ILIE Cristian-Alexandru1, CAMILAR Veronica-Delia1, CRUCEANU Corina-Andreea1, MITITELU Magdalena2*, UDEANU Denisa Ioana2, IONIȚĂ Ana Corina2, DĂRĂBAN Adriana3
1 Pharmaceutical Laboratory Speciality, Faculty of Pharmacy, ”Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest (ROMANIA)
2 Clinical Laboratory and Food Hygiene Department, Faculty of Pharmacy, ”Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest (ROMANIA)
3Phaculty of Pharmacy, „Vasile Goldis” Western University of Arad (ROMANIA)
*corresponding author: email@example.com
Hypersensitivity reactions to food are based on altered immune tolerance mechanisms. The term food hypersensitivity encompasses any adverse reaction caused by food exposure. Food allergies are more common in patients with a history of other atopic diseases, such as atopic dermatitis, asthma and allergic rhinitis. During extraordinary circumstances of the COVID-19 pandemic food insecurity and shortages may make it difficult to find nutritious, allergy-safe food. In regard to seeking medical help for allergic reactions, patients and families may have concerns about the risk of COVID-19 exposure in the Emergency Department. Food allergy is a condition that can lead to considerable morbidity and mortality, have a negative impact on quality of life and can involve high costs in terms of health care.
Keywords: food allergy, food antigens, immune response, COVID-19, food safety, acute allergy management
Allergy is a disproportionate and exaggerated reaction of an organism’s immune system to exogenous antigens (from the external environment) that are well tolerated by normal subjects. In sensitized organisms, allergies are produced by exogenous antigens called allergens. Most allergens are proteins, glycoproteins and, less frequently, pure carbohydrates, small molecule chemicals (isocyanates, anhydrides or formaldehyde), as well as some metals (eg chromium and nickel). The allergic response is an exaggerated reaction of the body’s immune system to the action of the allergen which it perceives as a potential danger. It can be inherited or acquired throughout life after contact with various allergens. The most important mediator of allergy is histamine (responsible for many allergic reactions of the body). When the immune system reacts to an allergen, it produces an antibody called immunoglobulin E (IgE), which is responsible for initiating the release of histamine [1,2]. The symptoms of an allergy persist as long as the allergen is present in the body. The general symptoms of an allergy can occur throughout the body if the substance that triggers the allergy is distributed in the body through the blood (for example, in the case of an allergy to bee or wasp stings). The cardiovascular system is affected, in particular, because the heart rate increases and blood pressure drops. Symptoms of an allergic shock may be manifested by respiratory failure, severe circulation problems, tachycardia, oedema and rash . People living with allergy are anxious and confused about what the current COVID-19 pandemic could mean for them in the short term and the long term: difficulties to find allergy-safe food and the risk of COVID-19 exposure in the hospitals.
The present paper reviews the core topics related to the food allergy with a special accent on COVID 19 pandemic and management of acute allergy during the Covid-19 pandemic, in adults and paediatric populations.
Data search. In order to connect the extended existing knowledge with the current unprecedented situation of COVID-19 pandemic we (1) re-analysed the core topics regarding the food allergies and (2) performed a systematic review on Databases (Google Scholar, Web of Science Core Collection, Medline, BCI, CCC, DRCI, DIIDW, KJD, MEDLINE, RSCI, SCIELO, ZOOREC) on search terms “Food allergy” “COVID 19” “COVID pandemic”, “SARS-CoV-2”, food allergy) AND TOPIC: (covid), on „All years” timespan. Were retrieved 8 results on main topics: acute allergy management, adapted protocols in COVID-19 pandemic, telemedicine in acute allergy, food allergies in children and nutrient supplementation to fulfil the nutritional requirements in the absence of the proper non-allergenic food.
