Food Allergy: Clinical Guidelines

List of Abbreviations

Terms and Definitions

Food allergens – are any substances, most often of protein nature, that stimulate IgE production or cellular immune response.

Elimination diet – a diet that excludes the causally significant allergen.

Diagnostic food challenge – a diagnostic procedure involving the trial introduction of small quantities of a food or foods previously excluded from the diet to assess the clinical response.

Food hypersensitivity (intolerance) – adverse reactions to food not mediated by immune mechanisms (food reactions not involving T- and B-cells, or IgE).

Oral allergy syndrome – manifestations of food allergy caused by cross-sensitization to pollen allergens, characterized by pruritus and/or mild edema of the oral cavity and laryngeal mucosa; acute symptoms of allergic rhinitis may also be present.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Food allergy (FA) – an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food (specific IgE-mediated reactions, cell-mediated immune responses (non-IgE-mediated), or a combination of both – mixed-type reactions). The use of the term "food hypersensitivity" in relation to immunologically mediated reactions to food is currently inappropriate [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

In the vast majority of cases, the causally significant allergens in FA are food proteins, both simple and complex (glycoproteins), less commonly polypeptides or haptens bound to food proteins. The molecular weight of most food allergens ranges from 10,000 to 70,000 Da [1, 2, 5].

The ability of a food protein to act as an allergen in genetically predisposed individuals depends on the presence of structural motifs – "epitopes" – capable of activating a Th2 immune response and inducing IgE antibody production [1, 5].

In addition, the quantity of antigenic molecules entering the body's internal environment is significant. Thus, impairment of the barrier function of the skin and gastrointestinal tract leads to excessive contact between antigen-presenting (dendritic) cells and various allergens, triggering a cascade of immune reactions and sensitization [6]: the production of specific IgE antibodies and an increase in the number of high-affinity receptors for them on the surface of immunocompetent cells.

Food allergens – any substances, most commonly of protein nature, that stimulate IgE production or a cellular immune response.

The so-called "big eight" foods most commonly causing allergic reactions include: cow's milk, hen's eggs, peanuts, tree nuts, fish, seafood, wheat, and soybeans [1-4]. Food allergens may alter their antigenic properties during the culinary processing of foods. Thus, protein denaturation upon heating causes some foods to lose their allergenicity, while others, conversely, become more allergenic [1, 2, 5].

Cow's milk protein (CMP) – the leading clinically significant allergen in early childhood [1, 2, 4, 5, 9]. The peak incidence of CMP allergy occurs during the child's first year of life. According to previous studies, the prevalence of CMP allergy in Europe was 2-3% among infants [6, 12, 19]; recent trends, including those identified by the volume of extensively hydrolyzed and amino acid formulas prescribed, demonstrate signs of overdiagnosis of CMP allergy in infants [7, 12, 132, 142]. Meanwhile, oral food challenge-confirmed CMP allergy has been documented in European and other studies in only 1% of infants, whereas various transient conditions occurring in infancy are overly interpreted as allergy in 15-20% of children [7, 132]. The overall prevalence of oral food challenge-confirmed CMP allergy in children under 2 years of age was 0.54%, with prevalence ranging from 0% to 1.3% in various countries [7, 142]. It has been shown that 50% of children with CMPA outgrow it within 1 year [7].

According to generalized data, by 4, 8, 12, and 16 years of age, 19%, 42%, 64%, and 79% of children, respectively, develop tolerance to CMP; this occurs earlier in non-IgE-mediated forms of allergy [4, 8].

Virtually any animal milk protein component can induce sensitization, but the most common are: β-lactoglobulin (Bos d 5), α-lactalbumin (Bos d 4), bovine serum albumin (Bos d 6), and γ-globulin, as well as α- and β-caseins (Bos d 8) [1, 2, 4]. On average, up to 70% of children with cow's milk protein allergy are tolerant to boiled milk [72]. α-lactalbumin, β-lactoglobulin, and bovine serum albumin are heat-labile proteins, so sensitization to them is a predictor of reaction to thermally unprocessed milk [19, 131]. Unlike the aforementioned proteins, casein is heat-stable. The presence of such sensitization may indicate milk intolerance in any form [20, 72, 131]. In addition, bovine serum albumin is the major beef allergen, which can cause cross-reactions in 13-20% of children with CMPA when consuming raw or undercooked meat; prolonged heat treatment prevents the development of such reactions [102, 131]. Milk from other mammals, including goat's milk, also possesses allergenic properties. Furthermore, goat's milk can act as a cross-reactive allergen in patients with CMPA with a frequency of over 85%, and can also serve as an independent allergen, causing severe reactions in patients tolerant to cow's milk. The use of adapted infant formula in the first hours and weeks of a child's life is of great importance in the pathogenesis of cow's milk protein allergy (CMPA) in young children, leading to excessive intake of foreign protein, which, against the background of intestinal barrier and immune response immaturity, leads to early sensitization to CMP [10, 104]. However, breastfed infants can also develop clinically significant CMPA due to transcutaneous sensitization or the passage of food proteins into breast milk (in rare cases) [12, 138].

In chicken eggs, 13 protein allergens have been identified, among which the most significant are ovomucoid (Gal d 1) – a heat-stable protein, ovalbumin (Gal d 2), conalbumin/ovotransferrin (Gal d 3), lysozyme (Gal d 4), ovoglobulin, as well as egg yolk livetin (Gal d 5) – heat-labile proteins. The heat lability of some of these determines the fact that about 60-70% of patients with hen's egg allergy are able to tolerate small amounts of egg proteins in extensively heat-processed foods [73]. Nevertheless, a high level of sensitization to ovomucoid is a predictor of hen's egg intolerance regardless of the preparation method [10, 74].

According to two large population-based studies, manifestations of egg allergy resolved in 45-47% of children by 2 years of age, in 66% by 4 years of age, and in 71% of children by 6 years of age [80, 81].

Soy. Soybeans or products containing soy protein can frequently cause allergic reactions. It is a so-called hidden allergen, as it is often used in food products as a texturizer, emulsifier, and protein supplement. In pediatric practice, sensitization to soy occurs in approximately 0.4% of cases, and about 70% of patients outgrow it with age [78, 79].

The most pronounced allergenic activity is exhibited by: glycinin – 11S globulin (Gly m 6), 7S globulin (Gly m 5) and conglycinin (β and γ-fractions), especially its β-fraction, 2S albumin (Gly m 8). Detection of specific IgEs to Gly m 5 and/or Gly m 6, Gly m 8 may be associated with systemic reactions [25]. The presence of antibodies to Gly m 4 (PR-10 family) may manifest as oral allergy syndrome, but in the case of concomitant birch sensitization, the consumption of uncooked soy in such patients can provoke severe reactions and anaphylaxis [131]. Isolated sensitization to profilin or soy glycoproteins is accompanied by mild symptoms of oral allergy syndrome or no clinical manifestations and indicates tolerance to heat-processed soy [24-27].

Peanuts, like peas, beans, and soybeans, belong to the legume family. Peanut proteins contain a wide spectrum of allergens: vicilin, profilin, conglutin, glycinin, etc. Peanuts are widely used in the food industry and frequently become a so-called hidden allergen. Sensitization to peanut epitopes Ara h 1, Ara h 2, Ara h 3, Ara h 6/7 is associated with severe reactions to this product [131]. Roasting and boiling enhance its allergenic properties. Peanut allergy is widespread, characterized by severe reactions, including anaphylaxis; only 20% of children with sensitization appearing in the first 2 years of life subsequently develop tolerance [2].

It has been established that up to 50% of anaphylactic reactions in children and adolescents in Europe and America are associated with sensitization to peanuts and tree nuts [102].

The nut group includes walnuts, pecans, pistachios, cashews, Brazil nuts, beechnuts, chestnuts, hazelnuts, almonds, macadamia nuts, and others. Manifestations of IgE-mediated nut allergy can be characterized by both severe symptoms with primary sensitization to these products and oral allergy syndrome occurring in patients with seasonal allergic rhinitis [75]. When cross-allergy to nuts develops, symptoms are usually mild and localized in the oropharynx (sometimes accompanied by acute allergic rhinitis), and specific IgEs are produced against heat-labile proteins, PR-10 homologs found in pollen. Anaphylaxis in the presence of isolated sensitization to the PR-10 protein group can occur, but is rare [75]. Nuts such as cashews, hazelnuts, walnuts, almonds, and others contain 7S storage proteins and 11S globulins and 2S albumin, which exhibit pronounced allergenic properties and lead to cross-reactions between different nut species. Important proteins of hazelnut and cashew are Cor a 14 and Ana o 3, respectively, sensitization to which is highly likely to be associated with the development of food allergy to them [3, 131]. Up to 75% of children with nut allergies have simultaneous sensitization to various types of nuts, which often develops already in childhood [76].

Cereal proteins. Allergic reactions to cereal products are quite common, primarily to wheat gliadin, rye, barley, and oat gluten, and less commonly to corn, rice, and buckwheat proteins. Sensitization to cereals usually develops no earlier than the second half of life against the background of complementary feeding. Sensitivity to ω-5-gliadin (Tri a 19) indicates a high risk of immediate reactions in children, as well as severe systemic reactions induced by physical exertion in adolescents and adults. Isolated sensitization to profilin or wheat glycoproteins is usually characterized by manifestations of oral allergy syndrome or the absence of clinical symptoms, as well as the development of tolerance to heat-treated wheat. By the age of 4 years, more than 50% of children develop tolerance to gliadin [28-30].

Fish and seafood. The sarcoplasmic protein from the parvalbumin group possesses the most allergenic properties, characterized by high thermostability and practically not being destroyed during cooking. Thus, the thermostable sarcoplasmic protein — cod M-protein — passes into the vapor distillate during boiling, has a specific odor, and becomes an inhalant allergen for sensitized individuals. Parvalbumins of various fish species often have a homologous structure, which explains the wide spectrum of cross-sensitization to various fish species in most patients. Nevertheless, its structure may vary. This explains the existence of cases of monosensitization to certain fish families. Currently, species such as cod, salmon, pollock, and herring are considered the most allergenic [77]. Fish and seafood allergens are capable of causing severe systemic reactions when even extremely small amounts enter the body, including through the inhalation of vapors (inhalant allergen exposure) during fish cooking. Fish allergy rarely tends to decrease with age, often persisting in adolescents and adults. However, according to recent data, in 45% of children, fish allergy resolves by adolescence [3].

