Allergy to cow’s milk is the most frequent food allergy in infants and young children, affecting 2.5% of the population.
The majority of children allergic to cow’s milk proteins acquire tolerance to it spontaneously. Non-IgE-mediated allergy tends to resolve earlier in childhood, whereas IgE-mediated allergy can persist into adolescence and beyond.
The clinical manifestations of cow’s milk allergy include reactions typically mediated by IgE, such as urticaria, angioedema and anaphylaxis; mixed reactions, such as atopic dermatitis or eosinophilic esophagitis, and reactions not mediated by IgE, such as proctocolitis and enterocolitis.
Diagnosis is based on careful clinical history and prick test type tests or specific IgE determinations, and in some cases provocation tests. In the case of non-IgE mid-pictures, the clinical history is essential, and sometimes it is necessary to perform gastrointestinal examinations.
The treatment consists in the avoidance of cow’s milk proteins, extensively hydrolyzed formulas or soy formulas are used. Soy formulas should not be used in cases of predominantly digestive symptoms, in cases that do not tolerate these formulas you have to use elemental formulas based on amino acids. Oral immunotherapy with milk has promising results, but an experimental therapy should still be considered. At present there are no studies with anti-IgE treatment.
Cow’s milk proteins are among the first antigens with which the child has contact, usually the first non-homologous antigen that the child receives in significant quantities. Cow’s milk protein allergy (CMPA) is the most common food allergy pathology in young children, but it is uncommon in adults.
Food allergy to cow’s milk presents a wide variety of clinical symptoms, because immunological responses to cow’s milk proteins can be mediated by immunoglobulin E (IgE) and not mediated by IgE. Adverse reactions to cow’s milk without immune mechanism, such as lactose intolerance or others, are not included in this chapter. There must be a direct relationship between the ingestion of cow’s milk proteins and the onset of symptoms, and the immunological mechanisms must be involved in the reaction.
The APLV affects 2% of children under four years of age and constitutes the most frequent food allergy in the infant and young child. In studies conducted in our country, the APLV corresponds to a quarter of the children affected by any food allergy, and ranks third as a cause of food allergy after eggs and fish.
Acute allergic responses to cow’s milk are mediated by IgE against various allergens in cow’s milk; all cow’s milk proteins are potential allergens and polysensitization to several of them occurs in the majority of patients.
Cow’s milk contains more than 40 proteins, all of which can act as antigens in the human species. Cow’s milk contains caseins (alphaS1, alphaS2, beta and kappa caseins) and seroproteins (alpha lactalbumin [ALA], beta lactoglobulin [BLG], bovine lactoferrin, bovine serum albumin [BSA]), and bovine immunoglobulins, BLG is a protein that does not exist in the human species and is found in breast milk in microgram quantities due to dairy products ingested by the mother, these minimum amounts are the reason why it is the protein with the highest number of sensitizations in the first moment; the proportion of caseins / seroproteins is approximately 80/20 in cow’s milk, a proportion that is artificially modified to achieve formulas adapted for infant feeding; the cooking modifies the allergenicity of the seroproteins, especially BLG, this may explain the better tolerance of the widely heated milk (for example, milk in baked products) 4; Yogurt is also better tolerated by individuals sensitized solely to seroproteins, due to the fermented and acidified milk, which decreases the amount of intact seroprotein.
Clinic due to APLV usually appears during the first year of life when starting artificial lactation in most children, it is exceptional to start during the second year of life, usually after a longer or shorter period of breastfeeding . Patients with APLV can present a wide range of reactions, both mediated and non-IgE-mediated.
In the reactions mediated by IgE, the clinic appears between minutes and two hours after the cow’s milk intake, almost always before one hour elapsed. The intensity of reactions varies from mild to reactions that can compromise the child’s life such as anaphylaxis. Clinical symptoms can affect the skin, oropharynx, upper and lower respiratory tract, gastrointestinal system and cardiovascular symptoms. The vast majority of children (75-92%) have more than one symptom.
Acute dermatological symptoms (erythema, urticaria and angioedema) are the most frequent clinical symptoms. It usually starts with erythema and / or urticaria peribucales, which can later be generalized. With certain frequency, we find infants with APLV whose first and even only manifestation is the intense rejection to bottle feeding of cow’s milk.