Food allergies are anaphylactic reactions that occur quickly after ingesting allergenic food. Symptoms of a food allergy could be: itching (itching), hives, swelling of the throat, eyes or tongue, nausea, vomiting, diarrhoea, and in more severe cases, low blood pressure, dizziness, fainting and even cardiac arrest. An anaphylactic reaction can develop quickly and can be fatal. People allergic to a certain food may also have allergic reactions to related foods (a person allergic to shrimp may also be allergic to crab or lobster). There are also people prone to such allergies, asthma and food allergy often occur together. Usually, food is tolerated after cooking but there are also protein substances resistant to high temperatures (fish parvalbumin). Sensitization (production of IgE antibodies) to food allergens can occur through the gastrointestinal tract, skin and, less frequently, through the respiratory tract . The symptoms of a food allergy can range from mild to severe, and severe forms can be triggered by subsequent contact with a food that has previously triggered a mild allergic reaction. The most severe allergic reaction is anaphylaxis, a life-threatening allergic reaction that can affect respiratory function or cause a dramatic drop in blood pressure with impaired heart rate. Anaphylaxis can occur within minutes of exposure to trigger foods, can be fatal and urgently requires the administration of epinephrine (adrenaline).
The effects of food processing on food allergens
Any food protein could have an allergenic effect if it could be absorbed in its entirety or in the form of unaltered fragments. But the intrinsic properties of the protein, the overall composition of the food and the processing of any kind of food, have the same effect on the immune response of the human body. During food processing, their allergenic potential can be altered by different parameters. Thus, the allergenic effect can be unchanged, decreased or increased by processing . The molecular basis of changes in the allergenic effect is the inactivation or destruction of epitopes (binding site between antibody and antigen), the formation of new epitopes or the facilitation of access to hidden epitopes by denaturing the native allergen. These changes are important because they affect the ability of antibodies to bind to modified proteins, and in the case of IgE-type antibody binding, it can alter the ability to exert allergic reactions. The main processing methods that can affect the allergenic effect of food are: heat processing, enzymatic hydrolysis, fermentation, high pressure processing and preservation .
Thermal modification of proteins is important in food allergies because heat treatment can bring substantial changes in their allergenic abilities. The magnitude of these changes is influenced by temperature and the duration of the heat processing process. Most often, the loss of the tertiary structure of proteins is followed by its cleavage, the loss of the secondary structure at 55-70o C, the rupture of disulphide bonds at 70-80o C, the formation of new inter- and intramolecular interactions, the rearrangement of disulphide bonds at 80- 90o C, and the formation of aggregates at 90-100o C. Above these temperatures, other chemical changes can occur such as the generation of covalent bonds between lysine residues and other constituents of the protein matrix, generating new molecular adducts. Most of the time, thermal processing destroys epitopes from conformational structures, while linear epitopes can remain unchanged. There is also the possibility that epitopes hidden in unprocessed protein structures, become exposed after heat processing and thus generate allergic reactions . In the case of milk and milk proteins, the degree of structural modification of the proteins depends on both the heating temperature and the type of protein. Casein, for example, is temperature stable because it has no secondary, tertiary or quaternary structures that can be altered by heating. This indicates that heating milk can only partially alter the allergenic potential of milk. It seems that sterilization by heating at 120o C causes the denaturation of 75% of milk proteins, but the IgG binding capacity of α-lactalbumin and β-lactoglobulin increases slightly (the level being considerably below the values obtained by pasteurization). Therefore, in the case of these two proteins, heating can bring to the surface epitopes hidden in them . Egg is a food whose allergenicity is considerably altered by cooking or processing. Egg whites contain proteins with a higher allergenic potential than egg yolks. There are four major allergens in egg whites: ovalbumin, ovotransferrin, ovomucoid and lysozyme. Of these, ovalbumin is sensitive to heat processing, and ovomucoid is the most stable . In a clinical study, 38 patients with a known egg white allergy were tested by administering heated egg white, lyophilized egg white and egg-free egg white. Of these, 21 had a negative reaction to the heated egg white and a positive reaction to the lyophilized egg white, 17 had a positive reaction to both administrations. Of the latter, 16 did not respond to egg white without ovomucoid. This study shows that ovomucoid can be considered the main responsible for allergic reactions, and heat processing only partially changes the body’s response to allergens in egg whites. Another study performed on children allergic to egg proteins shows that up to 85% of them can tolerate the egg if the heating process is prolonged . In the case of peanuts, the type of heating greatly affects the allergenicity. Ara h 1 and 2 proteins develop a different behaviour depending on the type of heat processing. In the case of baking peanuts (dry heat at high temperature), an increase of up to 90% in their allergenic potential is reported. A possible explanation for this behaviour would be the generation of trimers at high temperatures. In contrast, when fried in oil or boiled, the allergenic potential has a slight decrease compared to raw peanuts. These data may explain the geographical differences observed in the prevalence of peanut allergies, with allergies being rarer in countries where they are processed by frying or boiling (China) than in countries where they undergo baking (Western Europe) .