Seafood, possessing pronounced allergenic properties, includes crustaceans (shrimp, crabs, crayfish, lobsters) and mollusks (mussels, scallops, oysters, squid, octopus, etc.). Seafood allergy can be severe, up to anaphylaxis; as a rule, it is observed throughout life or may first appear in adulthood [138]. This is due to the fact that the absolute majority of proteins are thermostable. Some proteins, such as shrimp tropomyosin (Pen m 1), show cross-reactivity with house dust mite allergens [77, 131].

Age-related features of food sensitization

It has been established that the frequency of allergies to various foods changes with age. Tolerance may develop to such products as cow's milk, chicken egg, wheat, and other cereals. At the same time, food allergy can debut both in adolescence and in adulthood [138], which may be due to the prolonged exclusion of a certain product from the diet and the loss of tolerance to it; allergy to red meat that arose after a tick bite ("alpha-gal syndrome", associated with sensitization to the galactose-alpha-1,3-galactose (gal) molecule, which is expressed in most mammalian tissues); occupational activity, or other undetermined causes [59, 60].

Cross-allergic reactions. Cross-allergic reactions to various foods, as well as other allergens (mainly pollen and epidermal), which are caused by the presence of structurally similar proteins in their composition (Appendix A3.3), are of great practical importance.

Non-specific hypersensitivity reactions to food products and components

Some children may be sensitive to products containing histamine or enhancing its release from mast cells. The pathogenesis of such reactions is based on the non-specific release of mediators (mainly histamine) from target cells. Most frequently, such reactions develop after the consumption of products rich in histamine, tyramine, and histamine liberators; manifestations are usually "dose-dependent" and not severe (see Appendix A3.4). Complete exclusion of the product in this case is extremely rarely required; usually, it is sufficient to select a tolerated amount.

Reactions to food additives and other chemical substances contained in foods. The prevalence of reactions to food additives in the general population is 0.01-0.2%, whereas in patients with atopy it ranges from 2 to 7%. Anaphylactic reactions may develop in response to the consumption of products containing additives of natural origin obtained from plants, insects, or animals: annatto (E160b), carmine (E120), saffron, erythritol (ERT), guar gum (E412), carrageenan, gelatin, pectin (IIB) [22]. Sulfites and their derivatives, salicylates, benzoic acid (E210) and its derivatives (E211-E219), as well as tartrazine (E102), are the additives most frequently causing exacerbation of bronchial asthma [22]. Sensitivity to sulfites among patients with bronchial asthma is 5%. About 2.5% of the adult population in European countries possess sensitivity to salicylates, including those contained in food products. In general, it is higher in patients with concomitant acetylsalicylic acid intolerance [22, 31].

1.3 Epidemiology of the Disease or Condition

Data on the frequency of food allergy vary significantly [3, 12]. Manifestations of food allergy occur in an average of 3-10% of children and up to 10% of adults [3]. Of course, the problem is especially relevant in infancy and early childhood [1, 5]: thus, in infancy, according to Australian data, the frequency of food allergy reaches 10% [3]. Among children suffering from atopic dermatitis (AD), the frequency of food allergy reaches 30-40% [1, 2, 4, 9, 23]. A history of food allergy symptoms is noted in 17.3% of children [2]. According to a recent systematic review, the lifetime prevalence of any physician-diagnosed food allergy was 9.3% for children and 5.0% for adults, respectively [133].

1.4 Features of Coding the Disease or Condition

L27.2 – Dermatitis due to ingested food;

K52.2 – Allergic and alimentary gastroenteritis and colitis;

T78.1 – Other manifestations of abnormal reaction to food.

Comments: examples of diagnostic formulations are given in Appendix A3.1. For coding features of food anaphylaxis, see the clinical guidelines «Anaphylactic shock». For coding features of atopic dermatitis accompanied by food allergy, see the clinical guidelines «Atopic dermatitis».

1.5 Classification of the disease or condition

The modern classification of food allergy manifestations is based on the clinical and immunological principle.

IgE-mediated reactions (syndromes):

• Oral allergy syndrome (cross-reactive food allergy due to sensitization to pollen allergens)

• Urticaria/angioedema (acute)

• Rhinoconjunctivitis/bronchial obstruction/stridor due to laryngeal edema (including exacerbations in patients with bronchial asthma and allergic rhinitis)

• Gastrointestinal disorders (nausea, vomiting, abdominal pain, and diarrhea)

• Anaphylaxis – a severe, life-threatening reaction, in some cases induced by cofactors such as physical activity, stress, etc.

Mixed IgE- and non-IgE-mediated reactions:

• Exacerbations of atopic dermatitis in typical rash sites

• Eosinophilic gastrointestinal pathology (including eosinophilic esophagitis)

• Exacerbations of asthma

Non-IgE-mediated manifestations (including cellular reactions):

• Food protein-induced enterocolitis, proctitis, proctocolitis

• Food protein-induced enteropathy

• Contact dermatitis

• Heiner syndrome

1.6 Clinical presentation of the disease or condition

Clinical manifestations of food allergy and the age at onset vary depending on the pathogenesis of the reaction.

I. IgE-mediated reactions (occur from several minutes to 2 hours after ingestion of a food containing the causative allergen [2, 3, 14]):

• Oral allergy syndrome (caused by sensitization to pollen allergens) is characterized by pruritus, mild edema of the lips and/or oral cavity; it may be accompanied by acute nasal symptoms (rhinorrhea, nasal congestion), and ear pruritus. Manifestations occur in the presence of seasonal allergic rhinitis (most often after the onset of respiratory symptoms). Both persistence and seasonal dependence are possible.

• Acute urticaria – pruritic wheuls lasting on the skin for no more than 24 hours. Symptoms resolve within 1–2 days after discontinuation of the allergen.

• Angioedema – allergic angioedema most commonly occurs in the soft tissues of the head; the overlying skin is of normal color or slightly hyperemic. It may be moderately painful and warm to the touch, and some patients experience a burning sensation. Angioneurotic edema resolves within 24–48 hours, leaving no residual skin changes, except in cases of trauma caused by rubbing or scratching. These symptoms occur upon ingestion of the causative food or upon its contact with the skin or mucous membranes.

• Rhinoconjunctivitis – rhinorrhea, nasal pruritus, and nasal congestion occurring at the time of food consumption or a few minutes later. Persistent symptoms of allergic rhinitis are not a manifestation of food allergy.

• Bronchospasm/bronchial obstruction/stridor – wheezing, cough, labored intermittent breathing, and hoarseness are rare isolated manifestations of food allergy; they may occur upon inhalation of allergen aerosol, mostly arising in the context of anaphylaxis, and rarely as an isolated symptom. They are more common in young children than in adults.

• Digestive disorders – nausea, vomiting, abdominal pain, colic, diarrhea, and rarely constipation with soft stools. Symptoms are non-specific; in children, they must be differentiated from functional gastrointestinal disorders.

• Anaphylaxis – a rapidly progressive, multisystem, life-threatening reaction. Criteria for anaphylaxis [92, 136]:

  1) Acute onset of the illness (from several minutes to several hours) with involvement of the skin and/or mucous membranes (e.g., generalized urticaria, including with angioedema, pruritus or flushing, edema of the lips, tongue, uvula) and at least one of the following features:

  a. Respiratory compromise (e.g., dyspnea, bronchospasm, stridor, decreased peak expiratory flow (PEF), and hypoxemia)

  b. Decreased blood pressure (BP) or associated symptoms of target organ dysfunction (e.g., hypotension [collapse], syncope, urinary incontinence)

  2) Two or more of the following features occurring rapidly after exposure to a probable allergen for the given patient (from several minutes to several hours):

  a. Skin and mucosal involvement (e.g., generalized urticaria, flushing, edema of the lips, tongue, or uvula).

  b. Respiratory compromise (e.g., dyspnea, bronchospasm, stridor, decreased PEF, hypoxemia)

  c. Decreased BP or associated symptoms (e.g., hypotension [collapse], syncope, urinary incontinence)

  d. Persistent gastrointestinal symptoms (e.g., cramping abdominal pain, vomiting)

  3) Decreased BP after exposure to a known allergen for this patient (from minutes to several hours):

  a. Infants and children: low systolic BP¹ (age-dependent) or a decrease in systolic BP >30%;

  b. Adults: systolic BP <90 mm Hg or a decrease of >30% from the individual's baseline.

• Food-dependent exercise-induced anaphylaxis – occurs predominantly in adolescents and adults; food triggers anaphylaxis only if followed by physical exertion (delayed reactions from 30 min to 4 hours).

II. Mixed – IgE- and non-IgE-mediated reactions (occur from several minutes to several days after ingestion of the causative food, including delayed reactions) [2]:

• Exacerbation of atopic dermatitis – redness in typical areas with characteristic erythematous-squamous skin lesions accompanied by pruritus and dry skin, having age-specific localization patterns. Associated with food allergy in 30–40% of children with moderate-to-severe atopic dermatitis, and significantly more often in young children [2].

• Eosinophilic gastrointestinal disorders – symptoms depend on the level of the gastrointestinal tract involved and the degree of eosinophilic inflammation.

