JOURNAL OF FOOD ALLERGY EDITORIAL BOARD Official Journal of the Brazilian Society of Food Allergy - SBAA EDITOR-IN-CHIEF Prof. Aderbal Sabra University Unigranrio, Rio de Janeiro, Brazil CONSULTING EDITORS Katie Allen John Walker-Smith University of Melbourne, Melbourne, Australia Emeritus Prof of Paediatric Gastroenterology University of London, Londo, United Kingdom Jaime Ramirez Mayans Marcello Barcinski Instituto Nacional de Pediatría, S.S, Mexico FIOCRUZ, Rio de Janeiro, Brazil Joseph A. Bellanti Georgetown University Medical Center, USA Mauro Batista Morais Paulista School of Medicine, Sao Paulo, Brazil Jorge Amil Dias Centro Hospitalar S. Joao, Portugal Simon Murch Warwick Medical School, United Kingdom Jorge Kalil School of Medicine USP and Annamaria Staiano Instituto Butantan, São Paulo, Brazil University of Naples, Federico II, Italy Giuseppe Iacono Maria Del Carmen Toca Di Cristina Hospital, Italy University of Buenos Aires, Argentina Glenn Furuta Neil Shah Univ. of Colorado Denver School of Medicine, USA Great Ormond Street Hospital Olivier Goulet Institue of Child Health University of Paris 5 René Descartes, Paris, France University College London, United Kingdom Harland Winter Harvard Medical School, USA Journal of Food Allergy Address: Visconde de Piraja, 330 / 311, 22410-001, Rio de Janeiro, Brazil Telephone: + 55 21 2513-2161 E-mail: [email protected] Website: www.journalfoodallergy.com J FOOD ALLERGY JOURNAL OF FOOD ALLERGY Volume 1, Number 2 April - June, 2012 CONTENTS Editor’s Comment Aderbal Sabra.............................................................................................................................................................. 147 Original Articles Gastro-intestinal motility and cow’s milk protein allergy Yvan Vandenplas, Elisabeth De Greef, Thierry Devreker, Bruno Hauser, Gigi Veereman-Wauters ..........................149 Is there a link between Cow´s Milk Protein Allergy and Renal Tubular Acidosis? Cervantes-Bustamante R, Ramirez-Mayans JA, Cadena-León J, Zapata-Castilleja C, Zárate-Mondragón F, Hernández-Bautista V, Montijo-Barrios E, Cazares-Mendez M ................................................................................156 Clinical Features of Eosinophilic Esophagitis in a Consecutive Series of Pediatric Patients in an Australian Tertiary Referral Center Mark Nethercote, Ralf G Heine, Shivani Kansal, Shaun SC Ho, CW Chow, Don Cameron, George Alex, Bircan Erbas, Nicholas Osborne, Luke Stevens, Dominique Davidson, Katrina J Allen ...................................................... 163 Score for the diagnosis of food allergy Aderbal Sabra, Isaac Tenório, Selma Sabra UNIGRANRIO, Service Food Allergy........................................................................................................................ 173 Review Article Ass’s milk in allergy to Cow’s milk protein: a review Pasquale Mansueto, Giuseppe Iacono, Aurelio Seidita, Alberto D’Alcamo, Salvatore Iacono, Antonio Carroccio .. 181 Information for Authors ........................................................................................................................................... 194 J FOOD ALLERGY Editor’s CommEnt Editor’s Comment Issue number two of JFA is proud to offer you the best articles in Food Allergy, produced by leading groups in this field all over the world. Article number one in this issue is from BELGIUN, “Gastro-intestinal motility and cow’s milk pro- tein allergy” by Yvan Vandenplas, Elisabeth De Greef, Thierry Devreker, Bruno Hauser, Gigi Veereman- Wauters UZ Brussel, Vrije Universiteit Brussel, from Brussels, Belgium. This nice paper brings to us extra light in the basic findings of disruption of the GI motor activity in patients with Food Allergy. The motor activity in food allergy compromises the GI transit and is related to reflux, dyspepsia, small bowel distention and constipation. Article number two in this issue is from MEXICO, “Is there a link between Cow’s Milk Protein Allergy and Renal Tubular Acidosis?” by Cervantes-Bustamante R, Ramirez-Mayans JA, Cadena-León J, Zapata-Castilleja C, ZárateMondragón F, Hernández-Bautista V, Montijo-Barrios E, Cazares-Mendez M, Gastroenterology and Nutrition Department, Immunology Department, Instituto Nacional de Pediatría, S.S., from Mexico City, Mexico. This nice paper brings new concepts that must be considered in patients with food allergy and renal tubular acidosis. Article number three in this issue is from AUSTRALIA-UK, “Clinical Features of Eosinophilic Es- ophagitis in a Consecutive Series of Pediatric