Food Allergies and Anaphylaxis

1. Introduction

The immune-mediated adverse reactions to food, culminating in the life-threatening systemic syndrome of anaphylaxis, represent a critical area of study in clinical immunology and pharmacology. These conditions impose a significant burden on public health, affecting quality of life and carrying the risk of fatal outcomes. The prevalence of food allergy has increased in many industrialized nations over recent decades, making its understanding essential for all healthcare practitioners. The management of these conditions sits at the intersection of preventive medicine, acute emergency care, and long-term therapeutic strategy, requiring a nuanced grasp of immunological mechanisms, diagnostic precision, and pharmacotherapeutic intervention.

The historical understanding of food allergy has evolved from nonspecific descriptions of food intolerance to a detailed molecular characterization of immune pathways. The identification of immunoglobulin E (IgE) and its receptor systems in the latter half of the 20th century provided the foundational framework for comprehending immediate hypersensitivity reactions. Subsequent research has elucidated complex cellular interactions, genetic predispositions, and environmental modifiers that dictate clinical presentation.

For medical and pharmacy students, proficiency in this domain is paramount. Pharmacists are often the first point of contact for patients seeking over-the-counter remedies or education on epinephrine auto-injectors. Physicians across specialties, particularly in primary care, pediatrics, emergency medicine, and immunology, must be equipped to diagnose, manage acute episodes, and guide long-term care. The pharmacology of agents used in treatment and prevention, from receptor antagonists to biologic modifiers, requires detailed understanding.

Learning Objectives

• Define food allergy, distinguishing it from food intolerance and other adverse food reactions, and describe the immunological basis of IgE-mediated and non-IgE-mediated pathways.
• Explain the pathophysiology of anaphylaxis, detailing the sequence of mast cell and basophil degranulation, mediator release, and their systemic effects.
• Identify the common food allergens, risk factors for severe reactions, and the clinical criteria for diagnosing anaphylaxis.
• Evaluate the pharmacological management of acute anaphylaxis, with emphasis on the primary role, mechanism of action, and administration of intramuscular epinephrine.
• Discuss the principles of long-term management, including avoidance strategies, emergency action plans, and emerging therapies such as oral immunotherapy.

2. Fundamental Principles

Core concepts in this field are built upon precise definitions and a clear theoretical framework of immune dysregulation. A foundational vocabulary is required to navigate the clinical and scientific literature accurately.

Core Concepts and Definitions

Food Allergy: An adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. This immune response may be immunoglobulin E (IgE)-mediated, non-IgE-mediated (cell-mediated), or involve mixed mechanisms.

Food Anaphylaxis: A severe, life-threatening, generalized or systemic hypersensitivity reaction, most commonly IgE-mediated, that occurs following exposure to a food allergen. It is characterized by rapid onset and involvement of multiple organ systems.

Food Intolerance: A non-immune adverse reaction to food, which may be metabolic (e.g., lactase deficiency), pharmacologic (e.g., reaction to caffeine or histamine in spoiled fish), or idiopathic. It does not involve an adaptive immune response.

Sensitization: The production of specific IgE antibodies following exposure to an allergen, detectable by skin prick test or serum assay. Sensitization alone does not equate to clinical allergy, which requires both sensitization and a reproducible clinical reaction upon exposure.

Oral Tolerance: The normal physiological state of systemic immune non-responsiveness to antigens administered via the oral route. The breakdown of oral tolerance to dietary proteins is a central event in the development of food allergy.

Theoretical Foundations

The development of food allergy is conceptualized as a two-phase process: sensitization and elicitation. Sensitization involves the initial exposure where antigen-presenting cells in the gut mucosa process the food protein and present it to naïve T helper (Th) cells. In genetically predisposed individuals and under permissive environmental conditions (e.g., disrupted epithelial barrier, altered microbiome), this promotes a Th2-polarized response. Th2 cells secrete cytokines such as interleukin (IL)-4 and IL-13, which drive B cells to class-switch and produce allergen-specific IgE. These IgE antibodies bind with high affinity to FcεRI receptors on the surface of mast cells and basophils, completing sensitization.

Upon subsequent exposure, the elicitation phase is triggered. The allergen cross-links two or more adjacent IgE molecules bound to the FcεRI receptor. This cross-linking induces rapid receptor aggregation and intracellular signaling, leading to calcium influx and the exocytosis of preformed and newly synthesized inflammatory mediators from mast cells and basophils. This degranulation event is the central effector mechanism of the immediate hypersensitivity reaction.

Key Terminology

• Allergen: A typically harmless protein capable of triggering an IgE-mediated immune response.
• Degranulation: The rapid release of mediators from mast cell and basophil cytoplasmic granules.
• Epinephrine (Adrenaline): The first-line pharmacological agent for the treatment of anaphylaxis; an alpha- and beta-adrenergic agonist.
• Atopy: The personal or familial tendency to produce IgE antibodies in response to ordinary environmental exposures, manifesting as eczema, allergic rhinitis, or asthma.
• Oral Food Challenge (OFC): The controlled, graded administration of a suspected food under medical supervision to confirm or rule out a clinical allergy; considered the diagnostic gold standard.
• Component-Resolved Diagnostics (CRD): The measurement of specific IgE antibodies against purified native or recombinant allergen molecules, which can help assess the risk of severe systemic versus mild reactions.