III. Non-IgE-mediated manifestations driven by cellular reactions (delayed reactions occurring from 1 hour to several days after ingestion of the causative food) [2]:

• Food protein-induced enterocolitis syndrome. Disease onset typically occurs under 1 year of age. Acute manifestations are characterized by protracted vomiting starting approximately 1–4 hours after ingestion of the causative food (most commonly cow's milk, egg, soy, wheat, rice, oats, legumes) in the absence of classic IgE-mediated allergic skin or respiratory symptoms [100]; it may be accompanied by pallor, hypotension, signs of dehydration, and lethargy [100]. Diarrhea may occur within 24 hours after food ingestion. The acute course of food protein-induced enterocolitis can mimic infectious gastroenteritis, intussusception, sepsis, metabolic crisis, or even necrotizing enterocolitis. The delayed onset and absence of cutaneous and respiratory symptoms point to a systemic reaction distinct from anaphylaxis. In severe cases, it may progress to hypothermia, methemoglobinemia, acidemia, and hypotension mimicking sepsis. Sometimes symptoms are chronic in nature: frequent episodes of vomiting, diarrhea, failure to thrive (growth and weight delay), and lethargy [100]. This form of food allergy is rare, predominantly affecting infants and young children; symptoms can be severe and require emergency care for the child. However, this condition typically resolves by 5–7 years of age or earlier.

• Food-induced enteropathy – chronic diarrhea and malabsorption with steatorrhea, accompanied by weight loss and growth retardation.

• Food-induced proctitis, proctocolitis – characterized by the presence of blood in the stool without marked impairment of the child's general well-being. The most frequent cause of this condition is allergy to cow's milk protein, eggs, and less commonly to soy and cereals [139–141]. It occurs predominantly in infants and usually resolves by 1–2 years of age.

• Contact dermatitis occurs with prolonged direct skin contact with food products, primarily as a result of occupational exposure.

• Heiner syndrome – a rare hypersensitivity reaction to cow's milk proteins occurring in infants or young children. This condition is characterized by growth failure, gastrointestinal symptoms (vomiting, diarrhea), and respiratory symptoms (cough, dyspnea, wheezing) resulting from lung damage by circulating immune complexes, which may culminate in pulmonary hemosiderosis.

¹ Low systolic blood pressure in children aged 1 month to 1 year is defined as <70 mm Hg, from 1 to 10 years as less than (70 mm Hg + [2 × age]), and from 11 to 17 years as <90 mm Hg.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The universally accepted criterion for establishing a diagnosis of IgE-mediated food allergy is the presence of specific IgE antibodies to specific food allergens in combination with various allergic manifestations upon exposure to this allergen [146, 147, 148]. The "gold standard" of diagnostics is the oral food challenge test [146].

However, it should be remembered that in the presence of clinical reactions, the absence of specific IgE does not rule out food protein allergy

Criteria for mixed IgE- and non-IgE-mediated reactions, as well as non-IgE-mediated manifestations (including cellular reactions), are described in the relevant clinical guidelines.

! Establishing the link between exposure to the causative factor, the type of clinical manifestations, and the time of their onset is essential.

Allergy evaluation of a patient with suspected food allergy includes a thorough medical history taking and clarification of dietary habits, which are of fundamental importance for diagnosing food allergy [1, 2, 3, 15], as they can help establish the diagnosis, suggest the mechanism—IgE- or non-IgE-mediated—and determine potential food triggers.

The predictive value of the medical history regarding immediate symptoms of food allergy, both separately and in combination with skin prick testing or the determination of food allergen-specific IgE antibodies in the blood, reaches 100% [2, 3] (See Appendix B).

Depending on the clinical situation, diagnostic interventions may include testing for specific IgE class antibodies (quantification of total immunoglobulin E in the blood), skin prick testing, a diagnostic elimination diet, and an oral food challenge (provided a food diary is kept). A basophil activation test (flow cytometric analysis of allergen-induced basophil activation) may also be performed, provided this method is available.

Depending on clinical indications, other diagnostic methods may be prescribed for differential diagnosis. A physical examination, assessment of concurrent allergic diseases, identification of risk factors, and a burdened family history will also assist in establishing the diagnosis.

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, it is necessary to evaluate:

• The relationship between symptoms and the causative allergen;

• The nature of the reaction and the time of onset (immediate or delayed type);

• Clinical symptoms and their severity;

• Reproducibility of the reaction;

• Presence of contributing factors;

• Efficacy of ongoing therapy;

• Family history;

• Presence of comorbid conditions, including allergic diseases

2.2 Physical Examination

A standard clinical examination should be performed, paying special attention to height and body weight, skin condition, signs of atopy, and other allergic diseases.

2.3 Laboratory Diagnostics

Comment: The choice of allergological examination method is determined by the availability and equipment of the allergology office and the presence/absence of contraindications to skin testing with allergens (see subsection 2.4).

Determination of food allergen-specific IgE antibodies in the blood (quantification of antibodies to antigens of plant, animal, and chemical origin in the blood) is a diagnostic method for IgE-mediated food allergy.

Among the advantages of laboratory diagnostics, it is worth noting the absence of contraindications to the diagnostic test, age restrictions, or any risk of developing severe systemic allergic reactions, as well as the ability to simultaneously determine specific IgE to a large number of allergens (multiplex assays using an allergy microarray).

Determination of food allergen-specific IgE antibodies in the blood (sIgE) is indicated for patients in the following cases:

• there are contraindications to skin allergy testing, and the allergen cannot be identified from the medical history;

• patients with widespread skin conditions (atopic dermatitis, recurrent urticaria), as well as pronounced dermographism;

• in cases where it is impossible to discontinue medications that affect the results of skin testing.

• young children.

Currently, the following methods are used in clinical practice:

- colorimetric method;

- fluorimetric method using a cellulose sponge as a solid-phase matrix;

- chemiluminescent method using biotinylated allergens and a solid phase with avidin particles;

- solid-phase immunofluorescence (e.g., using an automatic immuno-chemiluminescent analyzer for in vitro diagnostics of allergic, autoimmune, and inflammatory diseases/in vitro diagnostic laboratory immunofluorescence analyzer, which has high sensitivity for detecting specific IgE at ultra-low concentrations and, according to independent studies, is the most accurate and stable).

The detection limit for sIgE is lower compared to that of total IgE molecules. In most laboratories, it ranges from 0.01 to 0.35 kU/L for sIgE (and 2–5 kU/L for total IgE).

The potential risk of clinical manifestations in the presence of sensitization is determined not only by the sIgE level, but also by the type of allergen. At the same time, highly positive test results do not necessarily imply increased severity of clinical symptoms or the development of anaphylactic shock, for instance.

For pediatric practice, the optimal approach is to assess sensitization by the level of sIgE to specific food allergens using a test system that features fixed threshold sIgE ranges that determine the risk of clinical symptoms and indicate their correlation with age [3]. Positive test results only indicate the presence of sensitization. Conversely, the absence of specific IgE does not rule out a diagnosis of food allergy. All obtained results must be interpreted strictly in the context of symptoms and anamnestic data.

Component-resolved diagnostics (molecular allergology), a modern diagnostic method based on advances in molecular biology and biotechnology, makes it possible to detect IgE antibodies to purified molecules (individual allergen components).

Molecular allergology provides additional information on the nature of sensitization to individual proteins within a product and helps predict the clinical manifestations and course of food allergies. For example, this method helps clarify whether sensitization is directed against thermostable or thermolabile components of the causative allergen. Furthermore, molecular diagnostics allows for distinguishing true sensitization from cross-reactivity, assessing the risk of acute systemic or local reactions, and predicting the likelihood of developing tolerance or progression to a persistent form of allergy.

Polycomponent microarrays for molecular diagnostics with a wide panel of allergens (quantification of antibodies to antigens of plant, animal, and chemical origin in the blood) may be used [3, 20].

Determination of specific IgE to allergen components (quantification of antibodies to antigens of plant, animal, and chemical origin in the blood) is performed to identify true sensitization [3]. Component testing is particularly useful for patients with pollen sensitization: the presence of specific IgE to allergen extracts containing cross-reactive molecules in the absence of sensitization to individual components represents a false-positive result and is of no clinical significance [3].

Comment: these tests allow for the detection of non-specific mediator release from basophils in the presence of an allergen, independently of the IgE molecule. Their use is limited due to high cost, low availability, and lack of uniform standardization.

Comment: If celiac disease is suspected (see Clinical Guidelines for the provision of medical care for celiac disease), the examination is carried out by appropriate specialists in accordance with the clinical guidelines. Depending on the results or if clinically indicated, IgG antibodies to tissue transglutaminase (determination of tissue transglutaminase antibody levels in the blood), IgG and IgA antibodies to endomysium (determination of endomysial antibody levels in the blood), HLA typing methods (DQ2/DQ8), esophagogastroduodenoscopy, and duodenal biopsy may be performed. Serological tests should be performed while maintaining a normal diet, without gluten restriction.

Comment: performed for the purpose of differential diagnosis with primary hypolactasia and alactasia.

2.4 Instrumental Diagnostics

Comments: Patients with pronounced and persistent gastrointestinal symptoms, developmental delay, or iron deficiency anemia that cannot be explained by other causes (when celiac disease, various levels of eosinophilic gastrointestinal pathology, inflammatory bowel diseases, etc. are suspected) are indicated for an initial consultation with a gastroenterologist with the prescription of symptom-appropriate tests (e.g., esophagogastroduodenoscopy, etc., and pathological examination of biopsy material if necessary) in accordance with the relevant clinical guidelines.

2.5 Other Procedures

Comments: this method is effective in diagnosing IgE-mediated food allergy. The sensitivity and specificity of the method depend on the type of allergen [3]. Skin tests are recognized as the "gold standard" in the diagnosis of allergic diseases for the initial confirmation of an allergy diagnosis. It is a fast, safe, minimally invasive, and sensitive method. It is preferable to use the prick test – the skin prick test – which is the only test that can be widely used even in young children, is fast and easy to perform, informative for both the physician and parents, yields a low percentage of false-positive results, and is safe [3, 15, 95, 135]. In the absence of standardized allergen extracts, in some cases, prick tests with native allergens (percutaneous allergen skin tests) are permitted: certain types of fruits and vegetables that do not have a locally irritating effect, nuts, eggs, raw fish, and milk [95, 135]. Despite the absence of age restrictions for prick tests, their results in children under 2 years of age should be interpreted with caution [15].

Only trained medical professionals capable of interpreting results and managing potential adverse reactions should perform this test!

Scratch tests are inferior to prick tests due to greater invasiveness, resulting in a higher frequency of false-positive and systemic reactions.

Intradermal tests carry a high risk of adverse effects during administration and are therefore not currently used for the diagnosis of food allergy.

