Food Allergy

Overview and Prevalence:

A food allergy has been defined by the National Institute of Allergy and Infectious Diseases (NIAID) as an “adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food”. The prevalence of food allergies has been estimated to affect 5% of adults and is approaching 8% of children in westernized countries. Food allergy is also dramatically increasing in prevalence. It is not known yet why the increase in prevalence has occurred, but risk factors such as delayed introduction, increased hygiene, genetics, gut flora, vitamin D deficiency, atopy, use of antacids, and obesity have been indicated. There are over 160 foods that cause allergic reactions, but the “big 8” allergens, which account for over 90% of food allergies, are milk, egg, peanut, tree nuts, shellfish, fish, wheat, and soy.

Food sensitivities can be divided into food allergies and food intolerances; individuals can tolerate a higher threshold level of the latter. Food intolerances do not involve the immune system and include anaphylactoid reactions, metabolic food disorders and idiosyncratic reactions. One of the most common food intolerances is lactose intolerance. Affected individuals are not able to metabolize lactose due to a deficiency of intestinal β-galactosidase.

Food allergies are further differentiated into IgE-mediated reactions and cell-mediated reactions. IgE-mediated allergies are reactions to milk, eggs, peanuts, etc. while cell-mediated or non IgE-mediated reactions include celiac disease. IgE-mediated allergies are considered immediate hypersensitivities, while cell-mediated food allergies encompass delayed hypersensitivities with symptoms developing 24-72 hours after exposure to the allergen.

IgE-Mediated Food Allergy:

The IgE-mediated allergic reaction begins through a sensitization phase. Allergen specific IgE antibodies are produced by plasma cells after exposure to foods containing the allergen. This occurs through a TH2 response producing interleukin-4 and -13 which then drive allergen-specific B cells to produce IgE. Sensitization occurs when the allergen-specific IgE becomes attached to the surface of mast cells in the tissues and basophils in the blood.

The second stage of the allergic response is elicitation. Upon exposure to foods containing the allergen, the antigen (allergenic protein) will cross-link the allergen specific IgE molecules on basophils and mast cells. Through degranulation, these cells release mediators such as histamine, leukotrienes and prostaglandins. Histamine immediately increases blood flow and causes smooth muscle contraction. Prostaglandins and leukotrienes cause smooth muscle contraction, increase vascular permeability and stimulate mucus production. The increase in blood flow can carry the mediators to other parts of the body and produce a systemic reaction.

The symptoms of an IgE-mediated allergic reaction are influenced by the amount of IgE present, the route of exposure, and the amount of allergen, therefore, symptoms can range from mild to severe. Mucosal mast cell activation causes diarrhea and vomiting through transepithelial fluid loss and smooth muscle contraction. Hives and itching are produced through mast cell activation in the cutaneous tissues. Respiratory issues such as asthma also occur. The most severe response, although rare, is the systemic reaction of anaphylaxis. This reaction lowers blood pressure, constricts the airways, and swells the epiglottis leading to suffocation.

Food-related acute allergic reactions account for over 200,000 visits per year to emergency departments in the United States. Children under the age of 18 accounted for 25,000 visits per year. Of the emergency department visits, 90,000 each year are probably related to anaphylaxis. Thankfully, food-related fatalities from anaphylaxis are relatively uncommon. From 1994-1999 and 2001-2006, 32 and 31 cases, respectively, of fatal food-induced anaphylaxis were reported. The foods most frequently implicated in fatal reactions were peanuts and tree nuts; milk-related fatalities increased from 1 case to 4 cases between the two time periods. Adolescents and young adults were the most affected age category and of all the fatalities, all but one had asthma. Unfortunately, timely administration of self-injectable epinephrine was not available or used in almost all of the cases. In a study of non-fatal emergency department visits, only 11% of individuals had administered epinephrine. Increased education about the treatment of food-related anaphylaxis, especially to the most susceptible age group, young adults, is necessary.

Natural History of Milk Allergy:

Currently no cure exists for food allergy, so consumption of the offending food must be entirely avoided in order to prevent allergic reactions. Generally, a food allergy will develop in the first two years of life. Resolution of food allergy is less likely for certain allergens than others. Individuals allergic to egg, milk, wheat, and soy have a higher potential for allergy resolution during childhood, but allergies to peanut, tree nuts, fish, and shellfish are more persistent throughout life. An additional predictor of persistent allergy is allergen-specific serum IgE (sIgE) levels; those with higher initial levels are less likely to experience allergy resolution.

Milk allergy is particularly associated with childhood resolution. A consortium of observational studies published in 2013 found that over 50% of subjects had cow’s milk allergy (CMA) resolution by 5 years of age (median). Based on examinations of milk specific-IgE levels, skin prick test (SPT)-induced wheal sizes and atopic dermatitis severity, an algorithm was produced that can predict the resolution of CMA in patients less than 15 months of age. The resolution of milk allergy was greatly associated with lower milk-specific IgE levels, smaller SPT wheal sizes, and the absence of significant atopic dermatitis. The resolution rates of CMA published in the late 1990s indicated 71-87% recovery in children by the age of 3. It was noted that milk protein IgE sensitized infants had an increased risk of persistent CMA. It appears that milk allergy is becoming more persistent.

The effect of including baked milk in the diet on inducing tolerance to milk products was recently investigated. Those that included dietary baked milk in their diets were able to tolerate unheated milk at a faster rate than those that avoided all baked-milk products. Additionally, those that were able to tolerate baked milk were also more likely to have a transient type of IgE-mediated cow’s milk allergy. Individuals with transient milk allergy produce antibodies to conformational (tertiary structure) proteins. As baking destroys conformational milk protein epitopes, these individuals were able to tolerate baked milk. Conversely, those individuals who produce antibodies against sequential epitopes (which are heat-stable) were more likely to have a persistent milk allergy.

Diagnosis of Milk Allergy: 

‘Self-diagnosis’ of food allergy has become more commonplace as the awareness of food allergy grows, but a proper diagnosis is the best course of action. It has been generally found that the population overestimates their allergies. Through a meta-analysis of prevalence data, it was found that 35% of people reporting a reaction to food think that they have a food allergy while the prevalence of food allergy was found to be only 3.5% when considering oral food challenge results.

The recommended components of food allergy diagnosis involve medical history, physical examination, elimination diets, skin prick tests (SPTs), allergen-specific serum IgE (sIgE) measurements, and oral food challenges (OFCs).

The medical history should investigate the types of foods and amounts that were consumed prior to symptoms to determine if any foods are more likely to be related to an IgE-mediated allergy. The timing and analysis of symptoms is of more use when diagnosing immediate hypersensitivity reactions rather than delayed reactions. A physical exam can help to determine if visible symptoms are consistent with an allergic reaction.

The potential trigger foods identified through the medical history are used to evaluate SPTs and sIgE levels. Both of these methods can detect sensitization, but do not determine the severity of the reaction. For example, SPT wheal size is not correlated with allergic reaction severity (the coexistence of asthma is the best predictor of severe reactions). These methods should be used in conjunction as the results will not always correlate (SPTs generally over-diagnose) and neither method should be used solely for diagnosis. sIgE testing measures the presence of allergen-specific antibodies in the serum while skin-prick tests measure IgE bound to cutaneous mast cells.

The results of SPTs and sIgE levels can be further refined through an oral food challenge (OFC). Generally, allergists do not prefer conducting OFCs unless necessary because they are risky, time-consuming and expensive. An elimination diet may be used if the risk of an OFC is particularly high. However, double-blind, placebo[1]controlled food challenges are the gold standard for true food allergy diagnosis. OFCs determine whether the food can be ingested without triggering an immediate clinical reaction. A study of presumed food allergic children found that 89% of OFCs were negative; a proper diagnosis allows an increase in the quality of life and a more robust diet. Finally, a food allergy diagnosis is supported when the OFC is positive and the results correlate with the medical history and laboratory tests.

It should be noted that there are several food allergy diagnosis methods which are not recommended including: intradermal tests, total serum IgE measurements, atopy patch test, applied kinesiology, allergen-specific IgG4, and electrodermal testing.

Component resolved diagnosis (CRD) has been recently developed as a method of food allergy diagnosis. However, CRD is not ready to replace current methods. CRD aims to determine the specific allergenic protein source through analysis of proteins derived from rDNA technology or natural sources. This enables identification of reactivity to allergenic proteins rather than the entire food. This approach is useful when cross-reactivity may be a concern. A challenge associated with CRD is determining the cut-off values for diagnosis. Using CRD for diagnosis of peanut and hazelnut allergies is promising, while conflicting results have been found with other allergens, including milk. 

Prevention and Treatment of Milk Allergy: 

Prevention of Sensitization

Future methods and therapies to prevent food allergen sensitization are gaining research progress and funding recently. The Learning Early about Peanut Allergy (LEAP) study provided a monumental shift in recommendations about introduction times of allergenic foods. The study followed over 500 infants (4-11 months at introduction) with severe eczema or egg allergy and divided them into a group that consumed peanut products regularly and a group that avoided peanut products until 60 months of age. After evaluation at 5 years of age, the avoidance group had a prevalence of peanut allergy of 17.2%, while the consumption group had a peanut allergy prevalence of only 3.2%. Later in 2015, the American Academy of Pediatrics retracted their recommendations about early food avoidance and published interim guidelines that recommended that peanut-containing products be introduced to infants with a high risk of peanut allergy at 4 to 11 months.

Other prevention guidelines have been clarified as more information is obtained. Allergen avoidance during pregnancy and breastfeeding is not recommended. Additionally, exclusive breast-feeding for at least four months is encouraged. A recent study investigated the effect of early introduction of allergenic foods into the diets of breast-fed infants on development of food allergy. The prevalence of food allergy in the early introduction group (3 months age) and the standard introduction group (6 months age) was 2.4% and 7.3%, respectively (in subjects that adhered to the protocol).

Another prevention tactic focuses on adjusting internal environmental exposures by influencing the gut bacteria. Probiotic supplements provide health-promoting bacteria and potentially increase synthesis of IgA and IL-10, suppress TNF-α, inhibit casein[1]induced T-cell activation and CD4, and Toll-like receptor 4 signaling. Consistent results have not been found to determine whether probiotics affect allergy symptoms or tolerance. A study of 119 CMA infants found that the placebo and probiotic treatment groups had no difference in tolerance to cow’s milk after the 12 month treatment period.

Building Tolerance (Desensitization)

Recently, immunotherapy (oral (OIT), sublingual (SLIT), and epicutaneous) approaches have been attempted to desensitize allergic individuals. Currently no oral, sublingual or epicutaneous immunotherapies for foods are recommended for routine treatment, but research on these methods is continuing.

A recent oral immunotherapy trial with 14 CMA children found that 13 children were desensitized at conclusion of the immunotherapy and 6 tolerated milk after one month of milk avoidance. A comparison of OIT and SLIT with CMA children was completed in 2011. The OIT group’s oral food challenge threshold was 6140 or 8140 mg, while the SLIT group’s was 940 mg. SLIT was less effective than OIT, and had less adverse events during treatment. A general consensus of immunotherapy has similarly concluded that OIT is more effective than SLIT. Omalizumab, an anti-IgE monoclonal antibody, has been researched in conjunction with OIT. Three CMA children undergoing OIT had severe reactions and subsequently underwent OIT with omalizumab. The patients reached a cow’s milk dose of 40, 50, or 80 ml after treatment and no moderate or severe reactions were reported (69). Omalizumab is a promising adjunct to improve efficacy and safety of immunotherapy.

An epicutaneous immunotherapy approach for peanuts that utilizes a skin patch has received approval for a phase III clinical trial. The peanut patch delivers the peanut allergen directly to the outermost layers of the skin and is able to activate the immune system and induce desensitization without passing the antigen into the bloodstream. After the phase II study, 50% of patients that took the highest dose patch were able to tolerate 1g of peanut protein during an oral food challenge.

Preventing Elicitation

Currently, no treatment exists for food allergy. Thus, allergen avoidance is essential. Allergic individuals must diligently read labels of packaged foods, and inquire about ingredients and cooking methods when eating at restaurants, air travel, schools, and homes. Many advocacy organizations exist and provide information to allergic individuals and the caregivers, schools, and restaurants that serve them. Research on threshold levels, amount of allergen to elicit an allergic reaction, has been conducted, but no thresholds have been accepted on a regulatory level. The acceptance of thresholds could have a positive impact on necessary precautionary labelling and the variety of foods that allergic individuals can safely consume.

Treatment of Reactions

It is important to attempt to completely avoid the allergen and be prepared to treat allergic reactions or symptoms as they occur. The best way to treat an allergic reaction, especially anaphylaxis, is to administer auto-injectable epinephrine. Unfortunately, that is not understood or applied in many cases. In a study of US food-related emergency department visits, only 16% of patients received a prescription for auto-injectable epinephrine upon discharge. A random telephone survey in the US asked people who could have anaphylactic reactions about their plan for treatment. Only 11% would self-administer epinephrine while others would go to hospital (34%), self-administer antihistamine.

Education about administration of auto-injectable epinephrine and prevention of further reactions through reading of food packaging labels, and proper meal preparation or selection is needed.

For more information, please Chat with us Ask The Expert.