Patients in an Australian Tertiary Referral Center” by Mark Nethercote, Ralf G Heine, Shivani Kansal, Shaun SC Ho, CW Chow, Don Cameron, George Alex, Bircan Erbas, Nicholas Osborne, Luke Stevens, Dominique Davidson, Katrina J Allen from the Murdoch Childrens Research Institute (MN, RGH, NO, LS, KJA), Department of Gastroenterology & Clinical Nutrition, Royal Children’s Hospital (RGH, SK, SSCH, DC, GA, KJA), Department of Paediatrics, University of Melbourne (RGH, NO, KJA), Department of Allergy & Immunology, Royal Children’s Hospital (RGH, KJA), Depart- ment of Anatomical Pathology, Royal Children’s Hospital (CWC, DD), School of Public Health, LaTrobe University (BE), Melbourne, Australia and European Centre for Environment and Human Health, Peninsula College of Medicine and Dentistry, University of Exeter (NO), United Kingdom, UK. The way cases of EE are rising all over the world and its clinical features present the same perspective in Australia as in UK, as shown in this article by Katie Ellen and her associates. Article number four in this issue is from Rio de Janeiro-BRAZIL, and expresses the experiences of Prof Sabra and his group of associates, which have been dealing with food allergy patients for more than 40 years at the Department of Food Allergy at UNIGRANRIO. His group was the first to describe and publish in Nom-IgE food allergy. The anecdotal way that food allergy is denoted by several clinicians is now on the path to soon disappear. This article is a joy in the way to facilitate the diagnosis of food allergy, based in clinical observation and focused and logical anamnesis, in a disease without good biomarkers in the lab tests for diagnosis. “Score for the diagnosis of food allergy” is the paper, by Aderbal Sabra, Isaac Tenório, Selma Sabra, from the Department of Food Allergy, UNIGRANRIO, Rio de Janeiro, Brazil. Article number five in this issue is from ITALY, a nice revision about the use ass milk in the treat- 147 J FOOD ALLERGY Editor’s CommEnt - Continued ment of food allergy. This paper is from the traditional group of Prof Giuseppe Iacono, a professor with large experience publishing about food allergy for several years. The article “Ass’s milk in allergy to Cow’s milk protein: a review” by Pasquale Mansueto, Giuseppe Iacono, Aurelio Seidita, Alberto D’Alcamo, Salvatore Iacono, Antonio Carroccio, from the Internal Medicine, Policlinico University Hospital of Palermo, (PM, AS, ADA), Pediatric Gastroen terology, “Di Cristina” Hospital (GI, SI), Palermo and Internal Medicine, Hospital of Sciacca (AC), ASP Agrigento, Italy. JFA is proud to announce that in the next issue, number three, in press, we will publish the Consensus in “Caw’s Milk Allergy” by the Latin American Society of Pediatric Gastroenterology, Hepatology and Nutri- tion – LASPGHAN. “Call for papers” for JFA issue four are open. Manuscripts submitted for publication should be sent by e-mail with attached text files and figures to: [email protected] Aderbal Sabra, MD, PhD Editor-in-Chief Journal of Food Allergy 148 J FOOD ALLERGY ORIGINAL ARTICLE Journal of Food Allergy, Vol. 01 (2): 149-155, April-June - 2012 Gastro-intestinal motility and cow’s milk protein allergy Yvan Vandenplas, Elisabeth De Greef, Thierry Devreker, Bruno Hauser, Gigi Veereman-Wauters UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium ABSTRACT Cow’s milk protein allergy (CMPA) causes gastrointestinal (GI) motility anomalies. Diagnostic tests do not reliably differentiate between CMPA and functional GI manifecations. Symptoms of both conditions overlap. A decrease of symptoms with an extensive hydrolysate and relapse during challenge is not a proof of immune mediated reactions, since hydrolysates fasten gastric emptying. And a delayed gastric emptying is a pathophysiologic mechanism of gastro- oesophageal reflux (GER). Thickened formula reduces regurgitation. If a thickened formula does not reduce regurgita- tion, CMPA may be the underlying condition. A thickened extensive hydrolysate may induce more rapid improvement, but does not differentiate between CMPA and GER. Conclusion: As long as there are no objective diagnostic tools to separate GER from CMPA, the physician has two op- tions: first treat the most likely diagnosis, and switch to the other option if after 2-4 weeks there is no improvement. Another option is to treat both conditions with one intervention, what will not result in a diagnosis but induce a more rapid improvement of the complaints. Key words: Constipation, Gastroesophageal Reflux, Lactose Intolerance, Milk Hypersensitivity J Food Allergy. 2012; 1: (2) 149-155 INTRODUCTION The overlap between frequent (functional) more than one organ system is involved (mainly gastro-intestinal complaints such as gastro- gastrointestinal (GI) and cutaneous symptoms, esophageal reflux (disease) (GER(D)) and or GI and more general symptoms or more rare constipation and gastro-intestinal manifestations GI and respiratory tract symptoms), a systemic or of cow’s milk protein allergy (CMPA) are a topic (auto-)immune or allergic reaction is very likely of debate since many years. The debate is the (1). consequence of the fact that objective diagnostic The debate is focused on cow´s milk since criteria for each of the entities are lacking. Since this is the major food allergen in young infants. not one manifestation is specific for CMPA, and While regurgitation decreases strongly between 6 since the same is true for GER(D) and constipation, and 12 months of age (2), tolerance to CMP does and since all conditions are relatively frequent, only develop after the age of one year (1). There it is a fact that some of the allergic infants will is a pathophysiologic overlap: an allergic reaction present with GER(D) and/or constipation and that causes inflammation and secretion of substances some of the infants with GERD or constipation such as histamine, serotonin. The GI-tract reacts to will have CMPA. Many infants with CMPA the inflammation by altering motility. As a result, present symptoms in different organ systems (1). the question raises if there is “coincidence” or if Since gastrointestinal manifestations are only part “one is the logic consequence of the other”. From of the spectrum of symptoms caused by CMPA, the point of view of the gastroenterologist looking this paper does not discuss CMPA in general. If to the GI-tract as an organ responsible for transport 149 Motility and food allergy of food from mouth to anus, regurgitation and are more frequently linked to non-IgE mediated constipation are mainly regarded as “functional allergy. In daily routine, there is no diagnostic disorders”, since anatomic malformations are testing for non-IgE mediated allergic reactions. infrequent. Definitions have been proposed in the But, immunoglobulin free light chains (Ig-fLCs) Rome III criteria (3). dependent allergic hypersensitivity responses have The recent changes in formula been demonstrated to occur (in mice) (4). Also, in composition, such as addition of nucleotides, long children affected with IgE-mediated and non-IgE chain poly-unsaturated fatty acids (LcPUFAs), mediated CMPA or atopic dermatitis (AD), serum prebiotic oligosaccharides and/or probiotics, are Ig-fLC concentrations were increased, implying likely to interfere in this debate. All these novelties the relevance of Ig-fLC measurements in the claim to induce a better immune response and to diagnosis of human allergic disease (4,5). These decrease allergy. They also potentially change GI findings suggest that in the future parameters may tract motility. It is for example claimed that stools become available to contribute to the diagnosis of are softer with the added pre- and probiotics. CMPA, although the overlap between “allergic” Most of the epidemiologic data on CMPA/I date and “non-allergic” children is important (4). The from before these additions. Epidemiologic data relationship between Ig-fLC and gastro-intestinal collected after the formula changes listed above in symptoms has not been investigated. unselected populations are missing. If the claimed The old term “intolerance” gives rise to theoretical benefit results in a clinical benefit, the confusion. In order to avoid this, “intolerance” is incidence of frequent GI complaints should have proposed to be restricted to the incapacity to fully decreased. digest carbohydrates, mainly disaccharides, of CMPA is a reproducible clinically which lactose is the most important one. Primary abnormal reaction to cow´s milk protein (CMP) lactose intolerance is an almost non-existing due to the interaction between one or more milk disease at this age. Thus, if lactose intolerance proteins and one or more immune mechanisms. occurs in infants, it is almost always secondary to About 90% of the patients develop symptoms another disease and the consequence of atrophy or before the age of 3 months depending on the damage of the villi. Low lactase activity may also moment of CMP introduction or within 2 months be the consequence of a transitory slow maturation after introduction. CMPA rarely develops after the in which case the undigested lactose acts as a age of 12 months. Improvement or disappearance prebiotic. As a consequence, the term “adverse of symptoms on a CMP-free diet adds substantial reaction” would be preferable to “intolerance”. evidence to the diagnosis. A factor which often is The question arises how to make the difference not considered is the time needed for improvement between an “allergic reaction of which the of symptoms; the sooner, the more likely that immunologic mechanism involved cannot be allergy may be involved. If the reintroduction of shown in routine” (non-IgE mediated allergy) and CMP causes relapse of symptoms, the diagnosis a “functional” symptom? Bearing this in mind, seems established, since a challenge-test is the term “non-IgE mediated CMPA” will be used considered as the golden standard diagnostic test. to designate this group of infants with adverse Although false positive diagnostic testing reactions to CMP and no increase of specific IgE (specific IgE, skin prick test, patch test) does occur, or no clear positive dermatological contact tests the diagnosis of CMPA is “likely” if patients present such as skin prick or patch tests. with suggestive symptoms and (one of) these test GER(D) has always been mentioned as show(s) positive results. But, CMP can also lead one of the presenting manifestations of CMPA. to non-IgE dependent reactions. Some symptoms Buisseret mentioned “vomiting” as a typical 150 Motility and food allergy presenting symptom of CMPA in a Lancet paper signs and symptoms, the milk volume that in 1978 (5). Forget reported in 1985 a small series provokes the symptoms and to give symptomatic of 15 children presenting with recurrent vomiting, treatment if needed (10). The starting dose during not responding to GER therapy, that became milk challenge should be lower than a dose that symptom-free on a CMP-free diet (6). Difficulties can induce a reaction and increase stepwise to 100 to demonstrate the relation between CMPA and mL (1,10). More details on the practical aspects GER are illustrated in the study by Nielsen et al. (7). of a challenge test are discussed elsewhere (1). To The authors performed a 48 hour pH monitoring rule out a false positive test result due to lactose in infants presenting with GERD and cow milk intolerance the challenge procedure should be hypersensitivity; they could demonstrate that the performed with a lactose-free CMP-containing pH monitoring was more abnormal in infants with milk (10). Challenges should be carried out in a “GERD and allergy” than in the other groups, but hospital setting in the following circumstances: a challenge test did not increase reflux (7). Ravelli a previous history of immediate type allergic et al. used electrogastrography to show that gastric reactions, unpredictable reaction such as in infants motility reacted different to a CMP-challenge in with positive IgE sensitivity who has never been control infants, infants with GERD and infants given cow’s milk or has not been given cow’s with CMPA (8). This abnormal motility could be milk for a long time; severe atopic eczema (due to related to a delayed gastric emptying (8). A cow´s difficulty in assessment) (10). milk challenge increases weakly acidic reflux (pH It is known that a double blind challenge > 4 and < 7) in children with CMPA and GER reduces the number of infants considered (9) Impedance-pH monitoring may therefore be “allergic” after a positive open challenge with useful in identifying a subgroup of infants with about one third (11). Infants that react 24 hours cow’s milk protein-induced GERD (9). or even later to a challenge or react only to large Unfortunately, only rough estimates can volumes, may not be picked-up by a double be made on the prevalence or incidence of GI- blind challenge. Although symptoms during the manifestations of CMPA. The consequence of challenge are most of the time the same as the the definition that not every allergic reaction is original presenting symptoms, this is not a dogma. IgE mediated in combination with the fact that During challenge, presenting symptoms may differ today only IgE-reactivity can be measured in from the original. As said before, infants with non- daily routine is that non-IgE mediated allergy IgE mediated CMPA tends to become tolerant to has become a synonym for intolerance or adverse CMP more rapidly than those with IgE mediated reaction. Studies using a stringent scientific CMPA. The higher the IgE level, the more likely approach focus mainly on IgE mediated allergy the allergy is going to persist (12). This means that and/or a positive challenge test, and report 2 to 5% if a challenge is performed some months after the as the incidence of CMPA. However, up to 10 % initial suspected diagnosis and turns out negative, or even 15% of the infants seem to develop “some it cannot be concluded that the original diagnosis adverse” reactions to cow´s milk. of CMPA was erroneous. A negative challenge There is a quite broad consensus that in only means that at the moment of the challenge the infants a challenge test can be performed “open”, food is tolerated. And a positive challenge does mainly because of the complexity of a double blind not confirm that the immune system is involved. challenge (1). If no symptoms are elicited within Bearing all the above in mind, it seems two weeks of regular cow´s milk feeding, CMPA reasonable to estimate that between 5 to 10 % can be excluded. Challenge tests can be performed of the formula fed infants will develop some in an in-patient or out-patient setting to document 151 Motility and food allergy adverse reaction to CMP. Unfortunately, there include them in guidelines (10). The NASPGHAN- are insufficient data on the number of supposed ESPGHAN guidelines on the management of allergic infants that present “only” with GI regurgitation and reflux, recommend in distressed manifestations. About 20 % of all 3-4 month and regurgitating infants a therapeutic approach old infants regurgitate more than 4 times a day, with either thickened formula or either an and this seems to be a threshold for mothers to extensive hydrolysate (13). If a thickened “regular seek medical help (13). It is probably reasonable infant formula” results in a significant reduction of to estimate the (recent) prevalence of infant episodes of regurgitation, allergy seems unlikely constipation below 5%. Prebiotic-supplemented since protein structure did not change. But what formula is well tolerated by full-term infants. It if an extensive hydrolysate results in a significant increases stool colony counts of bifidobacteria and reduction of regurgitation? Since hydrolysates lactobacilli and results in stools similar to those of have a much faster gastric emptying than native breastfed neonates without affecting weight gain protein, and since delayed gastric emptying is (14,15). The administration of L reuteri (DSM a pathophysiologic mechanism causing GER, 17938) in infants with chronic constipation had improvement of regurgitation with a hydrolysate a positive effect on bowel frequency, even when cannot be considered as a proof of allergy. Partial there was no improvement in stool consistency hydrolysates are not indicated in the treatment and episodes of inconsolable crying episodes (16). of CMPA (1,10). Partial hydrolysates may be In the light of the difficulties to distinguish tolerated in about half of the infants with IgE- between allergy and adverse reactions and mediated CMPA (17). Partial hydrolysates are functional disorder, the question arises if “the also considered to be more “easily digested”, overall prevalence of GI-complaints” could although scientific evidence for this statement not be considered as an equivalent for “IgE and is missing. Several infant formula companies non-IgE mediated” allergy? In order to obtain commercialised thickened partial hydrolysates. As more accurate data on prevalence and incidence, a consequence, a thickened extensive hydrolysate pro-active data collection via questionnaires in may be considered as a treatment option in infants representative population samples is mandatory to presenting with troublesome regurgitation and in minimise the impact of parental coping with these whom “allergy” would be a plausible diagnosis frequent symptoms. on clinical grounds. This attitude would mean In daily primary health care, it is not that a number of non-allergic infants are given easy and possibly even not clinically relevant an extensive hydrolysate for no reason, and that to separate functional disorders from non-IgE a number of allergic infants are given a thickened mediated allergy if therapeutic options tackling formula for no reason. But, up to now there is no both conditions can be offered. Efficacy of certain convincing literature regarding nutritional adverse therapeutic interventions do not help to separate events of a thickened formula or an extensive non-IgE mediated allergy from functional GI- hydrolysate, if cost is not considered. In difficult manifestations. The recommended treatment of cases, amino acid based formula (AAF) may CMPA is elimination of CMP from the mother´s contribute to separate infants with CMPA from diet in breastfed infants, amino acid based formula those with reflux. Indeed, about 5% of the CMPA in formula fed infants with “severe” manifestations infants may still react to an extensive hydrolysate of CMPA (life threatening symptoms, failure to (1). If that is the case, the infant will improve with thrive) or extensive hydrolysates for the majority AAF. Mainly because AAF are very expensive, of infants (1,10). Published evidence with the and because reimbursement systems differ from new rice hydrolysates is too recent and limited to country to country, there is still debate whether 152 Motility and food allergy AAF should be used “first line” (in all infants) or as a “functional disorder” on soy formula exists, “second line” (only in infants not improving on probably with the same frequency as functional eHF). A long-term elimination diet and feeding constipation with regular infant formula. Again, restrictions may lead to intake problems during whether this is “functional” or “non-IgE mediated diversification. In “clear-cut” CMPA, the CM-free allergy” can be debated. Is constipation really a diet is recommended at least during 6-9 months symptom of CMPA? According to data from Italy, and up to the age of 1 year (1). the incidence of constipation is not different in The difficulties to diagnose CMPA atopic and non-atopic children (19). Therefore, strengthen the importance of prevention. Infant constipation as single manifestation of CMPA formula is derived from cow´s milk for the simple seems to be relatively rare. “Anti-constipation reason that there are there are many cows and formulas” have been commercialised. Although because cows provide a lot of milk. There is broad some of these formulas have been evaluated consensus that almost every constituent of cow´s in small trials (20,21), scientific evidence is milk needs to be adapted according to better fulfil very limited. Since extensive hydrolysates are the nutritional needs of infants: the total amount known to cause greenish semi-solid stools, their and proportion of protein, the amount of minerals, use could be considered, although there are no the addition of nucleotides, LcPUFAs, etc. So, data on the efficacy of extensive hydrolysate in why not accept that it would also be preferable to infant constipation. An interaction between GER/ change the structure of the proteins and feed every regurgitation and constipation has been advocated infant a (partial) hydrolysate? Unfortunately, data as well. Frequent regurgitation will result in an showing benefit of doing so are limited to at-risk excessive loss of water, and may therefore be populations. There are very limited data showing considered as a risk factor for constipation. a reduction of CMPA in the general population. In older children, the relation between This is merely the consequence of methodological functional GI disorders and CMPA seems better problems regarding the size of the needed study established. In a case control study; 10/52 subjects populations. There are in absolute numbers more (19.2%) with a diagnosis of CMPA but with a mean allergic children in the non-at risk group than in age of 8.1 ± 4.48 years, met the Questionnaire the at-risk group, for the simple reason that the on Pediatric Gastrointestinal Symptoms Rome non-at-risk group is much larger. III version criteria for diagnosis of an FGID (7 Regarding constipation, a similar irritable bowel syndrome, 2 functional dyspepsia, criticism can be hypothesised. Several studies 1 functional abdominal pain), whereas none in the mentioned constipation as a (frequent) symptom control group did (22). of CMPA. But milk, especially casein, is known to constipate. Hydrolysates are known to cause CONCLUSION soft, greenish stools. One of the studies on CMPA and reflux used soy formula as treatment, thus It is extremely difficult, virtually still avoiding the stool-softening effect of hydrolysates impossible today, to separate “non-IgE mediated (18). However this study can be criticised because allergy” from “functional disorders” in infants it was reported that soy formula was effective in presenting with GI adverse reactions to cow’s 100% of the CMPA allergic infants, while there is milk based formula. consensus that at least some (around 10%) CMPA If more than one organ system is involved, infants develop also allergy to soy. Moreover, the diagnosis of “allergy” is much more likely paediatric gastroenterologists “know” (although than “functional disorder. epidemiologic data are missing) that constipation In distressed infants presenting with 153