Like the results of specific IgE testing, skin test data are interpreted in conjunction with patient history and clinical presentation. For contraindications to skin testing, see Appendix A3.2.

Comments: A diagnostic elimination diet is a universal method that confirms the diagnosis in both IgE-mediated and non-IgE-mediated forms of food allergy. In the presence of clinically significant symptoms and a high probability of allergy to a specific protein, a diagnostic elimination diet is prescribed by excluding products containing that protein (during breastfeeding, such products are excluded from the mother's diet). The duration of the diagnostic diet depends on the clinical picture and must be long enough to assess the reduction/disappearance of clinical symptoms. The duration can range from a few days in children with immediate-type reactions (e.g., angioedema, vomiting, skin manifestations occurring within 2 hours) to 2–4 weeks in children with delayed and prolonged manifestations (in non-IgE forms, such as exacerbation of atopic dermatitis, proctocolitis, etc.).

If multiple food allergies are suspected during the diagnostic period, a hypoallergenic diet is prescribed, excluding all suspected foods from the diet. Keeping a food diary is advisable. The algorithm for the diagnosis and management of children with food allergies at stage 1 is presented in Appendix A3.5.

Comments:

Diagnostic food introduction (trial feeding / oral food challenge) is a diagnostic procedure consisting of the trial administration of small amounts of a previously unconsumed or eliminated food(s) to assess clinical reaction.

Diagnostic food introduction (trial feeding / oral food challenge) also helps exclude the risks of unjustified food elimination, including fear of consuming certain foods.

The procedure is carried out under the supervision of an allergist-immunologist and medical personnel trained in managing acute allergic reactions. Required conditions include access to 100% oxygen and an anti-shock kit (see clinical guidelines "Anaphylactic Shock").

After completion of the test, the child must remain under medical observation for at least 4 hours.

Mild reactions can be managed with symptomatic treatment depending on the type of clinical manifestations and usually do not require hospitalization.

Moderate to severe reactions may require emergency care and hospitalization of the patient in a specialized department.

When deciding to perform this procedure, factors influencing the severity of the reaction should be considered [3]:

• previously documented reactions to small or trace amounts of the suspected allergen,

• presence of bronchial asthma of any severity,

• presence of poorly controlled asthma, allergic rhinitis, or atopic dermatitis,

• use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, benzodiazepine derivatives, certain antidepressants (e.g., non-selective monoamine reuptake inhibitors),

• presence of allergy to peanuts, tree nuts, fish, seafood, and milk.

Diagnostic food introduction (trial feeding / oral food challenge) is performed when [3]:

1. there is sensitization to food products and at least one of the following criteria is met:

- the product has never been consumed before and/or allergy to a related group of products is diagnosed (cross-reactions, e.g., nuts and peanuts; pollen and vegetables/fruits; house dust mites and mollusks and crustaceans),

- the product was previously tolerated but has not been consumed for a long time (suspected loss of tolerance),

- food allergy symptoms and medical history do not match the results of the allergy workup,

- confirming the development of tolerance to the product,

- confirming tolerance to the product in a thermally processed form (e.g., in milk or egg allergy).

2. sensitization is not confirmed and at least one of the following criteria is met:

- reaction to the suspected product,

- the patient and/or parents experience anxiety and/or avoid consuming the product,

- need to confirm the development of tolerance to a specific product.

Medicines intake of which may cause a false-negative test result: drugs with antihistamine properties (e.g., tricyclic antidepressants, benzodiazepines, and systemic antihistamines and medications with antihistamine properties (benzodiazepine derivatives, certain antidepressants (e.g., non-selective monoamine reuptake inhibitors, other antidepressants)), as well as drugs for the treatment of obstructive airway diseases (bronchodilators), omalizumab** and ketotifen [3].

Diagnostic administration of the product (trial administration / oral food challenge) is the sequential administration of the suspected product in escalating doses.

Start with the minimum previously tolerated dose or according to a semi-logarithmic escalation schedule (i.e., 1 – 3 – 10 – 30 – 100 – 300 – 1000 – 3000 (mg)). Doses are administered sequentially at 20-60 minute intervals (depending on the product and the previously described reaction), with the monitoring of all vital signs and a physical examination performed after each administration [3, 150].

Thus, the final dose in case of a negative test result (no food allergy, presence of tolerance) is 3 g of protein.

A positive test – presence of a food allergy, absence of tolerance – is established when symptoms appear at any of the administered doses. Depending on the severity of symptoms and the involvement of various organs and systems, the allergist-immunologist decides on the further management of the patient.

Comments: Initial appointment (examination, consultation) with an allergist-immunologist is necessary to establish the diagnosis, conduct the examination and differential diagnosis, and select therapy. An initial appointment (examination, consultation) with a gastroenterologist may be performed in cases of refractory gastrointestinal symptoms to clarify the diagnosis, select and adjust therapy. An initial appointment (examination, consultation) with a dermato-venereologist may be performed for persistent skin manifestations of atopic dermatitis to select and adjust therapy. Children with polyvalent food allergies may undergo an initial appointment (examination, consultation) with a dietitian to formulate a balanced diet. Participation of other specialists in the diagnostic and treatment process, as well as other instrumental and laboratory tests, is carried out when necessary according to indications.

2.6 Medical genetic counseling and prenatal diagnosis

• For differential diagnosis with hereditary diseases and syndromes, it is recommended to consider an initial/follow-up appointment (examination, consultation) with a geneticist for patients with food allergy refractory to standard therapy and/or in questionable cases, and/or when a genetic etiology of the disease is suspected [83, 93].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

2.7 Differential diagnosis

Comments:

• Diseases of a different etiology accompanied by skin manifestations;

• Enzymatic and/or metabolic food intolerance:

  - lactose intolerance,

  - galactosemia,

  - carbohydrate malabsorption caused by specific enzyme deficiencies (e.g., sucrase-isomaltase deficiency, etc.),

  - intolerance to fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).

• Pharmacological reactions to food intake (effects of caffeine, tyramine, capsaicin, ginger, horseradish, alcohol, solanine, histamine liberators, monosodium glutamate, etc.), see Appendix A 3.4.

• Toxic reactions to food:

  - infectious gastritis/enteritis;

  - histamine toxicity (scombroid fish poisoning);

• Functional gastrointestinal disorders in infants;

• Other conditions:

  - gastroesophageal reflux disease (GERD)

  - irritable bowel syndrome;

  - inflammatory bowel disease;

  - gustatory rhinitis;

  - infectious/post-infectious urticaria;

  - chronic stress;

  - mental disorders.

• Celiac disease.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

• In cases of mild manifestations of food allergy and a limited number of causally significant allergens, it is recommended to selectively use an elimination diet as monotherapy for therapeutic purposes [32, 33, 36].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comments: The etiological treatment consists in the exclusion of causally significant foods from the diet.

Compliance with the elimination diet must be accompanied by monitoring of the child's anthropometric and physical development indicators.

Food allergy diet therapy is staged:

Stage 1 – diagnostic – exclusion of the product to confirm its significance (7 days - 4 weeks). At this stage, a diagnostic, trial introduction of the suspected product is possible to confirm its significance in the development of food allergy symptoms;

Stage 2 – therapeutic – an elimination diet to induce tolerance to the causally significant product (6 - 18 months)

Stage 3 – expansion of the diet (including the trial introduction of the product that caused the reaction). See Appendix A3.6.

The duration of the elimination diet and the induction of tolerance are individual. The minimum periods of exclusion from the diet are determined by international documents – at least 6 months, in the presence of severe reactions – at least 12-18 months [2, 3, 12]. Often, in addition to causally significant allergens, it is necessary to exclude products with cross-reactivity. Cross-reactions are also possible between non-food allergens and food products (see Appendix A3.3).

Given the high probability of developing tolerance to various foods in children, periodic allergy testing is possible to monitor sIgE levels to food proteins in the blood or perform skin prick tests with the food product (once every 6-12-18 months depending on the allergen) [2, 3].

Comments: for food allergy in breastfed infants, the pediatrician's strategy is to maintain breast milk in the child's diet to the maximum extent possible (see Appendix A3.7). Studies show that the proteins of major food allergens (milk, eggs, peanuts, and wheat) pass into breast milk in low concentrations capable of causing an IgE-mediated allergic reaction in only 1 in 1000 breastfed children with food allergy if the mother consumes the corresponding foods [138]. In the case of an exclusively breastfed infant with proctocolitis, the question of whether the mother needs to be prescribed a diet is still under discussion [12, 140-141]. In the case of rare episodes of blood streaks in the stool, in the absence of other symptoms of atopy in exclusively breastfed infants, dietary interventions should be limited during the first month of the onset of these symptoms, as this is generally a benign and self-limiting condition [12].

A diagnostic elimination diet excluding cow's milk protein should be considered in formula-fed infants with blood in the stool, followed by a diagnostic reintroduction of the formula to confirm the recurrence of symptoms [2, 12, 20].

• Infants and young children with mild to moderate symptoms of cow's milk protein allergy are recommended to use specialized formulas ( extensively hydrolyzed formulas). In severe cow's milk protein allergy and/or ineffectiveness of extensively hydrolyzed formulas, the prescription of amino acid-based formulas is recommended [1, 2, 12, 5, 9, 17, 46-51]. See Appendix A3.9.

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments: according to current requirements, the criterion for the effectiveness of a therapeutic formula is the results of clinical studies demonstrating the absence of allergic reactions to it in 90% of children with a confirmed diagnosis of cow's milk protein allergy (see Appendix A3.8).

• For children with cow's milk protein allergy, when long-term adherence to a dairy-free diet is necessary, the selective use of a soy formula is recommended for therapeutic purposes and to correct the protein component of the hypoallergenic diet [112, 128, 129, 151].

GCR ALOC 2Level of recommendation grading — A (Level of evidence — 2)

Comments: Systematic reviews on soy formula studies have shown that soy formulas possess adequate nutritional value [127–129]. Modern soy formulas are supplemented with appropriate amounts of amino acids (including methionine, taurine, carnitine). A systematic review of studies on the effects of soy on early sexual development revealed no evidence of negative hormonal effects of soy [112, 151].