Enzymatic hydrolysis is the most widely used industrial process to reduce protein allergenicity. For example, proteases are used to reduce the allergenic potential of soy, actinase to reduce the allergenicity of rice, and trypsin and chemotrypsin which are used to produce hydrolyzed formulas. The type and degree of hydrolysis depend on the primary structure of the protein, but also on the secondary or tertiary one and on the post-translational changes (eg glycosylation). Most proteolytic treatments generate partial hydrolysis, so not all epitopes are destroyed. Moreover, proteolysis can destroy some epitopes but can also unblock linear epitopes that have been buried in the structure or located in hydrophobic domains of the protein, becoming available for IgE binding. Some peptides resulting from partial hydrolysis are still allergenic because they contain epitopes and / or may form allergenic aggregates. For example, treatments of nuts with trypsin or elastase, soy with protease and wheat with bromelain reduce the likelihood of triggering allergic reactions in sensitized individuals who consume these foods . Biochemical methods of food processing often involve the use of enzymes such as proteases, oxidases or transglutaminases. Although enzyme-mediated proteolysis did not destroy IgE-reactive epitopes in peanuts or peaches, treatment with casein or wheat protein transglutaminase resulted in decreased allergenicity. Biochemical processing of food has a greater potential to modify food proteins than their mechanical handling. Therefore, these methods have a higher potential to reduce food allergenicity. However, in some cases, these methods fail to reduce the allergenic potential, may increase the allergen potential, or may reveal neo-epitopes that have been masked in the native protein but become accessible and / or reactive after protein denaturation / renaturation. Much of current research is dedicated to understanding exactly how traditional food processing methods influence food allergenicity.
A low ability to bind IgE with β-lactoglobulin was observed in fermented milk and yogurt. In these highly pasteurized products, the protein is partially hydrolyzed by the enzymatic activity of the starter culture, which can destroy some epitopes. IgE binding can be prevented by the structure of the protein gel and other aggregates. Lactic fermentation under the action of lactic acid bacteria (Lactobacillus helveticus and Streptococcus thermophilus) also decreased the binding capacity of IgE with α-lactalbumin and β-lactoglobulin in skim milk. There are insufficient clinical data on the effects of milk fermentation on the allergenic potential . Fermentation of soy and its products with bacteria and yeast (eg Lactobacillus plantarum, Bifidobacterium lactis, Saccharomyces cerevisiae) generally reduces the ability of IgE to bind to soy allergens (up to 89%). All tested products containing soy (eg yogurt) have very low immunoreactivity. However, the potential allergen was kept in a soy sauce, a fermented product that contains both wheat and soy. Soy sauces made by fermenting soy protein retain some of the allergenicity in soy (10-30% of that of soy flour) through the fermentation/production process. IgG-ELISA and PCR analysis do not detect allergenic residues left in soy sauce .
High pressure processing
This processing method involves exposing food to extremely high pressures (100-800 MPa) and aims to inactivate microorganisms. High pressure alters the hydrogen bonds in proteins, showing various effects on food allergens present, depending on the structure of the proteins, the types of epitopes involved and the processing conditions. The rice grains, immersed in distilled water, at pressures between 100-400MPa, released allergenic proteins from the composition by solubilizing them. At this pressure, between 0.2 and 0.5 mg / g of rice were released, the maximum amount being obtained at a pressure of 300-400 MPa. In the case of soybean seeds immersed in distilled water and subjected to pressures of 300 MPa in a time between 0-180 min, the solubilized proteins were in a percentage between 0.5-2.5%. No changes in shape, color and size were observed between treated and untreated soybeans. However, in soybean germs obtained by treating seeds at high hydrostatic pressure, a decrease in immunoreactivity was observed, probably due to a better exposure of proteins to enzymatic hydrolysis during germination .
