gliadin antibodies (AGA IgG) to elevated IgG anti-betalactoglobulin in CMA patients: in fact, it was recorded in 38 cases (15%). None of these patients suffered from coeliac disease. Although in our experience an isolated IgG AGA positivity can indicate wheat allergy, it is noteworthy that in the IgG AGA positive patients included in this study, the symptoms disappeared and IgG AGA returned to normal on a cow’s milk-free diet which, however, included wheat and its derivatives.

    The diagnosis of food intolerance is often difficult and must be exclusively based on the symptoms recorded on an elimination diet and successive double-blind food challenge. However, ours' and others’[1] results clearly indicate that the help of the IgG anti-food assay would be viewed as an important tool in deciding whether to begin the hard way of the elimination diet or not. We hope that further clinical research can add other positive evidence to these results and fall the bad prejudice on the IgG anti-food assay.

    References

    1) Atkinson W, Sheldon TA, Shaath N, Whoewell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 1459-64.

    2) Iacono G, Carroccio A, Cavataio F, Montalto G, Lorello D, Kazmierska I, Soresi M, Campo M. IgG anti-betalactoglobulin (betalactotest): its usefulness in the diagnosis of cow’s milk allergy. Ital. J. Gastroenterol. 1995; 27: 355-60.

    3) Udall JN. Serum antibodies to exogenous proteins: the significance? J Ped Gastroenterol Nutr 1989; 8: 145-6.

    4) Iacono G, Carroccio A, Cavataio F, Montalto G, Kazmierska I, Lorello D, Soresi M, Notarbartolo A. Gastro-esophageal reflux and cow’s milk allegy in infants: a prospective study. J All Clin Immunol 1996; 97:822-7.

    5) Cavataio F, Iacono G, Montalto G, Soresi M, Tumminello M, Campagna P, Notarbartolo A, Carroccio A. Gastroesophageal reflux associated with cow's milk allergy in infants: which diagnostic examinations are useful? Am. J. Gastroenterol. 1996; 91: 1215-20.

    6) Iacono G, Cavataio F, Montalto G, Florena A, Soresi M, Tumminello M, Notarbartolo A, Carroccio A. Intolerance of cow’s milk and chronic constipation in children. N. Engl. J. Med. 1998; 338: 1100-4.

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  3. Author's reply

    Dear Editor

    John Hunter states that the generally held view is that IgG testing for food intolerance is not of value and gives references in support of this contention.[1] However, the consensus of these papers and others is that the research is of poor quality and better designed studies are needed to resolve this question. Designing trials in this field, which meet all the criticisms that can be levelled at them, is always going to be difficult. However we believe that we have conducted a pretty robust trial, which is the first in the field.

    In his letter Hunter also implies that IBS and food intolerance have the same basis. However, it is entirely possible that IgG antibodies may be important in IBS, where we now know that there is an inflammatory component in some cases, whereas they may not be relevant in food intolerance in general. Furthermore, it is likely that only a subset of patients are likely to have an immuno-inflammatory basis to their condition and these might be the very individuals who respond to dietary exclusion based on IgG antibodies. This would fit with our results where only a proportion of patients responded despite all having antibodies. This, of course, limits the specificity and usefulness of the test unless such subgroups can be identified beforehand. We should also bear in mind that an immunological reaction in the gut, as opposed to other forms of food intolerance, may make the gut more susceptible to other perturbing stimuli such as stress, rather than necessarily causing symptoms directly.

    It is of interest that Hunter singles out the level of IgG to cashew nuts, among other foods, as an anomaly. Since undertaking this study we have been asking patients about cashew nut consumption and found an extraordinary high intake of this item. Of course, we do not know what the level of consumption is in the general population.

    This study was undertaken independently, the data in are the data, they are not overstated and just because they challenge current dogma is not enough reason to reject them without further research. Progress in unravelling the pathophysiology of IBS will only be made if we continue to explore new avenues of research as well as re-examining issues that may have been regarded as unimportant in the past.

    Reference

    1. Hunter J O. Food elimination in IBS: the case for IgG testing remains doubtful [electronic response to Atkinson W et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl.com 2004 URL direct link to eLetter.

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  4. Food elimination in IBS: the case for IgG testing remains doubtful

    Dear Editor

    I have read with interest the study of a diet for IBS based on serum IgG levels to foods.[1]

    In rigorous elimination diet studies, about one third of IBS patients turn out not to have food intolerance.[2-4] Yet everyone tested for food-specific IgG in this study had some positive reactions and was therefore subject to dietary recommendations. This does not suggest that serum IgG is a particularly useful test.