However, soy formulas are not the first-choice products for food allergy. The use of soy formulas is possible in children with cow's milk protein allergy in the absence of sensitization to soy proteins in both IgE- and non- IgE-mediated food allergy to cow's milk proteins [151].

• In cow's milk protein allergy, the therapeutic use of partially (moderately) hydrolyzed protein formulas, formulas based on goat's milk or milk of other mammals is not recommended and unjustified due to the lack of evidence of their efficacy [1, 2, 4, 5, 11, 49, 52–55].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments: Formulas based on partially (moderately) hydrolyzed protein may be insufficiently effective in children with confirmed cow's milk protein allergy. Formulas and products based on unmodified (non-hydrolyzed) milks—goat, sheep, camel, and other mammals—are not recommended for children with cow's milk protein allergy due to the high frequency of cross-reactions.

Comments: Drinks made from soy, rice, almond, coconut, or chestnut are incorrectly referred to as "milk"; however, they do not meet the nutritional needs of infants and should not be used in their diet as an infant formula (see Appendix A3.8). Such drinks may be recommended for children older than 1–2 years to expand their diet in the presence of cow's milk protein allergy (rice drinks — from 4 years of age).

• Systemic antihistamines (1st generation) (chloropyramine**, mebhydrolin, clemastine) are not recommended for routine treatment of food allergies due to pronounced sedative and anticholinergic side effects [56, 92, 93, 94].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Drugs of this group impair cognitive functions: concentration, memory, and reduce learning ability in older children. Given the lack of approved systemic second-generation antihistamines, dimethindene may be prescribed to children under 6 months as a short course (dosing regimen for patients from 1 month to 1 year: 3–10 drops per dose 3 times a day).

• The use of systemic antihistamines (non-sedating, 2nd generation) in food allergies is possible for the relief of non-life-threatening manifestations presented as skin dermatoses (urticaria, pruritus, other allergic dermatoses accompanied by itching and rashes, conjunctivitis, rhinitis, etc.) [57].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments:

• Desloratadine is used in children from 6 months to 1 year at 1 mg (2 ml of syrup), from 1 year to 5 years at 1.25 mg (2.5 ml), from 6 to 11 years at 2.5 mg (5 ml) once daily in syrup form, and over 12 years — 5 mg (1 tablet or 10 ml of syrup) once daily.

• Cetirizine** is prescribed to children aged 6 to 12 months at 2.5 mg once daily, to children aged 1 year to 6 years at 2.5 mg twice daily or 5 mg once daily in the form of drops, and to children over 6 years — at 10 mg once daily or 5 mg twice daily.

• Loratadine** is used in children over 2 years of age. For children with a body weight of less than 30 kg, the drug is prescribed at 5 mg once daily; for children with a body weight of more than 30 kg — at 10 mg once daily.

• Levocetirizine is prescribed to children over 6 years of age at a daily dose of 5 mg, and to children aged 2 to 6 years — at 2.5 mg/day in the form of drops.

• Rupatadine is used in children over 12 years of age; the recommended dose is 10 mg once daily.

• For children under 6 months of age, given the lack of approved systemic antihistamines (second generation), dimethindene may be prescribed as a short course (dosing regimen for patients from 1 month to 12 years at the rate of 2 drops per 1 kg of the child's body weight or 0.1 mg/kg divided into 3 doses).

Certain systemic antihistamines (2nd generation) may also cause a mild sedative effect in some children.

• Long-term administration of drugs of this group for prophylactic purposes is not recommended due to lack of expediency [57, 58].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• All manifestations of anaphylaxis, as well as life-threatening manifestations of food allergy (especially with the development of cardiovascular and respiratory symptoms), are recommended to be managed by the administration of epinephrine** [58, 61, 62, 92, 136].

GCR CLEL 3Grade of Recommendation — C (Level of Evidence — 3)

Comment: the drug is administered by the ambulance team, in the emergency department, or in the emergency care unit. Following epinephrine** injection, the patient must be examined by an ambulance doctor/paramedic and, if indicated, monitored for at least several hours.

See clinical guidelines "Anaphylactic Shock".

Patients who have suffered anaphylaxis must carry an anti-shock kit, which must include 0.1% epinephrine** solution — 1.0 ml in ampoules.

In cases where urticaria and/or angioedema are symptoms of anaphylaxis, appropriate therapy is indicated (see clinical guidelines "Anaphylactic Shock").

Comment: the drug is administered by the ambulance team, in the emergency department, or in the emergency care unit. See clinical guidelines "Urticaria".

— to relieve symptoms (as a single dose, or if necessary as a short course — 3–7 days), prednisolone** may be used at a dosage of 1–2 mg/kg/day. Gradual withdrawal of systemic corticosteroids is not required for a short course of therapy. According to the instructions, dexamethasone** may also be used

• Patients with concomitant bronchial asthma are recommended to be informed about the potential risk of developing respiratory symptoms after ingestion of the causal allergen and the necessity of mandatory use of the appropriate medication to relieve developed bronchial obstruction [97].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: see clinical guidelines "Bronchial Asthma".

• External therapy for atopic dermatitis associated with food allergy is recommended to be carried out differentially, taking into account pathological skin changes, with the aim of relieving inflammation and pruritus, as well as restoring the hydro-lipid layer and barrier function of the skin, and ensuring proper daily skin care [96].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: see clinical guidelines "Atopic Dermatitis".

• Ketotifen is not recommended for the prophylactic treatment of food allergy manifestations due to the lack of proven efficacy [2, 66–71].

GCR CLEL 2Grade of Recommendation — C (Level of Evidence — 2)

• Specific immunotherapy is not recommended in routine practice due to the lack of standardized regimens, preparations with proven efficacy, and because of the risk of anaphylaxis and the likelihood of symptom recurrence after treatment [63–65].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments: is indicated only for patients with confirmed allergy to respiratory allergens, with concomitant respiratory symptoms, and is carried out using appropriate medications. Currently, clinical trials of specific immunotherapy using food allergens, while demonstrating some efficacy, do not confirm a long-lasting effect resulting from the treatment.

Comments: may be prescribed to patients with IgE-mediated food allergy to achieve desensitization.

The drug is administered at a dose of 75–600 mg subcutaneously every 2–4 weeks; the dose (in mg) and frequency of administration are determined by the baseline serum total IgE level (IU/mL) measured before the start of treatment and body weight (in kg) (Table 1). The optimal duration of therapy for IgE-mediated food allergy has not been established (up to 44 weeks in the study). The need to continue therapy should be periodically reassessed [149, 153, 154].

Table 1.

Dosages of #omalizumab** for food allergy ¹ in adults and children aged 1 year and older.

Notes:

¹Abbreviations and symbols

Currently, there are no data on the long-term efficacy of #omalizumab** in food allergy, especially in cases where culprit foods are not reintroduced into the diet or allergen-specific immunotherapy is not performed. It is likely that the effect of #omalizumab** will be lost after discontinuation of treatment. It should also be taken into account that prolonged exclusion of a food product from the diet may impair the quality of life in some patients.

3.2 Surgical Treatment

Not required.

Pain relief is not required.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not required

5. Prevention and Dispensary Observation

Primary prevention of FA – prevention of early-onset atopy.

Exclusive breastfeeding up to 4–6 months of age has a certain preventive effect [1, 2, 10, 37, 101], especially during the first week of the child's life [104].

There is no convincing evidence of a preventive effect of a strict hypoallergenic diet during pregnancy and breastfeeding for the prevention of allergic disease in the child. On the contrary, a diverse, complete diet is recommended whenever possible [10, 37, 98, 99, 104]. An individualized hypoallergenic diet excluding culprit allergens should be prescribed to the mother in cases where she herself suffers from food allergy.

Data on the efficacy of partially or extensively hydrolyzed formulas as a method for preventing FA development are inconclusive and continue to be debated [2, 37, 98, 99, 105, 106, 107]. Such a physiological phenomenon as oral tolerance and the concept of its formation regarding cow's milk proteins were previously investigated and described using partially hydrolyzed protein formulas (PHF) [109, 110, 152].

The authors of some recent publications [111] consider the use of PHF to reduce the risk of allergy development in children to be unjustified, based on the results of systematic reviews and meta-analyses of various formulas differing in protein source, degree, and method of hydrolysis, which does not allow for reliable conclusions regarding the true efficacy of a specific formula. The methodological features of these meta-analyses required additional study [106].

A number of studies, including those with a long-term 20-year follow-up, nevertheless demonstrate some preventive effect of hypoallergenic milk formula regarding the development of atopic dermatitis in children at risk for allergic pathology (as well as in infants from the general population) [114–118].

Currently, the expert community recognizes that to confirm the preventive efficacy of a specific formula, clinical studies are needed that confirm a reduction in the risk of FA development both in the short-term and long-term periods when used in children with a burdened allergic history who are not exclusively breastfed. Thus, the protein source, method, and degree of its hydrolysis are not sufficient grounds for determining the product's efficacy in reducing the risk of allergy development [113].

There is evidence indicating the impact of tobacco smoke on the risk of allergic diseases in children. Both active maternal smoking during pregnancy and passive smoking during the first year of the child's life can be associated with the risk of developing atopic dermatitis and food allergy later on [143, 144].

Comments: the key rule for introducing complementary foods to children at high risk of sensitization is prescribing single-ingredient products, as well as adhering to the principle of gradual diet expansion [108]. The presence of an infant's interest in food is an important condition for successfully starting complementary feeding. Preference should be given to local and seasonal products characteristic of the place of residence and season, taking into account the family's habitual diet. Traditionally in Russia, it is customary to start complementary feeding with vegetable puree or cereal porridge, but there are no strict recommendations on this matter; parents can choose other foods whose mechanical processing and size correspond to the child's age. The optimal interval between the introduction of new products has not yet been precisely determined, but researchers note the need to provide the child with a diverse diet and the undesirability of excessive prolongation when expanding the child's diet [106, 108].

