Food allergy

• The prevalence of food allergy has increased in recent decades and is now recognized as a substantial public health burden in developed countries, following the epidemics of asthma and allergic rhinitis that rose to prominence in the last few decades of the 20th century
• Food allergy


  The breakdown of clinical and immunological tolerance against ingested foods
• Types of food allergy

  • IgE-mediated diseases
  • Non-IgE-mediated conditions (eosinophilic oesophagitis, allergic proctocolitis, food protein-induced enterocolitis)
• The typical symptoms of food allergy include disturbances to the skin, respiratory tract and gastrointestinal tract as well as cardiovascular aberrations
• Anaphylaxis


  Immediate hypersensitivity to food that can involve several organ systems and induce life-threatening hypovolaemic shock and respiratory compromise
• Tolerance


  A key mechanism to prevent chronic inflammatory diseases, such as food allergies, later in life. Tolerance is acquired, relies on antigen exposure, is antigen-specific and represents a lifelong process that starts prenatally
• Innate and adaptive immune responses cooperate in a coordinated fashion to mount tolerance; with regard to food antigens, tolerance requires food antigen exposure, which starts in utero
• Extrinsic environmental and lifestyle factors, including the qualitative and quantitative composition of the microbiota, have been linked to food allergies
• Major advances have been achieved in basic, translational and clinical research, improving our mechanistic understanding of food allergy and enabling the development of therapeutic and preventive measures
• The main 'therapy' for food allergies remains strict allergen avoidance, which is not always possible and can lead to accidental reactions
• Exciting therapies are in clinical development, including treatment with biological therapies as well as allergen-specific therapies — such as oral, sublingual and epicutaneous immunotherapy
• Prevention of food allergies remains a key challenge. To develop effective preventive measures, the contributing factors for the development of food allergies need to be defined
• Hypotheses developed to explain the development of food allergies

  • Dual-allergen exposure hypothesis
  • Hygiene hypothesis
  • Vitamin D hypothesis
• This Primer provides a comprehensive overview of the recent advances in the field of food allergy in terms of mechanistic understanding, diagnostics, prevention and management
• Nonallergic reactions (for example, food intolerance) or food-induced dermatitis are not discussed in detail
• Globally, Australia has the highest prevalence of IgE-mediated food allergy, with 10% of infants demonstrating challenge-confirmed allergies to one or more foods
• Other developed areas such as Europe and the United States have prevalence estimates of 1–5%
• Estimating the prevalence of food allergies is difficult because the gold standard is the performance of a controlled food challenge, which can only be performed in specialized centres
• The proportion of cases due to food-related anaphylaxis admission is likely large, but definite numbers are not available
• The prevalence of food-related anaphylaxis in the general population is probably between 0.5% and 2.5% in the United States
• Population-based studies that assess changes in prevalence of food allergy have primarily focused on peanut allergy, with evidence of increasing prevalence in the United Kingdom and United States
• Many individuals with food allergy will naturally outgrow it over time, but the natural course highly depends on the causative allergen
• Hen egg and cow milk allergy are frequently outgrown, whereas peanut and tree nut allergies tend to persist for life
• Food allergy comprises several immunological mechanisms that drive the reactions to ingested antigens
• IgE-mediated food reactions


  Absorption of the allergen through the intestinal epithelium and access to the mucosa and bloodstream where immune effector cells reside are enhanced in those with food allergy. The ingested food allergens interact with IgE and its high-affinity Fc receptor (FcεRI) on mast cells in mucosal tissues and on circulating basophils, leading to the activation of these cells
• Mast cell and basophil activation


  Triggers the release of mediators that lead to very rapid physiological responses in a number of target tissues, including the gastrointestinal tract
• Unlike other forms of systemic anaphylaxis, reactions to food are not typically associated with elevations in plasma levels of tryptase
• Food reactions have been associated with elevated plasma levels of PAF, a product of activated macrophages, along with reduced amounts of its inactivating enzyme, PAF acetylhydrolase
• Reactions to food are not typically associated with elevations in plasma levels of tryptase
• The absence of detectable tryptase cannot be taken to exclude the possibility of anaphylaxis in a patient who has experienced an acute reaction to food
• Food allergen-induced basophil activation has been reported to induce the activation of platelets and formation of basophil–platelet complexes
• Food allergens most commonly associated with anaphylaxis


  • Peanuts
  • Tree nuts
  • Shellfish
• Severe reactions can occur with a wide range of foods, with cow milk and hen eggs being additional major triggers in young children
• In the Mediterranean basin, fruits and vegetables that contain low-molecular-mass lipid transfer proteins (which are highly cross-reactive between foods) are the major cause of anaphylaxis
• IgE antibodies that are produced in response to the oligosaccharide galactose-α-1,3-galactose (α-gal), which are typically introduced during tick bites, can lead to reactions that are delayed by several hours when ingesting mammalian meat
• Certain murine models administered high-dose intravenous antigen challenge can initiate an anaphylaxis response in the absence of IgE by cognate interaction with specific immunoglobulin G (IgG) antibodies bound to activating Fcγ receptors on effector cells
• There is evidence that under similar intravascular challenge, such IgG-mediated hypersensitivity reactions can arise in humans
• IgG signals can activate both the classic mast cell pathway of mediator release (similar to the IgE–FcεRI-mediated reactions) and an alternative pathway that results in the production of PAF by macrophages
• Only IgE antibodies trigger histamine release by mast cells and basophils
• Reactions to enteral challenge have been shown to be fully IgE-dependent in several murine models of food allergy