Acute gastrointestinal manifestations, vomiting and diarrhea may occur alone, but in 30% of cases are associated with other clinical manifestations. Vomiting is a frequent manifestation of IgE-mediated allergy, but it is exceptional that an immediate sensitization may cause prolonged diarrhea, in some cases the allergy of an immediate type may follow a pattern of acute diarrhea.
The respiratory symptoms consist of rhinoconjunctivitis, recurrent wheezing, stridor and cough, they are exceptional as isolated symptoms in the baby’s age, although they are found accompanying systemic manifestations.
The clinical signs of anaphylaxis are more frequent in the nursing period than in other ages. There are no data on the real incidence and prevalence of anaphylaxis by cow’s milk proteins, although it is known that cow’s milk is one of the most frequent foods with more anaphylactic reactions, fatal or almost fatal.
Clinical symptoms of anaphylaxis can be classified as severe life-threatening symptoms, glottis edema or anaphylactic shock, and generalized symptoms with involvement of more than one organ. Glottis edema begins a few minutes after ingestion and is usually accompanied by urticaria or facial angioedema. Anaphylactic shock begins in the first hour after ingestion, with a progressive decrease in blood pressure; It may or may not be accompanied by other symptoms described. The generalized symptoms tend to have a predominance of cutaneous symptoms, with erythema, pruritus, urticaria and angioedema, accompanied by vomiting, acute abdominal pain or respiratory distress.
IgE and non-IgE reactions can present with acute or chronic symptoms.
In children with atopic dermatitis of moderate to severe intensity at the age of the infant, an etiological study must be carried out and, sometimes, the cow’s milk but, given the nature of the atopic dermatitis, it is necessary to carry out a controlled provocation test to ensure the etiological responsibility of the milk of cow in atopic dermatitis. In these cases the Cow’s milk is the second allergen involved, since the egg is more frequent.
In eosinophilic esophagitis, the most frequent is cow’s milk. These patients have symptoms similar to gastroesophageal reflux, but they do not respond to conventional treatment for him, other frequent symptoms they include dysphagia, abdominal pain, vomiting and impaction Patients with gastroenteropathy eosinophilic symptoms of abdominal pain, nausea, vomiting, diarrhea and loss of weight.
Non-IgE-mediated reactions have a beginning of symptoms later, usually two hours after ingestion.
Allergic enterocolitis: is usually diagnosed in infants and represents the pathology most severe allergic gastrointestinal in this age group. It often happens as response to cow’s milk, but it can occur due to other proteins such as soy milk, cereals, especially rice and meats. Usually start before nine months of age. The Clinical varies depending on the intestinal portion affected; thus, if the affectation is of intestine thin, the clinic consists of vomiting
intense after the ingestion of the causative food, late-onset vomiting, usually between two and four hours after ingesting with great Impairment of general condition, pallor, hypotonia Dehydration and lethargy, usually
without affecting the blood pressure, which can to be followed or not by dyspeptic depositions a few hours later and can reach dehydration. If the affectation is in the portion distal small bowel or colon, the The onset of symptoms is much more insidious, with periods of dyspepsia with soft stools or with explosive and liquid stools that can get to cause impairment of the general state and flattening of the weight curve. The infants they are seriously ill, being able
get to dehydration and up to 46% of them they need income. Infants can present also irritability and abdominal pain
nonspecific. Breastfeeding seems to be a protective factor for induced enterocolitis for food proteins. There is no data described enterocolitis with breastfeeding Exclusive However, when the infant It is fed with adapted milk from birth, it is more frequent the enterocolitis with Greater involvement of colitis with more insidious onset with affectation of the weight curve and greater or lesser affectation of the general state, can reach hypoalbuminemia, along with the characteristics diarrhea and vomiting.
Infants with proctocolitis are characterized for a very good general condition, without impact on its development although it can get to see anemia if it takes to be made the diagnosis. The clinic always starts before six months of age, often before three months, with mucosanguinolentas depositions, with blood Red in breast-fed infants
exclusive maternal or with adapted formula; although it can be produced by others food, cow’s milk is the cause
frequent. After a few days of diet, the clinic usually remits and resolves after a variable period between six months and one year of diet, the most before one year of age. It is due to a inflammatory disorder of the rectum and the secondary colon to the intake of the causative proteins.
Protein-induced enteropathy develops usually before two years of age and often before 12 months. The clinical manifestation consists fundamentally in diarrhea, although it can be associated vomiting, which cause a malabsorptive syndrome In most cases; that start few weeks after the introduction of the causal food. It affects the growth of the infant, both in weight and size. Causes hypoproteinemia with hypoalbuminemia and increase of alpha1 antitrypsin in stool The most frequent causal food is the cow’s milk, but cases have been described with rice, soy, egg, chicken and fish. It is frequent that this clinical manifestation appears after an episode of acute gastroenteritis. The clinical manifestations and intestinal lesions are similar to those observed in the disease celiac; however, enteropathy loses proteins tends to resolve towards two years of age, although there are cases described of malignancy.
Other clinical situations that may occur because of allergy to cow’s milk are the gastroesophageal reflux; the colic of the infant, although the implication of cow’s milk is controversial, in intense cases it should be take into account and carry out a therapeutic test; and chronic constipation, especially if it is refractory to therapeutic measures usual.
The majority of children with APLV tend to get a natural tolerance, the cases do not mediated by IgE are resolved more quickly, The most common is that most these children tolerate milk before two years of age, only some of the cases of enterocolitis They persist until they are four years old.
The prognosis regarding clinical tolerance is favorable in most infants and children small with immediate hypersensitivity to cow’s milk proteins, getting the clinical tolerance of milk proteins in cow 28-56% a year old, 60-77% at two years, 71-87% at three years and 90% at six years If after five years they have not gotten tolerance to cow’s milk, are very few who will achieve it spontaneously.
The APLV is, in many cases, the evidence of a genetic predisposition that is going to express itself in the future with new diseases allergic It has been observed that approximately half of children with APLV develop allergy to other foods and up to 28% allergy to inhalants before three years of age.
For the clinical diagnosis it is essential to elaborate a detailed anamnesis with reference to the presence of family and / or personal background of atopy; the type of power received, maternal, artificial, presence of baby bottles sporadic; the age at the beginning of the symptom; the time elapsed between the intake of milk and the onset of symptoms; the type of symptoms and if factors have existed precipitants.
The history should be completed with an examination detailed physics and, if there are symptoms digestives, search for signs of malabsorption and / or malnutrition.
The search for specific IgE against proteins of full cow’s milk and its fractions protein is done in an attempt to find subgroups of patients with characteristics differentials; So, in a study in our country they find that the increase of casein-specific IgE is related to a greater difficulty to reach tolerance.
Skin tests are usually done by prick test technique, they must be done with correct technique and with extracts standardized The sensitivity of the tests cutaneous shows a great variability (41-100%) due to variations in age and type of clinic of the groups in study. If it is used whole milk and its main proteins for perform the skin tests, they have a negative predictive value (NPV) of 97%, according to a study carried out in our country.
The clinical profitability of the determination of Serum specific IgE in the diagnosis of Immediate allergy to cow’s milk proteins It is similar to that of skin tests. In patients with dermographism or atopic dermatitis to which it is not possible to carry out tests cutaneous, it is essential to make the determination of IgE specific for its diagnosis. Values above 2.5 KUI / l of specific IgE have a positive predictive value of a 90%, so the test of provocation9. Also the value of the specific IgE it can be a useful parameter for tracking of children diagnosed with allergy immediately to cow’s milk proteins, since its decline has been associated with the development of tolerance. Specific IgE has no value in the diagnosis of delayed reactions since, in general, they are not mediated by IgE. The elimination diets can be used in patients with chronic symptoms and skin tests or positive specific IgE; if the patient has not improved after two weeks of strict milk protein exclusion diet of cow, it is unlikely that the APLV is the cause of your symptoms; if after the exclusion diet clearly improves, it must be done a provocation test. The exclusion diets they are quite complicated in children older than one year, since many foods can have amounts of protein vaccines not specified in the labels. The diets of elimination are of great value in the syndromes not mediated by IgE; in cases of proctocolitis, the response period is usually of about two weeks and it is not necessary perform a subsequent exposure test, Given the benignity of the painting, at present the reintroduction of proteins is recommended milk after six months of diet exempt7. The positive response after a diet period of elimination of cow’s milk proteins in children affected with enterocolitis is usually rapid and the vomiting clinic disappears in when there is no contribution of the causal proteins, the response of the diarrhea clinic can be somewhat slower; the same happens in cases of enteropathy from cow’s milk, but also there is a positive response after a period more or less long elimination of protein vaccines in the diet.
The reference pattern to confirm the existence of APLV is the double blind provocation placebo controlled; however, due to how laborious it is and how much time it consumes, it is usually used only in research works or in cases of clinical disagreement and analytical or cutaneous tests11. In the infant, open provocation or in simple blind can be enough if it is negative or when it offers a clear positive result.
The provocation test must be carried out always in a hospital environment, prepared with resuscitation measures, and a detailed record of the amount administered, the time of administration and all incidents that occur in the observation period. The positivity of the provocation test may not be immediate, especially if the patient have been on a strict diet for some time free of cow’s milk proteins, so which, before being considered negative, must be carried out a control after a few days of ingesting cow’s milk proteins.
The provocation protocol proposed by the Spanish Society of Allergology and Immunology Pediatric Clinic is considered safe under the conditions described above.
Once the diagnosis of certainty has been made of APLV, a diet free of Cow’s milk proteins; this diet should be strict9,12. Currently this is the only really effective treatment, they have been used various drugs as preventive of the appearance of symptoms without satisfactory results.
Special care must be taken to inform all family members and people who are child’s charge, since small amounts of Cow’s milk proteins can be found in multiple foods. Unless it is shown sensitization accompanied by demonstrations clinics, it is not necessary to suppress of feeding the beef.
For the feeding of these infants we have of several types of formula, some based of soy proteins, others based on hydrolysates Proteins: casein, seroproteins, casein more seroproteins, or soy more collagen of pork, and elemental formulas based on amino acids.
The milk of other mammals can not be used, goat, sheep, for its protein similarity with cow’s milk.
The formulas based on soy protein whole have a high antigenic potential, although a multicentre Italian study demonstrates that soybean sensitization alone occurs in 6% of children allergic to food, and only one fifth of these They presented positive provocation with soy. These formulas should not be used when enteropathy and malabsorption and, although for some authors they are of choice in the treatment of APLV, its use in infants under six months is questioned.
Soy belongs to the family of legumes, their proteins have no cross-reactivity with cow’s milk proteins. I dont know has long-term studies and studies In the short term, it has been proven that nutritive point of view are suitable for children and adults, but not for newborns, in those that need to be supplemented with amino acids sulfur (methionine). The protein isolated from soy contains 1.5% phytic acid, these are thermostable and are difficult to eliminate, the formed phytates can bind to zinc and make it unusable, in addition, prevent iron absorption. Soy formulas for infants are generously enriched with zinc and provide relatively quantities important iron. The demonstration of normal growth suggests that the use of zinc is adequate and the nutritional status of iron is similar in these infants and in those who receive other formulas based on milk enriched with iron. As in soybean there is a glycopeptide that can decrease uptake iodine thyroid, also require addition of this mineral. Soy formulas have a very high amount of aluminum, manganese and phytoestrogens. The first cause decreased skeletal mineralization in premature infants or with alterations kidney, which contraindicates its use in these children, not causing alterations in he newborn born at term. The high amounts of manganese and its absorption, especially in situations of iron deficiency and the content in phytoestrogens (isoflavones) could cause adverse nutritional effects with its long-term administration that so far They have not been described.
Although soy formulas are safe, in the Currently there seems to be no conclusive indications for its priority use during the first months of life.
Soy formulas are cheaper and have better flavor than milk protein formulas hydrolysed
Another alternative is the formulas to Cow’s milk protein base widely hydrolysed The proteins extensively hydrolysates are derived from milk cow, in which most of the nitrogen it is in the form of free amino acids and peptides <1500 kDa and virtually none > 5000 kDa. These formulas have been submitted to different clinical trials where it is checked its hypoallergenicity. The formulas of extensively hydrolyzed cow’s milk proteins they can produce exceptionally allergic reactions in infants; Nevertheless, given that very sensitized infants may present adverse reactions to these hydrolysates, we must evaluate them previously. Before administering a formula based on these hydrolysates, its tolerance by provocation test open, under the supervision of the specialist. In the position papers of the Society European Pediatric Allergy and Immunology Clínica (ESPACI) and the Spanish Society of Clinical mmunology and Pediatric Allergy (SEICAP) these formulas are recommended for the treatment of the APLV.
Protein hydrolysates are obtained by three main technologies: treatment by heat, enzymatic hydrolysis and a combination of both. Enzymatic hydrolysis to often produces bitter peptides, depending of the enzyme used, the protein substrate and the extent of hydrolysis; the hydrolysis enzymatic is used in formulas based on casein.
The extensively hydrolyzed formulas of Cow’s milk can contain seroproteins, casein or both, no differences have been escribed in the evolution of the allergic clinic with the use of one or another type of formula extensively hydrolyzed, although it seems that they are obtained smaller peptides when uses the enzymatic method. They have been described anomalies of some nutritional parameters with these extensive hydrolyzed formulas (for example, aminogram, urea nitrogen in blood, retention and absorption of calcium and phosphorus), but in most infants They have shown to be safe and effective. The price is greater than that of protein-based formulas of whole soy.
The last therapeutic option available to us are the elementary formulas based on Synthetic amino acids, contain L-amino acids, glucose polymers and vegetable oils; With these formulas there is no risk of adverse reaction, and its main drawback is in the price, which is higher than that of the hydrolysed protein formulas.
Its only nitrogenous source is constituted by synthetic amino acids, mixture of amino acids essential and non- essential, with a profile based on human milk, with fats vegetables, lactose-free and supplemented with trace elements and vitamins.
Some works show satisfactory results in terms of stimulation and maintenance of growth, even higher than hydrolysates, although others show an absorption nitrogenated worse than the formulas of hydrolysates.
At present they have an unquestionable indication in the cases of APLV and non-mediated APLV by IgE, which do not tolerate the formulas of hydrolysates and soy. They are also used as a first option in cases of allergy multiple food.
Based on these considerations we propose a therapeutic algorithm for feeding of APLV-affected infants (Figure 1).
New therapeutic options
Oral immunotherapy with cow’s milk
Children affected by APLV can be classified in two distinct, transient and persistent phenotypes. It is possible that each of them is the result of different immunological mechanisms and require different therapeutic strategies. It seems that children with APLV transient have a more favorable response to treatment with oral immunotherapy. Children with persistent APLV need a longer treatment time, many they do not achieve desensitization and most have more serious adverse effects during the treatment although, on the other part, are the most benefited by such treatment.
Feeds that contain milk widely heated seem to be an alternative to oral immunotherapy with whole milk and are changing the diet paradigm strict exemption of cow’s milk for these children.
Figure 1. Therapeutic algorithm for the feeding of infants affected by protein allergy of cow’s milk
|<6 meses =||<6 months|
|Hidrolizados ampliamente hidrolizados =||Hydrolysates widely hydrolyzed|
|Si no tolera: hidrolizados ampliamente hidrolizados =||If not tolerated: hydrolysed extensively hydrolyzed|
|Si no tolera: fórmula elemental =||If you do not tolerate: elemental formula|
|Hidrolizados ampliamente hidrolizados No soja Fórmula elemental =||Hydrolysates widely hydrolyzed No soy Elemental formula|
|>6 meses =||> 6 months|
|Cualquier edad con clínica digestiva =||Any age with digestive clinic|
Currently there are numerous publications in which the immunotherapy treatment is used oral, but all conclude that it still it’s about an experimental therapy that it must be done only in specialized centers and that they have measures of revival; there are no common criteria in regarding the guidelines to be used and more recently Studies are beginning to appear on safety and adverse effects of this treatment.
Treatment with anti-IgE
Treatment with monoclonal antibodies Humanized anti-IgE produces a decrease in the levels of free IgE and a regulation of the high affinity receptors for IgE (FcεRI), which causes an inhibition of the synthesis of specific IgE. The combination of treatment with anti-IgE and specific immunotherapy is currently being researched to aeroallergens but not for food. There is not studies published in APLV, although it would have the hypothetical advantage of decreasing the risk of associated reactions.
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