Secondary prevention – prevention of exacerbation

Patients with various clinical manifestations of food allergy should receive therapy depending on the nosological form and sensitization profile; they should be instructed on the need to always carry emergency medication(s) and have a clear action plan in an emergency situation.

The patient/legal representatives must also be instructed on the need to check food ingredient labels before consumption, as foods may contain culprit allergens. When visiting public catering establishments, one should also clarify the presence of allergenic components in dishes [2, 3, 97, 107, 136].

Dispensary follow-up (Active surveillance)

Dynamic follow-up tactics are determined by the nosological form and severity of the disease course.

The diagnostic program including therapy and selection of an individualized elimination diet in a hospital/day hospital/outpatient setting can take on average about 14 days. Patients with mild FA manifestations can be monitored on an outpatient basis, with appointments (examinations, consultations) by specialists (depending on the nature of the manifestation and as indicated: allergist-immunologist, dietitian, gastroenterologist, dermatovenereologist) at a frequency of once every 1–6 months. In case of severe and moderate reactions to food, the child may need hospitalization for examination, selection of therapy and diet correction, and rehabilitation measures (once every 3–12 months, depending on the nature of pathological manifestations).

6. Organization of Medical Care

Patients with food allergy, depending on necessity, may be provided with any type, condition, and form of medical care stipulated by the legislation of the Russian Federation.

The management of patients with food allergy is primarily carried out by an allergist-immunologist, pediatrician/general practitioner (family physician); a dietitian, gastroenterologist, dermatovenereologist, and other specialists may be involved based on medical indications.

Routine vaccination in patients with food allergy is carried out in accordance with the National Immunization Schedule.

6.1 Indications for planned hospitalization

1. Performing diagnostic and therapeutic methods requiring prolonged (daytime or round-the-clock stay) medical observation and monitoring of instrumental or clinical-laboratory parameters;

2. Performing diagnostic and therapeutic methods requiring medicinal sedation;

3. A condition requiring active treatment and round-the-clock medical supervision (severe pain syndrome, surgical correction of tone disorders or skeletal deformities, selection of anticonvulsant therapy, organization of nutritional support, organization of respiratory support);

4. A condition requiring high-tech treatment methods;

5. Lack of possibility to ensure a course of treatment using pharmacological and non-pharmacological methods in outpatient and day-patient settings;

6. The need for various types of expert evaluations or examinations in a medical organization when it is impossible to perform them in an outpatient setting.

6.2 Indications for emergency/urgent hospitalization

Acute life-threatening conditions and conditions threatening the development of complications that require urgent treatment, including intensive care, as well as round-the-clock medical observation and special types of examination and treatment.

6.3 Indications for hospital discharge

1. Absence of a threat to the patient's life and the risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. Stabilization of the condition and basic clinical and laboratory parameters of the pathological process, absence of the need for prolonged medical observation (day or round-the-clock stay);

3. The patient's examination and treatment plan has been completed, and recommendations for further monitoring and treatment have been given.

4. The need to transfer the patient to another medical organization or social welfare institution.

Organization of dietary nutrition for patients during inpatient treatment in medical organizations is carried out in accordance with Appendix 3 of the Order of the Russian Ministry of Health No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition"

6.4 Vaccination

When vaccinating children with food allergy, the National Immunization Schedule should be followed.

Comments: Research data have shown no association between vaccination and the subsequent development of food allergy. Food allergy is not a contraindication for routine immunizations. Vaccination is indicated for patients with food allergy to prevent/reduce the likelihood of a severe (complicated) course of vaccine-preventable infections. Vaccination is carried out in accordance with the Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On approval of the national immunization schedule and the immunization schedule for epidemic indications", and Methodological Guidelines MU 3.3.1.1095-02 "Medical contraindications to routine immunizations with national immunization schedule preparations".

Patients receiving immunosuppressive therapy should be consulted by a physician before vaccination with live vaccines; immunization with attenuated live vaccines should preferably be performed 4 weeks prior to initiating immunosuppressive therapy. In cases of confirmed chicken egg protein allergy, an appointment (examination, consultation) with an allergist-immunologist may be conducted prior to vaccination.

7. Additional Information

7.1 Outcomes and prognosis

The development of tolerance and prognosis largely depend on the type of allergen and the form of food allergy, as well as adequate management tactics for the child in the early stages of pathology development.

Comments: The duration of the elimination diet and the development of tolerance are individual. Further management tactics for the child are determined by the nature of clinical manifestations and the results of examination and monitoring. With a good treatment response in children with an IgE-mediated form of food allergy, the reintroduction of the previously excluded product is advisable to be performed after monitoring the level of specific IgE antibodies in the blood no earlier than 6 months from the start of the hypoallergenic diet, and in severe cases – after 12–18 months. For children with persistent IgE sensitization, the duration of elimination is extended. In the absence of specific IgE and a history of severe allergic reactions, a trial introduction of the product is carried out, on the basis of which a conclusion is made regarding the possibility of reintroducing the excluded product into the diet. The introduction of new or previously eliminated products must be carried out gradually, starting with small quantities, under the control of individual tolerance. There is evidence of the successful use of "milk" and "egg" ladders during the expansion of the diet of a child with a non-IgE-mediated form of food allergy, including for the purpose of developing tolerance [119, 120] (see Appendix A3.11). In recent years, studies have emerged in which the integrity of the intestinal epithelial barrier was studied as a diagnostic criterion for monitoring disease control and a marker of tolerance development during dietary expansion stages [121, 122]. Fecal calprotectin and zonulin have demonstrated the greatest informativeness and clinical significance as non-invasive criteria for assessing the intestinal barrier [123, 124]. A persistent decrease in fecal zonulin levels below 1.2 ng/mL and fecal calprotectin below 100 mcg/g in studies indicated the restoration of the intestinal barrier and the possibility of food tolerance development, allowing for the initiation of dietary expansion measures. An increase in these indicators served as a reliable predictor of disease exacerbation and the development of allergic inflammation. At the same time, the determination of zonulin and fecal calprotectin (testing for calprotectin levels in stool) over time made it possible to objectify the duration of elimination [125, 126]. However, to date, the availability of these methods in real clinical practice is low, and the degree of reliability in various phenotypic manifestations of cow's milk protein allergy requires additional studies.

Criteria for Evaluating the Quality of Medical Care

Table 1.

Table 2.

Quality criteria for medical care

References

Appendix A1. Working Group Composition

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatricians,

2. Allergists-immunologists;

3. General practitioners (family physicians);

4. General practitioners

5. Internists

6. Dermatovenerologists

7. Gastroenterologists;

8. Dietitians;

9. Medical students;

10. Residents and interns.

Methods used for evidence collection/selection: electronic database search.

Description of methods used to assess the quality and strength of evidence: the evidence base for the guidelines includes publications from the Cochrane Library, EMBASE, MEDLINE, and PubMed databases. The search depth was 15 years.

Methods used to assess the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for evidence analysis

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations.

To minimize potential bias, each study was evaluated independently. Any discrepancies in evaluations were discussed by the full panel of authors. If a consensus could not be reached, an independent expert was involved.

Evidence tables: compiled by the authors of the clinical guidelines.

Methods used to formulate the recommendations: expert consensus.

Good Practice Points (GPPs)

Recommended good clinical practice is based on the clinical experience of the authors of these guidelines.

Economic analysis

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Recommendation validation method

• External expert review.

• Internal expert review.

Description of the recommendation validation method

The draft of these recommendations was reviewed by independent experts who were primarily asked to comment on how comprehensible the interpretation of the evidence underlying the recommendations is.

Feedback was obtained from primary care physicians regarding the readability of these guidelines and their assessment of the importance of the proposed recommendations as a tool for daily practice.

All comments received from the experts were thoroughly systematized and discussed by the members of the working group (authors of the recommendations). Each item was discussed individually.

Consultation and peer review

The draft recommendations were reviewed by independent experts who were primarily asked to comment on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Key recommendations

The strength of recommendations (1–2) based on the corresponding levels of evidence (A–C) and good practice points (GPPs) (Table 1) are provided in the presentation of the guidelines text.

Table 3.

Scale for assessing the levels of reliability of evidence (level of evidence) for diagnostic methods (diagnostic interventions)

Table 4.

Grading system for levels of evidence for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 5.

Grades of Recommendation Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitation Interventions)

Updating of these clinical guidelines will be carried out at least once every three years. The decision to update will be made based on proposals submitted by medical professional non-profit organizations, taking into account the results of comprehensive assessments of medicinal products, medical devices, and clinical trials.

Appendix A3. Reference Materials

Standards of medical care: Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Standard of Pediatric Care"

Information on medicinal products: https://grls.rosminzdrav.ru/

Other documents used in the development of the clinical guidelines:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724);

2. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

3. Order of the Ministry of Health of the Russian Federation No. 1183n dated December 20, 2012, "On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers."

4. Order of the Ministry of Health of the Russian Federation No. 541n dated July 23, 2010. "Uniform Qualification Handbook of Positions of Managers, Specialists, and Employees, Section: Qualification Characteristics of Positions of Healthcare Workers."

5. Federal Law No. 489-FZ of December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' Regarding Clinical Guidelines."

6. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development and Revision of Clinical Guidelines, Their Standard Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines."

7. Order of the Ministry of Health of the Russian Federation No. 617n dated June 23, 2020, "On Amendments to Appendices Nos. 1, 2, and 3 to the Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, 'On Approval of the Procedure and Deadlines for the Development and Revision of Clinical Guidelines, Their Standard Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines'"

8. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 "On approval of the nomenclature of medical services".

9. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates, Procedure for Issuing Said Forms, Their Accounting and Storage."

Appendix A3.1 Examples of diagnosis formulation

Food allergy represents a pathogenetic mechanism in the development of certain diseases and/or symptom complexes and, accordingly, is not a nosological diagnosis. Nevertheless, given the high etiological and clinical significance of food allergy in the pathogenesis of a number of allergic diseases, the presence of food allergy (if necessary, specifying the main causative allergens) should preferably be included in the complete clinical diagnosis after indicating the primary nosological form.

