Milk allergy is an adverse immune reaction to one or more proteins in cow's milk. When allergy symptoms occur, those can be rapid or gradual in onset. The former may include anaphylaxis, a potentially life-threatening condition which requires treatment with epinephrine among other measures. The latter can take hours to days to appear, with symptoms including atopic dermatitis, inflammation of the esophagus, enteropathy involving the small intestine and proctocolitis involving the rectum and colon.
In the United States, 90% of allergic responses to foods are caused by eight foods, with cow's milk being the most common. Recognition that a small number of foods are responsible for the majority of food allergies has led to requirements to prominently list these common allergens, including dairy, on food labels. One function of the immune system is to defend against infections by recognizing foreign proteins. It should not over-react to food proteins. Stomach acids cause most proteins to become denatured, meaning to lose 3-dimensional configuration, and thus lose allergenicity. Heat via cooking can have the same effect. Immune tolerance is another safeguard to not over-reacting to food proteins.
Management is by avoiding eating any dairy foods or foods that contain dairy ingredients. In people with rapid reactions (IgE-mediated milk allergy) the dose capable of provoking an allergic response can be a few milligrams, so recommendations are to avoid dairy strictly.
Milk allergy affects between 2% and 3% of babies and young children. To reduce risk, recommendations are that babies should be exclusively breastfed for at least four months, preferably six months before introducing cow's milk. If there is a family history of dairy allergy then soy infant formula can be considered, but about 10 to 15% of babies allergic to cow's milk will also react to soy. The majority of children outgrow milk allergy, but for about 0.5% the condition persists into adulthood. Oral immunotherapy is being researched, but it is of unclear benefit.
Video Milk allergy
Signs and symptoms
Food allergies can have rapid onset (from minutes up to 2 hours), delayed onset (up to 48 hours or even 1 week), or combinations of both, depending on the mechanisms involved. The difference depends on the types of white blood cells involved. B cells, a subset of white blood cells, rapidly synthesize and secrete immunoglobulin E (IgE) a class of antibody which bind to antigens, i.e., the foreign proteins. Thus, immediate reactions are described as IgE-mediated. The delayed reactions involve non-IgE-mediated immune mechanisms initiated by B cells, T cells, and other white blood cells. Unlike with IgE reactions, there are no specific biomarker molecules circulating in the blood, and so, confirmation is by removing the suspect food from the diet and see if the symptoms resolve.
IgE mediated symptoms include: rash, hives, itching of mouth, lips, tongue, throat, eyes, skin, or other areas, swelling of lips, tongue, eyelids, or the whole face, difficulty swallowing, runny or congested nose, hoarse voice, wheezing, shortness of breath, diarrhea, abdominal pain, lightheadedness, fainting, nausea and vomiting. Symptoms of allergies vary from person to person and may vary from incident to incident. Serious danger regarding allergies can begin when the respiratory tract or blood circulation is affected. The former can be indicated by wheezing, a blocked airway and cyanosis, the latter by weak pulse, pale skin, and fainting. When these symptoms occur, the allergic reaction is called anaphylaxis. Anaphylaxis occurs when IgE antibodies are involved, and areas of the body that are not in direct contact with the food become affected and show severe symptoms. Untreated, this can proceed to vasodilation, a low blood pressure situation called anaphylactic shock, and death (very rare).
For milk allergy, non-IgE-mediated responses are more common than IgE-mediated. The presence of certain symptoms, such as angioedema or atopic eczema, is more likely related to IgE-mediated allergies, whereas non-IgE mediated reactions manifest as gastrointestinal symptoms, without cutaneous or respiratory symptoms. Within non-IgE cow's milk allergy, clinicians distinguish among food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP) and food protein-induced enteropathy (FPE). Common trigger foods for all are cow's milk and soy foods (including soy formula). FPIAP is considered to be at the milder end of the spectrum, and is characterized by intermittent bloody stools. FPE is identified by chronic diarrhea which will resolve when the offending food is removed from the infant's diet. FPIES can be severe, characterized by persistent vomiting 1-4 hours after an allergen-containing food, to the point of lethargy. Watery and sometimes bloody diarrhea can develop 5-10 hours after the triggering meal, to the point of dehydration and low blood pressure. Infants reacting to cow's milk may also react to soy formula, and vice versa. International consensus guidelines have been established for the diagnosis and treatment of FPIES.