    One notable finding of this study is that 87% of patients gave a high level of IgG to yeast. In two large-scale studies of IBS using diagnostic elimination diets, the percentages who had a symptomatic reaction to yeast when challenged, were 5.5% (out of 73 unselected IBS patients)[2] and 12% (out of 122 unselected IBS patients).[3] It seems implausible that yeast causes IBS symptoms in 87% of patients in Manchester but only 5-12% of patients in Oxfordshire and Cambridgeshire. The logical implication is that high levels of IgG against yeast do not reveal anything significant in relation to IBS symptoms.

    The same must be concluded about several other foods. The numbers of patients with positive responses to eggs, cow's milk and cashew nuts, as judged by IgG levels, are much higher than one would expect from empirical dietary studies,[2,3] while the numbers testing positive to chocolate and oranges are far too low. Again, it seems doubtful that IgG can reveal sensitivities accurately in IBS.

    The percentage of patients showing substantial benefit from this diet is disappointing. In studies using a well-conducted and rigorous elimination diet, the "number needed to treat" is between 1.5 and 2.2.[2-5] The "number needed to treat" in this study diets is 9. (The figure of 2.5, calculated on the basis of those who fully complied with the diet, abrogates the intention-to-treat principle.)

    This poor response to an IgG-based diet confirms the widely held view that IgG testing for food intolerance is not of value.[6-8] These results suggest that if IgG testing identifies food intolerances at all, it does so fortuitously and with a low degree of accuracy.

    The difference in outcome between the "true diet" and the "sham diet" group can largely be explained, not by specific identification of food reactions, but by the gross differences between the two diets. The "true diet" excluded milk products for 84% of patients and wheat for 49% (both foods are known to be common offenders in IBS) while the total number of foods avoided by the group was 498 (figure calculated from Table 2). For the "sham diet" group, 1.3% avoided milk, 8% avoided wheat, and the total number of foods avoided was only 453. These overall differences between the diets can easily explain the modest difference in outcome between the two diet groups. The same diet sheets, distributed randomly to the patients in each group regardless of IgG levels, would probably have produced the same overall result.

    The effectiveness of the blinding in this trial is questionable. The "nutritional advisor" giving support by telephone may have become aware of which patients were receiving the "sham diet" since this regularly excluded potatoes and rice, while the "true diet" rarely did so ? the reverse being true for wheat, milk and yeast. The views of the nutritional advisor on the likely effectiveness of the diets could inadvertently have been communicated to the patients, and influenced their assessment of the outcome.

    Before this trial was begun, it would have made sense to try to answer the more basic research question: do high levels of IgG against a food predict an adverse reaction to that food? Only one very small trial has so far done this.[9] It measured food-specific serum IgG in individual IBS patients and compared the results with those from food challenges (following a period of avoidance): there was no correspondence between the foods identified. Such work needs to be repeated with larger sample sizes.

    References

    1. Atkinson W, Sheldon T A, Shaath N, Whorwell P J. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 1459-1464.

    2. Nanda R, James R, Smith Itch, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut 1989; 30:1099-1104.

    3. Hunter J 0, Workman E, Alun Jones V. The role of diet in the management of Irritable Bowel Syndrome. In Gibson P R & Jewell D P (eds) Topics in Gastroenterology 1985; Vol. 12 Oxford:Blackwell Scientific.

    4. Stefanini GF, Saggioro A, Alvisi V, et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome. diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol 1995; 30:535-41.

    5. Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food. Ann Allergy 1985; 54:538-40.

    6. Barnes RM. IgG and IgA antibodies to dietary antigens in food allergy and intolerance. Clin Exp Allergy 1995; 25 Suppl 1:7-9.

    7. Zar S, Kumar D, Benson MJ. Food hypersensitivity and irritable bowel syndrome. Aliment Pharmacol Ther 2001; 15:439-49.

    8. Teuber SS, Porch-Curren C. Unproved diagnostic and therapeutic approaches to food allergy and intolerance. Curr Opin Allergy Clin Imunol 2003; 3:217-221.

    9. Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food hypersensitivity. Annals of Allergy 1988; 61:47-9.

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  5. Author's reply

    Dear Editor

    Mawdsley et al raises the important question as to whether patients with irritable bowel syndrome (IBS) would gain as much symptomatic improvement if recommended to exclude the top four foods (yeast, milk, whole egg and wheat) compared to an IgG antibody test-based diet.[1] In other words, does the test add specificity? This requires a trial which compares patients receiving an IgG antibody test-based diet to those advised to eliminate some or all of the top four foods. We are currently seeking funding for such a trial.

    There is some evidence however, from our trial that the IgG antibody test-based diet may provide a better response than simply eliminating a standard set of foods. When the change in IBS symptom severity score is compared for fully adherent true and sham diet patients who were advised to eliminate one or more of the top four foods, it is found that the true diet patients experienced a significantly greater reduction than the sham diet patients (difference=94; 95% CI: 18, 170; p=0.017).

    We agree with Carrock Sewell's comment that the food elimination diets in the true and sham groups were not similar in terms of content,[2] although they were for numbers of food types excluded. This was to some extent inevitable given the high prevalence of IgG antibodies to certain foods, such as yeast (86.7%) and milk (84.3%). However, the exclusion was not quite as unbalanced as implied since the so-called sugar foods were allowed in the "yeast positive" patients. Whilst we accept that a more balanced comparison would have been desirable, the principal point of the sham diet was to control for placebo effect. In future more care needs to be taken to match diets not just for number of food types excluded but also for types of food. We are still confident, however, that the difference in symptom improvement observed in our study for the true and sham diet groups is a real one. This is evidenced by the highly significant difference in worsening of symptoms between true and sham groups when patients reintroduced foods they had been asked to exclude (p=0.003).

    References

    1. Mawdsley JE, Irving PM, Makins RJ. IgG antibodies to foods in IBS [electronic response to Atkinson et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl.com 2004URL direct link to eLetter

    2. Carrock Sewell WA. IgG food antibodies should be studied in similarly treated groups [electronic response to Atkinson et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial] gutjnl.com 2004URL direct link to eLetter

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  6. IgG food antibodies should be studied in similarly treated groups

    Dear Editor

    The recent paper by Atkinson et al[1] regarding IgG food antibodies and irritable bowel syndrome (IBS) fails to compare like with like. Regardless of the IgG results, the treatment group excluded significantly different food to the control group, particularly those foods which appear to exacerbate symptoms of IBS. Of particular concern is the 'yeast exclusion' diet. A low yeast diet is not a recognised diet in standard textbooks of dietetics and nutrition. However, alternative practitioners offering such a 'yeast exclusion diet' sometimes recommend exclusion of a wide range of foods such as: bakery products, alcoholic beverages, many other beverages including commercial fruit juices, cereals, condiments, dairy produce, fungi, meat products (hamburgers, sausages and cooked meats made with bread or breadcrumbs), yeast extracts (Bisto, Marmite, Oxo, Bovril, Vegemite, gravy browning and all similar extracts), all B-vitamin preparations, and sometimes most worryingly, 'sugar foods' (sugar, sucrose, fructose, maltose, lactose, glycogen, glucose milk, sweets, chocolate, sweet biscuits, cakes, candies, cookies, puddings, desserts, canned food, packaged food, hamburgers, honey, mannitol, sorbitol, galactose, monosaccharides, polysaccharides, date sugar, turbinado sugar, molasses, maple syrup, most bottled juices, all soft drinks, tonic water, milkshakes, raisins, dried apricots, dates, prunes, dried figs, other dried fruit).

    So regardless of IgG antibody status, the dietary restrictions in one group are not controlled for by the other group, and hence the conclusion may not be valid.

    It would also be helpful to know if any of the patients with IgG antibodies to a particular antigen also had IgE antibodies to the same antigen.

    References

    1. Atkinson W, Sheldon TA, Shaath N et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 1459-1464

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  7. IgG antibodies to foods in IBS

    Dear Editor

    We read with interest the article by Atkinson et al[1]. The authors describe an important advance in our understanding of the putative role of inflammation in irritable bowel syndrome (IBS). However we wonder whether their conclusion that assay of IgG antibodies may have a role in identifying candidate foods for elimination to treat patients with IBS may be a step too far. The four foods to which the patients most commonly formed antibodies and hence the four foods most commonly eliminated from the "true diet", were yeast (86.7%), milk (84.3%), whole egg (58.3%) and wheat (49.3%). The "sham diet" involved eliminating foods to which the patients had not formed antibodies and, therefore, in the sham group the exclusion rates for yeast, milk, whole egg and wheat were very low (0%, 1.3%, 26.7%, and 8% respectively). It is therefore difficult to assess whether a diet excluding these foods would have lead to symptomatic improvement in all patients, regardless of their antibody status.

    Furthermore, the foods to which the study group commonly formed antibodies are similar to those already identified as leading to symptomatic benefit in patients with IBS when excluded from their diet. In a review cited by Atkinson et al,[2] it was noted that in eight trials of exlusion diets in IBS, seven identified dairy products, and five wheat as worsening symptoms. It is not clear whether the difference in improvement in symptoms seen in the current study between true and sham groups can be explained simply by the omission of these foods. This could, in practice eliminate the need for antibody testing.

    References

    1. Atkinson W, Sheldon TA, Shaath N et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004; 53: 1459-1464

    2. Burden S. Dietary treatment of irritable bowel syndrome: current evidence and guidelines for future practice. J Hum Nutr Dietet 2001;14:231-41

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