• Atopic dermatitis, widespread form, moderate severity, exacerbation. Food allergy (sensitization to cow's milk protein, wheat protein) (L27.2)

• Allergic urticaria. Food allergy (sensitization to chicken egg and milk proteins) Food-induced (egg) anaphylaxis (T78.1)

• Allergic gastroenteritis. Food allergy (K52.2).

Appendix A3.2 Contraindications for skin tests

The main contraindications for skin tests include exacerbations of the underlying disease, acute infectious diseases, tuberculosis, inability to cooperate with the patient; severe chronic cardiovascular diseases; pregnancy; HIV infection (human immunodeficiency virus), and anaphylaxis within the previous 30 days. Skin test results are affected by systemic antihistamines, tricyclic antidepressants (non-selective monoamine reuptake inhibitors, and a number of antipsychotics).

Before performing skin tests, systemic antihistamines must be discontinued for 3–7 days depending on the drug; otherwise, the test results will be false-negative.

The intake of tricyclic antidepressants (non-selective monoamine reuptake inhibitors) should be discontinued 1 month prior to skin testing (cutaneous allergen response testing); topical steroids (ATC D07 Corticosteroids, dermatological preparations) applied to the skin of the inner forearm—the skin testing site—2 weeks prior to testing; following treatment with systemic GCS (ATC H02A Systemic corticosteroids) at a dose of 50 mg/day (calculated as prednisolone**) for 7–10 days, skin testing should be postponed for 3–7 days, and for long-term use at a dose above 10 mg/day, for 3 weeks.

Systemic GCS (ATC H02A Systemic corticosteroids) at low doses (up to 10 mg/day) with short-term use, inhaled GCS (corticosteroids), bronchodilators (selective beta-2 agonists, adrenergic agents in combination with anticholinergics), and leukotriene receptor antagonists do not affect (or have a negligible effect on) skin test results.

Urticarial dermographism and other forms of chronic urticaria may cause false-positive test results.

Appendix A3.3 Cross-reactivity of food and non-food allergen sources.

Table 1. Cross-reactions between major non-food allergens and foods.

Table 2. Proteins causing cross-sensitization to allergens of various origins.

Appendix A3.4 Foods rich in histamine and histamine liberators

1. High-histamine foods

1.1. Native — tomatoes, spinach, eggplant; meat offal, seafood;

1.2. Canned and fermented meat products, deeply processed products (ham, gammon, sausages, cold cuts); fermented cheeses; fermented beverages; sauerkraut; canned fish: tuna, mackerel, anchovies, smoked herring and caviar;

2. Histamine-liberating foods: strawberries, chocolate, egg white; spices; papaya, pineapple; legumes (peas, soy, lentils, beans, peanuts) due to the presence of lecithin; grapes, bananas and citrus fruits (lemons, oranges, mandarins), pineapples, tomatoes, kiwi, nuts, alcoholic beverages and chocolate.

3. Food additives (E-100-E-518): annatto (E160b), carmine (E120), erythritol (ERT), guar gum (E412), carrageenan, gelatin, pectin (IIB), sulfites and their derivatives, salicylates, benzoic acid (E210-219) and its derivatives (E211-E219), as well as tartrazine (E102), azo dyes (E102-124), monosodium glutamate (E621), gelling agents, baking powder, humectants, emulsifiers, flavor enhancers, antioxidants, parting agents, sweeteners, baking ingredients, flavor enhancers, modified starches, antifoaming agents, stabilizers, flavoring condiments. Some of these are found in chewing gum, lozenges, and similar products.

Appendix A3.5 Algorithm for the diagnosis and management of patients with food allergy at stage 1 of diet therapy.

Appendix A3.6 Management tactics for children with food allergy (including cow's milk protein allergy) at stages 2 and 3 of diet therapy.

Appendix A3.7 Diet therapy for food allergy in infants who are breastfed

In case of food allergy in breastfed infants, the pediatrician's tactic is to preserve breast milk in the child's diet to the maximum extent possible.

The degree of restrictions and the set of foods in the mother's diet should be individual and depend primarily on the severity of the clinical manifestations of allergy in the child and the allergic pathology in the mother. Dietary correction is also possible when non-specific hypersensitivity reactions are suspected.

To maintain lactation, the mother should be prescribed a complete diet and calcium supplements (e.g., 1000 mg/day in divided doses). Therapeutic amino acid-based formulas can be used to correct the protein portion of the diet and ensure adequate vitamin and mineral intake for the mother.

For breastfed infants with severe food allergy manifestations that cannot be controlled by the mother's diet (e.g., in combination with severe atopic dermatitis, or allergic enterocolitis complicated by growth retardation and/or hypoproteinemia and/or severe anemia), temporary exclusion of breast milk and prescription of a therapeutic amino acid formula for a period of several days up to 4 weeks is possible for diagnostic and therapeutic purposes.

Appendix A3.8 Selection of a therapeutic formula for cow's milk protein allergy (in mixed or artificial feeding)

Currently, elimination diet therapy is the most effective management strategy for children with cow's milk protein allergy.

It is necessary to exclude cow's milk-based formulas and complementary foods containing cow's milk protein or other unmodified animal milk proteins (e.g., goat's, sheep's milk). If supplemental feeding is needed, an extensively hydrolyzed formula or an amino acid-based formula is used.

If the condition does not improve within 2–4 weeks of taking an extensively hydrolyzed formula, switching to an amino acid-based diet is recommended.

An elimination diet using a therapeutic formula is prescribed for a period of 6 to 12 months individually. Children with a history of severe immediate-type IgE-mediated reactions may remain on the elimination diet for up to 12–18 months, after which, following re-evaluation of specific IgE titers and confirmation of normal values, an attempt is made to introduce a product containing cow's milk protein.

Specialized formulas for children with cow's milk protein allergy

All therapeutic formulas are enriched with a complex of vitamins, macro- and microelements, and meet the requirements for ingredient composition, biological and nutritional value, and their effect on the physical and psychomotor development of children.

The composition of specialized formulas may vary; formulas with a predominance of peptides smaller than 1200 Da, enriched with additional (functional) components, should be chosen. It is important to pay attention to trace amounts of substances in the composition, which in some cases may be clinically significant.

An important functional component of specialized formulas is oligosaccharides structurally similar to breast milk oligosaccharides. Human milk oligosaccharides (HMOs) are key nutrients with proven clinical efficacy, including prebiotic effects: by protecting against pathogens, they contribute to the formation of the immune system, proper development of the microbiota, and the development of neuroimmune interactions.

Galacto- and fructooligosaccharides (GOS/FOS) have also demonstrated prebiotic effects in studies — a bifidogenic effect and a positive influence on the anti-infective immune response. The use of synbiotics (enriching the formula with both a probiotic and prebiotics — GOS/FOS and HMOs simultaneously) is promising.

The presence of medium-chain triglycerides in the formula significantly increases the digestibility of the fat component, which may be especially relevant for patients with gastrointestinal manifestations, including severe ones accompanied by malabsorption.

In a specialized formula, the presence of polyunsaturated fatty acids is important for the proper development of the nervous system and the formation of cognitive functions.

Amino acid formulas

Formulas containing free amino acids as the sole source of nitrogen are the optimal choice for children who react to extensively hydrolyzed formulas. The risk of such a reaction is less than 10% for all infants with cow's milk protein allergy, but it may be higher in the presence of severe enteropathy accompanied by hypoproteinemia and growth retardation. For this category of patients, amino acid formulas are the first-choice products. All amino acid formulas have a balanced fat and carbohydrate composition, are enriched with vitamins and microelements necessary for children, but have certain taste characteristics that sometimes make it difficult both to introduce such a formula into the diet of older children and to use it for a long time.

Amino acid formulas can be used both for a short period to diagnose milk protein allergy and as the basis of the diet for long-term use in patients with food allergy and in nursing mothers of children with cow's milk protein allergy.

Soy formulas

Soy formulas are not the first-choice products in the acute period of food allergy. Currently, their use is possible in children with food allergy from the first days of life with mild manifestations of cow's milk protein allergy in the absence of gastrointestinal disorders and soy protein sensitization.

Other indications for prescribing soy formulas include severe persistent lactose intolerance, including severe damage to the small intestinal mucosa, rare cases of hereditary (primary) lactase deficiency and galactosemia, as well as religious and ethical restrictions on the use of animal protein-based formulas.

Soy formulas can be used to correct the protein part of a hypoallergenic diet during the remission period if a milk-free diet needs to be followed for a long time in patients with cow's milk protein allergy.

Rice hydrolysate-based formulas A formula based on extensively hydrolyzed rice protein can be safe for children with cow's milk protein allergy.

Such a formula can be considered ² at the diagnostic stage, as a treatment method [12], as well as in some infants who refuse/do not tolerate extensively hydrolyzed formulas, or are raised in vegetarian families.

Appendix A3.9 Algorithm for selecting a therapeutic formula for children with various manifestations of cow's milk protein allergy.

Note. * – reaction to HCS or lack of positive dynamics during HCS intake for several weeks, SCORAD (see Atopic Dermatitis clinical guidelines); MCT – medium-chain triglycerides.

Appendix A3.10 Principles of introducing complementary foods to infants in the first year of life with food allergy.

Due to the wide range of therapeutic formulas available, the recommended timing for introducing complementary foods and dishes to patients suffering from food allergy practically does not differ from that of healthy children. Modern concepts of optimal food tolerance development require the introduction of complementary foods at the age of no earlier than 4 and no later than 6 months; in children with food allergy, it is also recommended to follow this timeframe. However, in each specific case, the question of the timing of complementary food introduction is decided individually, taking into account the child's readiness and the development of their food interest.

In case of underweight, porridge can be the first complementary food; if the child has an allergy to cow's milk protein and wheat – dairy-free and gluten-free (buckwheat, corn, rice), followed by vegetables.

To correct the protein part of the diet, meat puree is introduced into the child's diet. It is recommended to use specialized canned baby meat or home-prepared puree from any type of meat. Patients with cow's milk protein allergy can start with rabbit, turkey, pork, chicken, or horse meat. Patients with chicken yolk allergy should not be given chicken meat first.