Maps Milk allergy
Mechanisms
Conditions caused by food allergies are classified into three groups according to the mechanism of the allergic response:
- IgE-mediated (classic) - the most common type, manifesting acute changes that occur shortly after eating, and may progress to anaphylaxis
- Non-IgE mediated - characterized by an immune response not involving immunoglobulin E; may occur hours to days after eating, complicating diagnosis
- IgE and non-IgE-mediated - a hybrid of the above two types
Allergic reactions are hyperactive responses of the immune system to generally innocuous substances, such as proteins in the foods we eat. Some proteins trigger allergic reactions while others do not. One theory is resistance to digestion, the thinking being that when largely intact proteins reach the small intestine the white blood cells involved in immune reactions will be activated. The heat of cooking structurally degrades protein molecules, potentially making them less allergenic. Allergic responses can be divided into two phases: an acute response that occurs immediately after exposure to an allergen, which can then either subside or progress into a "late-phase reaction," prolonging the symptoms of a response and resulting in more tissue damage.
In the early stages of acute allergic reaction, lymphocytes previously sensitized to a specific protein or protein fraction react by quickly producing a particular type of antibody known as secreted IgE (sIgE), which circulates in the blood and binds to IgE-specific receptors on the surface of other kinds of immune cells called mast cells and basophils. Both of these are involved in the acute inflammatory response. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators called (cytokines, interleukins, leukotrienes, and prostaglandins) into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation, and smooth-muscle contraction. This results in runny nose, itchiness, shortness of breath, and potentially anaphylaxis. Depending on the individual, the allergen, and the mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system while eczema is localized to the skin.
After the chemical mediators of the acute response subside, late-phase responses can often occur due to the migration of other white blood cells such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial reaction sites. This is usually seen 2-24 hours after the original reaction. Cytokines from mast cells may also play a role in the persistence of long-term effects. Late-phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils.
Six major allergenic proteins from cow's milk have been identified: ?s1-, ?s2-, ?-, and ?-casein from casein proteins and ?-lactalbumin and ?-lactoglobulin from whey proteins. There is some cross-reactivity with soy protein, particularly in non-IgE mediated allergy. Heat can reduce allergenic potential, so dairy ingredients in baked goods may be less likely to trigger a reaction than milk or cheese. For milk allergy, non-IgE-mediated responses are more common than IgE-mediated. The former can manifest as atopic dermatitis and gastrointestinal symptoms, especially in infants and young children. Some will display both, so that a child could react to an oral food challenge with respiratory symptoms and hives (skin rash), followed a day or two later with a flare up of atopic dermatitis and gastroinstestinal symptoms, including chronic diarrhea, blood in the stools, gastroesophageal reflux disease (GERD), constipation, chronic vomiting and colic.
Diagnosis
Diagnosis of milk allergy is based on the person's history of allergic reactions, skin prick test (SPT), patch test, and measurement of milk protein specific serum immunoglobulin E. A negative IgE test does not rule out non-IgE mediated allergy, also described as cell-mediated allergy. Confirmation is by double-blind, placebo-controlled food challenges, conducted by an allergy specialist. SPT and IgE have sensitivity around 88% but specificity of 68% and 48%, respectively, meaning these tests will probably detect a milk sensitivity but will also be positive for other allergens.
Attempts have been made to identify SPT and IgE responses accurate enough to avoid the need for a confirming oral food challenge. A systematic review stated that for children younger than two years, cut-offs for specific IgE or SPT seem to be more homogeneous and may be proposed. For older children the tests were less consistent. It concluded "None of the cut-offs proposed in the literature can be used to definitely confirm cow's milk allergy diagnosis, either to fresh pasteurized or to baked milk."
Differential diagnosis
The symptoms of milk allergy can be confused with other disorders that present similar clinical features, such as lactose intolerance, infectious gastroenteritis, celiac disease, non-celiac gluten sensitivity, inflammatory bowel disease, eosinophilic gastroenteritis, and pancreatic insufficiency, among others.
Lactose intolerance
Milk allergy is distinct from lactose intolerance, which is a nonallergic food sensitivity, due to the lack of enzyme lactase in the small intestines to break lactose down into glucose and galactose. The unabsorbed lactose reaches the large intestine, where resident bacteria use it for fuel, releasing hydrogen, carbon dioxide and methane gases. These gases are the cause of abdominal pain and other symptoms. Lactose intolerance does not cause damage to the gastrointestinal tract. There are four types: primary, secondary, developmental, and congenital. Primary lactose intolerance is when the amount of lactase declines as people age. Secondary lactose intolerance is due to injury to the small intestine such as from infection, celiac disease, inflammatory bowel disease, or other diseases. Developmental lactose intolerance may occur in premature babies and usually improves over a short period of time. Congenital lactose intolerance is an extremely rare genetic disorder in which little or no lactase is made from birth.
Prevention
Research on prevention addresses the question of whether it is possible to reduce the risk of developing an allergy in the first place. Two reviews concluded that there is no strong evidence to recommend changes to the diets of pregnant or nursing women as a means of preventing the development of food allergy in their infants. For mothers of infants considered at high risk of developing cow's milk allergy because of a family history, there is some evidence that the nursing mother avoiding allergens may reduce risk of the child developing eczema, but the Cochrane review concluded that more research is needed.
Guidelines from various government and international organizations recommend that for the lowest allergy risk, infants be exclusively breastfed for 4-6 months. There does not appear to be any benefit to extending that period beyond six months. If a nursing mother decides to start feeding with an infant formula prior to four months the recommendation is to use a formula containing cow's milk proteins.
A different consideration occurs when there is a family history - either parents or older siblings - of milk allergy. The three options to avoiding formula with intact cow's milk proteins are substituting a product containing either extensively hydrolyzed milk proteins, or a non-dairy formula, or one utilizing free amino acids. The hydrolyzing process breaks intact proteins into fragments, in theory reducing allergenic potential. In 2016 the U.S. Food and Drug Administration (FDA) approved a label claim for hydrolyzed why protein being hypoallergenic. However, a meta-analysis published the same year disputed this claim, concluding that based on dozens of clinical trials there was insuficient evidence to support a claim that a partially hydrolyzed formula could reduce the risk of eczema. Soy formula is a common substitution, but infants with milk allergy may have an allergic response to soy formula. Hydrolyzed rice formula is an option, as are the more expensive amino acid-based formulas.
Treatment
The need for a dairy-free diet should be reevaluated every six months by testing milk-containing products low on the "milk ladder", such as fully cooked, i.e., baked foods, containing milk, in which the milk proteins have been denatured, and ending with fresh cheese and milk. Desensitization via oral immunotherapy is considered experimental.
Treatment for accidental ingestion of milk products by allergic individuals varies depending on the sensitivity of the person. An antihistamine such as diphenhydramine (Benadryl) may be prescribed. Sometimes prednisone will be prescribed to prevent a possible late phase Type I hypersensitivity reaction. Severe allergic reactions (anaphalaxis) may require treatment with an epinephrine pen, i.e., an injection device designed to be used by a non-healthcare professional when emergency treatment is warranted. A second dose is needed in 16-35% of episodes.
Avoiding dairy
Most people find it necessary to strictly avoid any item containing dairy ingredients. The reason is that the individual threshold dose capable of provoking an allergic reaction can be quite small, especially in infants. An estimated 5% react to less than 30 milligrams of dairy proteins, and 1% react to less than 1 milligram. A more recent review calculated that the eliciting threshold dose for an allergic reaction in 1% of people (ED01) with confirmed cow's milk allergy is 0.1 mg of cow's milk protein.
Beyond the obvious (anything with milk, cheese, cream, curd, butter, ghee or yogurt in the name), in countries where allergen labeling is mandatory, the ingredient list is supposed to list all ingredients. Anyone with or caring for a person with a dairy protein allergy should always carefully read food package labels, as sometimes even a familiar brand undergoes an ingredient change. In the United States, for all foods except meat, poultry and egg processed products and most alcoholic beverages, if an ingredient is derived from one of the required-label allergens, then it must either have the food name in parentheses, for example "Casein (milk)," or as an alternative, there must be a statement separate but adjacent to the ingredients list: "Contains milk" (and any other of the allergens with mandatory labeling). Diary-sourced protein ingredients include casein, caseinates, whey and lactalbumin, among others. The U.S. FDA has a recall process for foods that contain undeclared allergenic ingredients. The University of Wisconsin has a list of foods that could may contain dairy proteins, yet are not always obvious from the name or type of food. This list contains the following examples:
There is a distinction between "Contains ___" and "May contain ___." The first is a deliberate addition to the ingredients of a food, and is required. The second addresses unintentional possible inclusion of ingredients, in this instance dairy-sourced, during transportation, storage or at the manufacturing site, and is voluntary, and is referred to as precautionary allergen labeling (PAL).
Milk from other species (goat, sheep...) should not be used as a substitute for cow's milk, as milk proteins from other mammals are often cross-reactive. Nevertheless, some people with cow's milk allergy can tolerate goat's or sheep's milk, and vice versa. Milk from camels, pigs, reindeer, horses, and donkeys may also be tolerated in some cases. Probiotic products have been tested, and some found to contain milk proteins which were not always indicated on the labels.
Cross-reactivity with soy
Infants - either still 100% breastfeeding or on infant formula - and also young children - may be prone to a combined cow's milk and soy protein allergy referred to as "milk soy protein intolerance" (MSPI). A U.S. state government website presents the concept, including a recommendation that nursing mothers discontinue eating any foods that contain dairy or soy ingredients. In opposition to this recommendation, a published scientific review stated that there was not yet sufficient evidence in the human trial literature to conclude that maternal dietary food avoidance during lactation would prevent or treat allergic symptoms in breastfed infants.
A review presented information on milk allergy, soy allergy and cross reactivity between the two. Milk allergy was described as occurring in 2.2% to 2.8% of infants and declining with age. Soy allergy was described as occurring in zero to 0.7% of young children. According to several studies cited in the review, between 10% and 14% of infants and young children with confirmed cow's milk allergy were determined to also be sensitized to soy and in some instances have a clinical reaction after consuming a soy-containing food. The research did not address whether the cause was two separate allergies or a cross-reaction due to a similarity in protein structure, as which occurs for cow's milk and goat's milk. Recommendations are that infants diagnosed as allergic to cow's milk infant formula be switched to an extensively hydrolyzed protein formula rather than a soy whole protein formula.
Regulation of labeling
In response to the risk that certain foods pose to those with food allergies, some countries have responded by instituting labeling laws that require food products to clearly inform consumers if their products contain major allergens or byproducts of major allergens.
In the United States, the Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) requires companies to disclose on the label whether the product contains a major food allergen added intentionally: cow's milk, peanuts, eggs, shellfish, fish, tree nuts, soy and wheat. This list originated in 1999 from the World Health Organisation Codex Alimentarius Commission. To meet FALCPA labeling requirements, if an ingredient is derived from one of the required-label allergens, then it must either have its "food sourced name" in parentheses, for example "Casein (milk)," or as an alternative, there must be a statement separate but adjacent to the ingredients list: "Contains milk" (and any other of the allergens with mandatory labeling). Dairy food listing is also mandatory in the European Union and more than a dozen other countries.
FALCPA applies to foods regulated by the FDA, which does not include poultry, most meats, certain egg products, and most alcoholic beverages. However, some meat, poultry, and egg processed products may contain allergenic ingredients, such as added milk proteins. These products are regulated by the Food Safety and Inspection Service (FSIS), which requires that any ingredient be declared in the labeling only by its common or usual name. Neither the identification of the source of a specific ingredient in a parenthetical statement nor the use of statements to alert for the presence of specific ingredients, like "Contains: milk", are mandatory according to FSIS.
The value of allergen labeling other than for intentional ingredients is controversial. This concerns labeling for ingredients present unintentionally as a consequence of cross-contact or cross-contamination at any point along the food chain (during raw material transportation, storage or handling, due to shared equipment for processing and packaging, etc.). Experts in this field propose that if allergen labeling is to be useful to consumers, and healthcare professionals who advise and treat those consumers, ideally there should be agreement on which foods require labeling, threshold quantities below which labeling may be of no purpose, and validation of allergen detection methods to test and potentially recall foods that were deliberately or inadvertently contaminated.
Labeling regulations have been modified to provide for mandatory labeling of ingredients plus voluntary labeling, termed precautionary allergen labeling (PAL), also known as "may contain" statements, for possible, inadvertent, trace amount, cross-contamination during production. PAL labeling can be confusing to consumers, especially as there can be many variations on the wording of the warning. As of 2014 PAL is regulated only in Switzerland, Japan, Argentina, and South Africa. Argentina decided to prohibit precautionary allergen labeling since 2010, and instead puts the onus on the manufacturer to control the manufacturing process and label only those allergenic ingredients known to be in the products. South Africa does not permit the use of PAL, except when manufacturers demonstrate the potential presence of allergen due to cross-contamination through a documented risk assessment and despite adherence to Good Manufacturing Practice. In Australia and New Zealand there is a recommendation that PAL be replaced by guidance from VITAL 2.0 (Vital Incidental Trace Allergen Labeling). A review identified "the eliciting dose for an allergic reaction in 1% of the population" as 0.01 mg for cow's milk. This threshold reference dose (and similar results for egg, peanut and other proteins) will provide food manufacturers with guidance for developing precautionary labeling and give consumers a better idea of might be accidentally in a food product beyond "may contain." VITAL 2.0 was developed by the Allergen Bureau, a food industry sponsored, non-government organization. The European Union has initiated a process to create labeling regulations for unintentional contamination but is not expected to publish such before 2024.
Lack of compliance with labeling regulations is also a problem. As an example, the FDA documented failure to list milk as an ingredient in dark chocolate bars. The FDA tested 94 dark chocolate bars for the presence of milk. Only six listed milk as an ingredient, but of the remaining 88, the FDA found that 51 of them actually did contain milk proteins. Many of those did have PAL wording such as "may contain dairy." Others claimed to be "dairy free" or "vegan" but still tested positive for cow's milk proteins.
Prognosis
Milk allergy typically presents in the first year of life. The majority of children outgrow milk allergy by the age of ten years. One large clinical trial reported resolutions of 19% by age 4 years, 42% by age 8 years, 64% by age 12 years, and 79% by 16 years. Children are often better able to tolerate milk as an ingredient in baked goods relative to liquid milk. Childhood predictors for adult-persistence are anaphylaxis, high milk-specific serum immunoglobulin E (IgE), robust response to the skin prick test and absence of tolerance to milk-containing baked foods. Resolution was more likely if baseline serum IgE was lower, or if IgE-mediated allergy was absent so that all that was present was cell-mediated, non-IgE allergy. People with confirmed cow's milk allergy may also demonstrate an allergic response to beef, moreso to rare beef versus well-cooked beef. The offending protein appears to be bovine serum albumin.
Milk allergy has consequences. In a U.S. government diet and health surveys conducted in 2007-2010, 6,189 children ages 2-17 years were assessed. For those classified as cow's milk allergic at the time of the survey, mean weight, height and body-mass index were significantly lower than their non-allergic peers. This was not true for children with other food allergies. Diet assessment showed a significant 23% reduction of calcium intake and near-significant trends for lower vitamin D and total calorie intake.
Epidemiology
Incidence and prevalence are terms commonly used in describing disease epidemiology. Incidence is newly diagnosed cases, which can be expressed as new cases per million people per year. Prevalence is the number of cases alive, expressible as existing cases per million people. The prevalence of milk allergy in infants in developed countries is between 2% and 3%. This estimate is for antibody-based allergy; prevalence of allergy based on cellular immunity is unknown. Prevalence declines as children get older. National survey data in the United States collected 2005-2006 showed that from age six and older, the prevalence of serum IgE confirmed milk allergy was under 0.4%. For all age groups, a review of fifty studies conducted in Europe estimated 0.6% confirmed milk allergy.
Society and culture
With the passage of mandatory labeling laws, food allergy awareness has definitely increased, with impacts on the quality of life for children, their parents and their immediate caregivers. In the United States, the Food Allergen Labeling and Consumer Protection Act of 2004 causes people to be reminded of allergy problems every time they handle a food package, and restaurants have added allergen warnings to menus. The Culinary Institute of America, a premier school for chef training, has courses in allergen-free cooking and a separate teaching kitchen. School systems have protocols about what foods can be brought into the school. Despite all these precautions, people with serious allergies are aware that accidental exposure can easily occur at other peoples' houses, at school or in restaurants. Food fear has a significant impact on quality of life. Finally, for children with allergies, their quality of life is also affected by actions of their peers. There is an increased occurrence of bullying, which can include threats or acts of deliberately being touched with foods they need to avoid, also having their allergen-free food deliberately contaminated.
Research
Desensitization, which is a slow process of eating tiny amounts of the allergenic protein, until the body is able to tolerate more significant exposure, results in reduced symptoms or even remission of the allergy in some people and is being explored for milk allergy. This is called oral immunotherapy (OIT). Sublingual immunotherapy, in which the allergenic protein is held in the mouth, under the tongue, has been approved for grass and ragweed allergies, but not yet for foods. Oral desensitization for cow's milk allergy appears to be relatively safe and may be effective, however further studies are required to understand the overall immune response, and questions remain open about duration of the desensitization.
There is research - not specific to milk allergy - on probiotics, prebiotics and the combination of the two (synbiotics) as a means of treating or preventing infant and child allergies. From reviews, there appears to be a treatment benefit for eczema, but not asthma, wheezing or rhinoconjunctivitis. Several reviews concluded that the evidence cannot yet be recommended for clinical practice.
See also
- List of allergens (food and non-food)
References
External links
- Milk Allergy at Food Allergy Initiative
Source of article : Wikipedia
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