Preservation of food
The most used methods of preserving food, which preserves its nutritional value and organoleptic properties, are pH control, salting, smoking and adding spices and antioxidants. Insufficient data are currently available on the effect of these methods on food allergenicity. The effect of pH on the immunoreactivity of food proteins on processed and unprocessed foods was studied, taking into account a change in protein solubility, combined with heat exposure and a partial induction of protein hydrolysis, with the destruction of epitopes and decrease in allergenicity. The allergens Ana o 1, Ana o 2 and Ana o 3 present in cashews were examined in the range 1-13 of pH together with other processes (bleaching, microwave heating, baking and γ radiation). The study concluded that allergens are stable at pH changes, except at extreme values (1 and 13). Allergenic proteins present in peanuts are altered after incubation with acidic solutions. According to a study, Ara h 1 protein has been considerably reduced to pH 3 and 5 and undetectable to pH 1. Ara h 2 is not affected by pH 5, but decreases as the environment becomes more acidic. Ara h 3 and Ara h 6 are not affected by pH 3 or 5, but are visibly reduced to pH 1. Some preservation methods have been used to reduce food allergenicity, but data are only available on the effects on IgE binding capacity. Treatment with pulsed ultraviolet light (PUV) reduced the binding capacity of IgE in peanut extract cases, while γ radiation had no effect. Also in a soy extract treated with PUV reduced the immunoreactivity Gly m 5, and ultrasound decreased IgE binding capacity in shrimp proteins [11,16,17].
COVID 19 pandemic and the food allergy
In people with food allergy the risk of food allergy and the visits to the hospital should be limited to those unequivocally needed during the COVID-19 pandemic the food pattern should be known and the non-allergenic diet strictly followed but the nutritional needs should be fully covered. As recent estimates indicate that several million people are at risk of contracting COVID-19, uninfected patients with COVID-19 seeking medical care in an emergency situation are obviously exposed. A personal approach of the patient assisted by the doctor at distance generated a revised anaphylaxis algorithm replacing the standard management protocol – during the COVID-19 pandemic. Patients are evaluated according to the symptoms scale and advised to immediately use their epinephrine auto-injector (at least two available in the house) as soon as there are symptoms of a severe allergic reaction; afterwards patients should be distantly monitored for treatment efficacy (wheezing, shortness of breathing, difficulty breathing, throat swelling, faintness, hypotension), if severe symptoms persist or worsen, a second dose of epinephrine should be injected, and if prompt resolution of severe symptoms is not achieved, emergency services should be activated. The home management of the acute (food) allergy supposes a calm, informed and supplied patient and eventually family.
The most popular allergenic foods are: cow’s milk and its derivatives, preparations containing eggs, peanuts, nuts, sesame, poppy, mahogany, soy, fish, cereals containing gluten (wheat, rye, barley), some fruits (kiwi, strawberries, pineapple, coconut), chocolate, coffee, alcohol [18,19,20]. The way food is prepared is also important, so frying can increase the allergenic effect of some foods (seeds, nuts, peanuts and especially peanuts), in other situations by boiling the allergenic effect can be significantly reduced (eggs, soy). Food processing can decrease, not change or even increase the allergenicity of the proteins present. Given the multitude of proteins and very different structures, the action of processing is uncertain and difficult to predict. Although a single type of processing is unlikely to significantly reduce or eliminate an allergenic effect of a protein, IgE binding capacity can be significantly increased by combining two or more processing methods. However, the result is unpredictable.
As in people with food allergy the risk of food allergy and the visits to the hospital should be limited to those unequivocally needed during the COVID-19 pandemic (1) the food pattern should be known and the non-allergenic diet strictly followed (2) the nutritional needs should be fully covered, especially in children and special nutritional needs population (3) in the absence of certain non-allergenic nutritionally essential food the safest choice could be the nutritional supplementation (4) home management of the acute food allergy can limit the infection with SARS-CoV-2 virus in the emergency services units (5) a calm, informed, educated patient for the self-management of the disease will manage correctly the acute allergy with (6) availability of at least two adrenaline pens available and the open line with a doctor in order to evaluate the treatment response.
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