The first fruit complementary food is apple or pear puree. The introduction of fruit juices, fruit drinks, and compotes should preferably be postponed to a later age, as they contain a large amount of sugar.

In general, the color of the vegetable or fruit does not matter for introducing it into the diet of a child with food allergy.

Each new product is introduced into the child's diet gradually. Preference is given to single-ingredient products. A new product is included in the child's diet for the first time in an amount of no more than 5 ml (g), preferably during morning feedings, to be able to assess its tolerance during the day (appearance or intensification of skin rashes, changes in stool, etc.). If there is no allergic reaction, the volume of the new product can be increased to the age-appropriate amount within 3-5 days.

Appendix A3.11 Diet expansion for children with food allergy

At the stage of diet expansion for children with non-IgE-mediated cow's milk protein and/or egg white allergy, an allergist-immunologist may recommend the gradual introduction of foods within the framework of the so-called "milk" and "egg" ladders at home. The essence of the method lies in the step-by-step introduction of foods, starting with a small amount of them (the size of a pea), heat-treated for a long time, and ending with larger volumes and non-heat-treated products. The interval between the steps is about 1-3 months (but can be longer), while the child must consume foods corresponding to a certain step of the ladder at least 3 times a week. If food allergy symptoms occur at one of the steps of the ladder, one should return to the previous step and remain on it for at least 1 month.

Fig. 1. "Egg ladder", steps (adapted from [161]).

The egg ladder represents the sequential introduction of foods containing chicken egg proteins (Fig. 1):

1. Step. Long-cooked products containing chicken egg (in the oven for at least 30 minutes at 180ºC): pie, muffin, dry biscuit.

2. Step. Slightly cooked products containing chicken egg (high-temperature frying): pancakes, waffles, cutlets.

3. Step. Slightly cooked products containing chicken egg: French toast, boiled egg (hard-boiled for at least 10 minutes), omelet.

4. Step. Products containing raw eggs: fried eggs sunny-side up, sauces (e.g., mayonnaise), butter cream, ice cream.

Fig. 2. Milk ladder, steps (adapted from [160])

The milk ladder represents the sequential introduction of products containing cow's milk proteins (Fig. 2):

1. Step. Long-cooked products containing 10-20 ml of milk (in the oven for at least 30 minutes at 180ºC): dry biscuit.

2. Step. Long-cooked products containing milk (in the oven for at least 30 minutes at 180ºC): muffin, pie.

3. Step. Slightly cooked products containing milk (high-temperature frying): pancakes, waffles.

4. Step. Hard cheese or cheese in pizza.

5. Step. Fermented milk products (yogurt, cottage cheese, sour cream) and milk boiled for at least 3 minutes.

6. Step. Whole milk or adapted infant formula.

Children older than one year with a prolonged course of food allergy may need a long-term exclusion of a certain range of foods from their diet, which can lead to the development of deficiencies in various nutrients.

Table 1.

Products most frequently excluded from the diet of patients with food allergy and the resulting macro- and micronutrient deficiencies

The protein part of the diet is formed mainly due to meat products. In complex cases, specialized products for children older than one year – cow's milk protein hydrolysate-based formulas or amino acid formulas – can be used to correct the diet, which also make it possible to partially compensate for the micronutrient composition of the diet (however, this approach is difficult to implement in older children due to the taste characteristics of the listed formulas).

The most difficult aspect of diet adaptation is the correction of its micronutrient composition: the content of vitamins, minerals, essential amino acids, polyunsaturated fatty acids, etc.

With prolonged adherence to a dairy-free diet, the child must be additionally prescribed calcium preparations as monopreparations or in combination with a Vitamin D group preparation and its analogs. In cases where fish is excluded from the diet, in children older than one year, nutraceuticals or medicinal products of marine or plant origin are used to meet the requirement for w-3 class PUFAs (under tolerance control). Fat nutraceuticals can be prescribed during remission in age dosages (0.8-1.6 g/day) in courses of 30-40 days.

During remission, vitamin therapy using modern monopreparations is carried out according to indications.

Appendix A3.12 Decoding of notes

…** – the drug is included in the list of vital and essential drugs (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 "On approval of the list of vital and essential drugs for 2020, as well as lists of drugs for medical use and the minimum assortment of drugs required for the provision of medical care" (as amended)

#... – off-label use – outside the indications registered in the medicine instructions, is carried out by decision of the medical commission, subject to the signed informed consent of the parents (legal representative) and the patient over 15 years of age;

² Currently, high-hydrolyzed rice protein-based formula is not available in the Russian Federation.

Appendix B. Physician Action Algorithms

Algorithm for the diagnosis and management of patients with food allergy

Appendix B1. Algorithms for the management of children with cow's milk protein allergy and risk of its development

Fig. 1. Selection of formula in children at risk for developing allergy

(Adapted from [130])

Fig. 2. Management algorithm for children with mild to moderate cow's milk protein allergy – control of cow's milk protein tolerance development and diet expansion

(Adapted from [130])

Fig. 3. Management algorithm for children with severe cow's milk protein allergy – control of cow's milk protein tolerance development and diet expansion

(Adapted from [130])

Appendix C. Patient Information

Adverse reactions to food

The causes of adverse reactions to food can be various: allergy, gastrointestinal enzyme deficiencies, toxins, or bacterial contamination of products.

Food allergy is more common in children than in adults and can manifest with a wide variety of symptoms, ranging from mild to potentially life-threatening. Food allergy can be triggered by any plant or animal protein, but the most common causes of food allergy in children are cow's milk, chicken eggs, wheat, tree nuts, peanuts, fish, seafood, and soy. Meanwhile, vegetables and fruits are the rarest cause of food allergy in infants, but they may cause local skin reactions due to the irritating action of their juice. Such reactions are often incorrectly interpreted as symptoms of food allergy. It should be remembered that brightly colored vegetables and fruits are not more allergenic compared to similar ones of a lighter color. Allergy to stone fruits and certain vegetables occurs only in children with cross-reacting food allergy to plant pollen (pollinosis) and is accompanied by local oral itching, throat tickling, and mild swelling after consuming the product. Both healthy children and children with various allergic diseases (such as atopic dermatitis or allergic rhinitis, etc.) may be sensitive to foods containing high amounts of biogenic amines (histamine, tyramine) or promoting their rapid release in the skin: fermented foods (e.g., sauerkraut), aged cheeses, smoked or canned foods (e.g., fish, meat), citrus fruits, chocolate, etc. In this case, reactions are dose-dependent, never life-threatening, and parents can often determine the amount of the product that does not cause a reaction in the child on their own.

Food allergy causes a wide range of symptoms:

Table 1. Manifestations of food allergy.

Digestive system. In food allergy, the following symptoms may be present:

- itching or swelling of the lips, tongue, palate, and throat, abdominal pain, vomiting, or loose stools;

- infant colic (an uncommon cause of allergy); constipation with soft stools;

- poor appetite, chronic diarrhea, vomiting, failure to thrive, and growth retardation.

Skin. Acute urticaria and angioedema are common symptoms of food allergy, occurring from a few minutes up to 2 hours after ingestion of the offending food. Moderate to severe atopic dermatitis in infancy may be associated with food allergy in 30–40% of cases. Dermatitis that resolves with topical anti-inflammatory medications while the food is continued is not associated with food allergy.

Nose, eyes, and lungs. Hyperemia, eyelid itching, and lacrimation, as well as nasal congestion, nasal pruritus, watery rhinorrhea, and sneezing, can be symptoms of food allergy only in the case of acutely onset symptoms and most often within the framework of an anaphylactic reaction. Long-standing symptoms of isolated allergic rhinitis/conjunctivitis are almost never associated with food allergy.

In the presence of cross-reactivity between pollen and plant foods (e.g., fruits, vegetables, nuts), acute manifestations of allergic rhinitis and conjunctivitis may occur within a few minutes after consuming the product (e.g., oral pruritus and nasal mucosal discharge upon eating apples in children with pollinosis).

Anaphylaxis is the most serious allergic reaction involving 2 or more organ systems (e.g., urticaria and asphyxiation, or facial edema combined with vomiting). Its most severe and potentially fatal manifestation is anaphylactic shock, which presents with a sharp drop in blood pressure and loss of consciousness. If treatment is not initiated promptly, anaphylactic shock can lead to death. The primary treatment for any manifestation of anaphylaxis, even if not severe, is an epinephrine injection.

Diagnosis of food allergy

The diagnosis of food allergy is carried out using research methods that meet the requirements of evidence-based medicine and is primarily based on the anamnesis (medical history). Before visiting a doctor with complaints of certain symptoms, it is necessary to prepare clear information about the likely offending foods that caused the allergic reaction. A carefully prepared history by parents/legal guardians will significantly facilitate the doctor's work, improve cooperation between the patient and the physician, and, accordingly, increase the quality of medical care.

- An important diagnostic method is the diagnostic elimination diet with the exclusion of the suspected offending product for a period of 2 weeks to 1 month, followed by its reintroduction to clarify the recurrence of symptoms (except for cases of severe food allergy and anaphylaxis, as well as food protein-induced enterocolitis syndrome).

- Skin testing. Food allergens represented by food extracts and, in some cases, the foods themselves are used for skin testing. - Laboratory tests. To clarify the nature of the allergy, specific immunoglobulin E antibodies to food antigens are measured in the blood. However, it should be emphasized that negative results of this test do not rule out food allergy in the patient. Measurement of specific IgG ("food intolerance" testing) is not a diagnostic method for food allergy!

In some cases, if the method is available, a basophil activation test with suspected allergens is prescribed.

Treatment of food allergy

To date, there is no cure for food allergy. In the majority of children, symptoms resolve spontaneously by school age or earlier due to the development of oral tolerance to food.

• A diet excluding the offending food (elimination diet) is the primary means of preventing food allergy symptoms. In cases where several foods are excluded, a consultation with a clinical nutritionist is necessary to determine the balance and adequacy of the nutrition.

Important! The question of reintroducing a previously excluded product after the elimination diet period is decided by an allergist-immunologist strictly in accordance with the complaints, clinical presentation, and results of the examination.

• Symptomatic therapy. Prescribed by a physician based on the disease manifestations.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable