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Reviews: Yvan Vandenplas, Martin Brueton, Christophe Dupont, David Hill, Erika Isolauri, Sibylle Koletzko, Arnold P Oranje, and Annamaria Staiano Guidelines for the diagnosis and management of cow’s milk protein allergy in infants Arch Dis Child 2007; 92: 902-908 [Abstract] [Full text] [PDF]

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Diagnosis and management of cow's milk protein allergy

Anders O Thuijl, van, Anne Fleur A. Schoemaker, Wim M. C. van Aalderen, Aline B. Sprikkelman   (5 December 2007)

Importance of the definition, pattern and timing of symptoms in the evaluation of cow’s milk protein

Carlos H Larramendi   (28 January 2008)

Diagnosis and management of cow's milk protein allergy 5 December 2007
Anders O Thuijl, van, MD Academic Medical Centre Amsterdam, Anne Fleur A. Schoemaker, Wim M. C. van Aalderen, Aline B. Sprikkelman Send letter to journal: Re: Diagnosis and management of cow's milk protein allergy a.o.vanthuijl{at}amc.uva.nl Anders O Thuijl, van, et al.	Dear editor, With interest we have read the review by VandenPlas and coworkers (1) in which guidelines for the diagnosis and management of cow’s milk protein allergy (CMPA) in infants are discussed and general recommendations with respect to these issues are given. The authors present two diagnostic algorithms, on which we would like to comment. The authors developed separate diagnostic algorithms for exclusively breast-fed and formula-fed infants with a suspicion of CMPA. In both algorithms a clinical assessment divides the flow chart into two branches: suspicion of mild to moderate CMPA or suspicion of severe CMPA. Symptoms that put the child at an immediate life-threatening risk or may interfere with the child’s normal development, differentiate severe from mild to moderate CMPA. Children with a suspicion of severe CMPA are referred to a paediatric specialist and a food challenge will be performed in a hospital setting. Our first comment on the presented diagnostic algorithms concerns the manner at which the diagnosis CMPA is confirmed. Nowadays the food challenge, preferable a double blind placebo controlled challenge (DBPCFC), is the gold standard for the diagnosis of food allergy. The food challenge is part of a diagnostic procedure that includes three phases: elimination of the suspected food, challenge with the suspected food, and re-elimination. For simplicity and socio-economic reasons an open food challenge instead of a DBPCFC is recommended by the authors. It is well known that the diagnosis of food allergy based on an open food challenge will result in large numbers of false positive diagnoses. To limit this number of false positive diagnoses, the diagnostic procedure should include the three phases mentioned above. Unfortunately, in both diagnostic algorithms the re-elimination phase is not mentioned. Second, in the algorithm for formula-fed infants angio-edema and urticaria are described as mild to moderate symptoms. This implies that children with these symptoms are not referred to a paediatric specialist and a food challenge will be performed in a non-hospital setting, with which we strongly disagree. Urticaria and angio-edema are both manifestations of a systemic reaction and are the most common manifestations of anaphylaxis (2;3). No clear data are available that describe the risk of a severe life threatening allergic reaction in children suspected of CMPA with initial symptoms such as urticaria and angio-edema. For other food allergies such as nut allergy, it is known that severity of subsequent reactions can not be predicted by history alone (4). Furthermore, in children with initial mild symptoms such as atopic eczema dermatitis syndrome, acute allergic reactions to cow’s milk after a prolonged cow’s milk protein diet are described (5). In our opinion children with initial symptoms of angio-edema and generalized urticaria are at risk of a similar or even severe allergic reactions when they are challenged with the suspected food. Therefore, a challenge test should be performed in a hospital setting supervised by a medical staff experienced in recognizing and managing severe allergic reactions. Third, the instructions how to perform a food challenge in formula- fed infants are incomplete. The authors propose a challenge protocol with a stepwise increased dose scheme expressed in milliliters formula. No instructions are given about the amount of cow’s milk protein needed in each dose step. The amount of cow’s milk protein is different in each infant formula. Therefore the guideline should provide information about the amount of cow’s milk protein in milligrams needed in each challenge step. Furthermore, no instructions are given by the authors how to perform a food challenge in breast-fed infants. According to the national guideline of the baby health clinics in the Netherlands (6), we propose that a food challenge in breast-fed infants is performed by instructing the mother to drink a stepwise increasing amount of milk on three consecutive days (up to 500ml daily). If symptoms of CMPA re-appear, the challenge is followed up by a re-elimination phase of one week. If no reaction occurs, the mother is instructed to drink 500ml milk each day for the next two weeks and the parents are told to observe the child for late reactions. In summary, children suspected of CMPA need to complete a diagnostic procedure including a re-eliminiation phase to confirm the diagnosis CMPA. Furthermore, children suspected of CMPA with initial symptoms such as urticaria and angio-edema should be referred to a paediatric specialist and a food challenge needs to be performed in a hospital setting. Finally, instructions on how to perform a food challenge should include the amount of cow’s milk protein needed in each challenge step. Reference List (1) Vandenplas Y, Brueton M, Dupont C et al. Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child 2007; 92(10):902-908. (2) Lieberman P, Kemp SF, Oppenheimer J et al. The diagnosis and management of anaphylaxis: An updated practice parameter. Journal of Allergy and Clinical Immunology 2005; 115(3, Supplement 2):S483-S523. (3) Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U et al. Standardization of food challenges in patients with immediate reactions to foods--position paper from the European Academy of Allergology and Clinical Immunology. Allergy 2004; 59(7):690-697. (4) Wang J, Sampson HA. Food anaphylaxis. Clin Exp Allergy 2007; 37(5):651-660. (5) Flinterman AE, Knulst AC, Meijer Y, Bruijnzeel-Koomen CA, Pasmans SG. Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets. Allergy 2006; 61(3):370-374. (6) Kneepkens CM, van Drongelen KI, Aarsen C. Landelijke standaard voedselallergie bij zuigelingen. 5e druk. Den Haag; voedingscentrum, 2005.
Importance of the definition, pattern and timing of symptoms in the evaluation of cow’s milk protein 28 January 2008
Carlos H Larramendi, MD Allergy Unit. Hospital Marina Baixa, La Vila Joiosa, 03570 Alacant. SPAIN Send letter to journal: Re: Importance of the definition, pattern and timing of symptoms in the evaluation of cow’s milk protein chernandol{at}seaic.es Carlos H Larramendi	To the editor, I have read with interest the paper entitled “Guidelines for the diagnosis and management of cow’s milk protein allergy in infants”, by Vandenplas et al., recently published in your journal 1 I think that the paper deals with very important topics, but there are two points that I want to address: First, the paper does not define precisely cow’s milk protein allergy (CMPA), assuming indirectly that all cow’s milk related complains of immunologic or unknown cause are, or can be, “allergic”. The paper states properly that “CMPA results from an immunological reaction to one or more milk proteins.2 This immunological basis distinguishes CMP allergy from other adverse reactions to CMP such as lactose intolerance.5 CMPA may be immunoglobulin E (IgE) or non-IgE associated.6 In IgE-associated cases, CMPA may be a manifestation of the atopic diathesis”. But later on the immunological basis of CMPA seems to be neglected. For example, it discusses largely a paper 2 in which all double-blind placebo-controlled food challenges (DBPCFC) positive subjects are considered as allergic. In fact, DBPCFC is interpreted in the paper as the only diagnostic tool to diagnose CMPA. It can be assumed that for authors, CMPA means any kind of reaction related to milk proteins that can be confirmed by PCDBFC. In that sense, the guidelines can be in some way misleading, because they don’t seem to be intended for the diagnosis and management of CMPA as stated by the authors, but to the diagnosis and management of the whole constellation of cow’s milk protein related complaints of certain (as immediate IgE cow’s milk allergy) or uncertain ethiology (as failure to thrive). I think that this is indeed a very important topic, but it is definitely a different one. As several diseases or syndromes are included in the same bag, it is not surprising that no diagnostic method is presented as fully reliable, because it is difficult to find a test to fit several diseases. So, only elimination diets and cow’s milk challenge are considered as gold standards. Unfortunately, a positive challenge (excluding false positivities), only establishes a link between the food (milk in this case) and the symptoms, but provides no information about the pathogenesis 3. Not all reproducible conditions are allergic (as lactose intolerance, stated by the authors) and not all allergic conditions are easily reproducible (as exercise-induced anaphylaxis in older children and adults). Furthermore, elimination diets can be misleading if several other factors besides the milk (but related to symptoms, as concomitant GORD or coeliac disease) are present, with no or only partial improvement after milk-free diet implementation. I think the guidelines are directed to the diagnosis and management of cow’s milk protein syndromes, one or some of which are clearly allergic, others probably are and others probably are not, and the paper and maybe the title should reflect this fact. Secondly, in my opinion, authors could have divided the patients depending on the time span elapsed until the reaction occurs, data easily accessible to primary care physicians and general paediatricians and with diagnostic and prognostic relevance: Immediate symptoms occurring after milk intake are highly suggestive of immediate allergy (IgE-mediated) to milk proteins. In these cases the possibility of an anaphylactic reaction exists, and even fairly mild or moderate symptoms can precede severe anaphylactic reactions. Subjects with immediate reactions should be put on an elimination diet and should be referred for specialized evaluation. If only mild symptoms (as perioral erithema) have developed, at least a skin test or a specific IgE determination to milk should be performed. Also, in these cases, a positive allergologic study (skin tests, serum determination of specific IgE…) is very reliable 4. If negative, early reintroduction of milk is suggested. If positive, further allergologic study should be performed. In the case of delayed symptoms, the algorithms proposed by the authors will probably work much better. But even in this case, three possibilities exist and all are related to the presence or not of atopic diathesis: In the case of delayed symptoms associated with atopic diathesis, such as atopic eczema, the elimination diet should be implemented and after a period of time the patient should be reassessed, as indicated by the authors. If no differences in symptoms are observed, a challenge test prior to milk reintroduction should be performed with care, due to the possibility of developing an immediate reaction 5. In the case of delayed or chronic symptoms non-related with atopic diathesis, such as failure to thrive, elimination diet should be implemented for the shortest span needed to observe differences in symptoms. If no differences in symptoms are observed, milk should be reintroduced. In the particular case of non-immediate symptoms in which a specific IgE response to milk has been detected, but without any immediate symptom (i.e sensitization to CMP), the diet should be implemented only to evaluate the evolution of the delayed symptoms but not of the IgE, as asymptomatic sensitization to allergens has been described 6, 7. In the case of not observing differences, challenge tests prior to milk reintroduction should be performed again with care due to the possibility of developing immediate reactions 5, 7. In summary, in the algorithms presented, the importance of the time interval between the milk intake and the suspected reaction to milk is not sufficiently stressed. This information is easily accessible in the primary care setting and has important diagnostic relevance. Most infants with immediate symptoms may have IgE mediated allergy to cow’s milk proteins and should be referred for allergologic study, as milk challenges in the primary setting can be risky. On the other hand patients with delayed symptoms can be managed rather well in the way proposed by authors but subjects with atopic diathesis should be assessed with care. The proposed algorithms could be more useful if two additional branches are included, probably as the first step (before the intensity of symptoms): immediate symptoms (less than two hours after milk intake, for example) and non-immediate / delayed symptoms (more than two hours after milk intake). Finally, in my opinion, a clarification of the meaning of DBPCFC and a consensus on the nomenclature of cow’s milk related syndromes are needed. The classification proposed by Sampson of food allergy 8 can be a step on that direction. Carlos H Larramendi MD Allergy Unit. Hospital Marina Baixa 03570 La Vila Joiosa, Alacant. SPAIN chernandol@seaic.es Reference list 1. Vandenplas Y, Brueton M, Dupont C, Hill D, Isolauri E, Koletzko S et al. Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child 2007;92:902-8. 2. Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R, Varjonen E. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr 2002;140:219-24. 3. Bindslev-Jensen C, Skov PS, Madsen F, Poulsen LK. Food allergy and food intolerance--what is the difference? Ann Allergy 1994;72:317-20. 4. García-Ara C, Boyano-Martinez T, Díaz-Pena JM, Martín-Muñoz F, Reche-Frutos M, Martín-Esteban M. Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant. J Allergy Clin Immunol 2001;107:185-90. 5. Flinterman AE, Knulst AC, Meijer Y, Bruijnzeel-Koomen CAFM, Pasmans SGMA. Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets. Allergy 2006;61:370-4. 6. Bousquet J, Antó JM, Bachert C, Bousquet PJ, Colombo P, Crameri R et al. Factors responsible for differences between asymptomatic subjects and patients presenting an IgE sensitization to allergens. A GA2LEN project. Allergy 2006;61:671-80. 7. Larramendi CH, Martín Esteban M, Pascual Marcos C, Fiandor A, Díaz Pena JM. Possible consequences of elimination diets in asymptomatic immediate hypersensitivity to fish. Allergy 1992;47:490-4. 8. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113:805-19; quiz 820.