3. Detailed Explanation

A comprehensive understanding requires an in-depth exploration of the immunological mechanisms, the clinical progression of anaphylaxis, and the factors that modulate individual risk and reaction severity.

Immunological Mechanisms and Pathways

The pathophysiology can be categorized by the predominant immune mechanism involved.

IgE-Mediated Reactions

This is the most well-characterized and common mechanism for rapid-onset food allergy and anaphylaxis. As detailed in the theoretical foundations, the process hinges on allergen-specific IgE. The consequences of mast cell and basophil degranulation are mediated by a potent cocktail of preformed, newly synthesized, and chemotactic factors.

Preformed Mediators: These are stored in cytoplasmic granules and released immediately upon activation.

• Histamine: Binds to H₁ and H₂ receptors, causing vasodilation, increased vascular permeability, bronchoconstriction, intestinal smooth muscle contraction, pruritus, and tachycardia. It is considered a primary driver of many anaphylactic symptoms.
• Tryptase: A serine protease used as a clinical marker of mast cell activation. It can activate complement and protease-activated receptors, amplifying inflammation.
• Heparin: Contributes to anticoagulation and can modulate the activity of other mediators.
• Chymase, Carboxypeptidase A3: Other proteases with roles in tissue remodeling and inflammation.

Newly Synthesized Lipid Mediators: Generated from membrane phospholipids via the arachidonic acid pathway within minutes of activation.

• Prostaglandin D₂ (PGD₂): Causes bronchoconstriction, vasodilation, and increased mucus secretion. It is also a potent chemoattractant for Th2 cells and eosinophils.
• Leukotriene C₄ (LTC₄): Metabolized to LTD₄ and LTE₄, collectively known as the cysteinyl leukotrienes. These are extremely potent in causing prolonged bronchoconstriction, increased vascular permeability, and mucus production.

Cytokines and Chemokines: Released over hours, these molecules (e.g., TNF-α, IL-4, IL-5, IL-13) orchestrate the late-phase inflammatory response, recruiting eosinophils, neutrophils, and lymphocytes to the site, which can perpetuate symptoms for 24-48 hours.

Non-IgE-Mediated and Mixed Reactions

These reactions involve cellular immune mechanisms without the acute involvement of IgE. They typically have a delayed onset (hours to days) and often present with gastrointestinal or cutaneous symptoms.

• Cell-Mediated (Type IV Hypersensitivity): Allergen-specific T cells, particularly Th1 or Th17 subsets, drive inflammation. Examples include food protein-induced enterocolitis syndrome (FPIES), a severe vomiting and diarrhea illness in infants, and some forms of dietary protein-induced proctocolitis.
• Mixed IgE and Cell-Mediated: Conditions such as eosinophilic esophagitis (EoE) and atopic dermatitis (eczema) may involve both IgE and T-cell pathways, with eosinophils playing a prominent effector role.

The Clinical Syndrome of Anaphylaxis

Anaphylaxis is a clinical diagnosis based on a combination of symptoms and signs occurring rapidly after exposure to a likely trigger. The systemic release of mediators leads to effects across multiple organ systems.

Pathophysiological Sequence

The initial event is a massive shift of fluid from the intravascular to the extravascular space due to widespread vasodilation and increased capillary permeability, mediated by histamine, PGD₂, and leukotrienes. This results in effective hypovolemia and distributive shock. Concurrently, bronchial smooth muscle constriction (from histamine and leukotrienes) and increased mucus production compromise the airway. Coronary artery vasoconstriction and myocardial depression, potentially mediated by platelet-activating factor (PAF) and other mediators, can contribute to cardiovascular collapse. Gastrointestinal smooth muscle contraction leads to cramping, vomiting, and diarrhea.

Diagnostic Clinical Criteria

Diagnosis is typically made when any one of the following three criteria is fulfilled within minutes to hours of exposure:

1. Acute onset of illness (minutes to several hours) with involvement of skin/mucosal tissue (e.g., generalized hives, pruritus, flushing, angioedema) AND at least one of the following:
   • Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia).
   • Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia, syncope, incontinence).
2. Two or more of the following that occur rapidly after exposure to a likely allergen:
   • Skin/mucosal involvement.
   • Respiratory compromise.
   • Reduced blood pressure or associated symptoms.
   • Persistent gastrointestinal symptoms (e.g., cramping, vomiting).
3. Reduced blood pressure after exposure to a known allergen: systolic blood pressure less than 90 mmHg or greater than 30% decrease from that person’s baseline.

Factors Affecting Risk and Severity

The severity of a food allergic reaction is not predictable but is influenced by a confluence of host, allergen, and exposure-related factors.

4. Clinical Significance

The management of food allergy and anaphylaxis is a core clinical competency with direct implications for patient safety and outcomes. The pharmacological approach is stratified into acute emergency treatment and long-term preventive strategies.

Relevance to Drug Therapy

The acute treatment of anaphylaxis is one of the most time-critical pharmacological interventions in medicine. Delays in administering the correct agent are associated with poor outcomes, including death. Furthermore, the chronic management of food allergy involves patient education on avoidance and emergency preparedness, often centered on the prescription and appropriate use of epinephrine auto-injectors. Pharmacists play a vital role in ensuring patients understand the device mechanics, storage requirements, and indications for use.

Practical Applications and Pharmacological Management

First-Line Acute Management: Epinephrine

Intramuscular epinephrine is the unequivocal first-line treatment for anaphylaxis. Its pharmacological actions directly counteract the key pathophysiological processes.

• Alpha-1 Adrenergic Agonist Effect: Causes vasoconstriction, which reverses peripheral vasodilation, reduces edema, and increases blood pressure. This action counteracts distributive shock.
• Beta-1 Adrenergic Agonist Effect: Increases heart rate and myocardial contractility, supporting cardiac output.
• Beta-2 Adrenergic Agonist Effect: Promotes bronchodilation and may suppress further mediator release from mast cells and basophils.

The recommended dose is 0.01 mg/kg of a 1:1000 (1 mg/mL) solution, up to a maximum of 0.5 mg in adults and 0.3 mg in most children, administered by intramuscular injection into the mid-anterolateral thigh. The intramuscular route is preferred over subcutaneous due to more rapid and reliable absorption. Dosing may need to be repeated every 5-15 minutes if there is an inadequate response or symptom recurrence. The failure to use epinephrine, or significant delays in its administration, are consistently identified in reviews of fatal anaphylaxis cases.

Adjunctive Acute Therapies

These agents are considered secondary and should never delay or replace epinephrine administration.

• H₁-Antihistamines (e.g., diphenhydramine, cetirizine): May help relieve cutaneous symptoms like urticaria and pruritus. They do not treat upper or lower airway obstruction, hypotension, or shock. Sedating first-generation agents like diphenhydramine may obscure the clinical assessment of mental status.
• H₂-Antihistamines (e.g., ranitidine, famotidine): Sometimes used in combination with H₁-antagonists for additive effects on cutaneous symptoms, though evidence for their benefit in anaphylaxis is limited.
• Bronchodilators (e.g., albuterol): Used as adjunctive therapy for bronchospasm that persists after epinephrine administration. They are not a treatment for other systemic features of anaphylaxis.
• Glucocorticoids (e.g., methylprednisolone, prednisone): Given to potentially mitigate or prevent a biphasic or protracted reaction, which occurs in a minority of cases. Their onset of action is too slow to affect the initial acute phase.
• Volume Resuscitation: Large volumes of intravenous isotonic crystalloid (e.g., 1-2 liters in an adult, 20 mL/kg in a child) are often required to compensate for profound capillary leak. This is a critical supportive measure in hypotensive patients.
• Oxygen: Administered to all patients with respiratory distress or hypotension to correct hypoxemia.

Long-Term Management and Prevention

The cornerstone of management remains strict avoidance of the identified allergen. This requires meticulous reading of food labels, awareness of cross-contamination risks, and effective communication in restaurant settings. All patients with a history of anaphylaxis, or those with food allergy and asthma, should be prescribed an epinephrine auto-injector and provided with a written emergency action plan. Regular review of device technique and expiry dates is essential.

Pharmacological prevention is an area of active research and evolving clinical practice. Oral Immunotherapy (OIT) involves the daily ingestion of small, gradually increasing amounts of the allergenic food protein to induce desensitization—a temporary state of increased reaction threshold while on therapy. While OIT can raise the threshold for reaction, it does not typically induce permanent tolerance (sustained unresponsiveness after therapy cessation) in most patients. The process carries a significant risk of allergic reactions, including anaphylaxis, during the updosing and maintenance phases. It is generally considered for selected patients under the care of allergy specialists.

Other investigational approaches include epicutaneous immunotherapy (a patch delivering allergen through the skin) and sublingual immunotherapy, as well as biologic agents such as omalizumab, a monoclonal anti-IgE antibody. Omalizumab may be used as an adjunct to OIT to reduce the frequency and severity of treatment-related reactions, or it is being studied for its potential to modify the allergic disease itself.

5. Clinical Applications and Examples

The application of theoretical knowledge is best illustrated through clinical scenarios that highlight diagnostic reasoning, acute management decisions, and long-term strategic planning.

Case Scenario 1: Initial Presentation and Diagnosis

A 3-year-old boy with a history of moderate atopic eczema is given a small piece of peanut butter cookie at a party. Within 10 minutes, he develops perioral urticaria, facial angioedema, and repetitive coughing. His parents administer a children’s antihistamine and bring him to the emergency department. On arrival, he is anxious, with audible wheezing, a widespread urticarial rash, and a heart rate of 140 bpm. Blood pressure is normal for age.

Clinical Reasoning and Management: This presentation meets clinical criteria for anaphylaxis (acute skin/mucosal involvement plus respiratory compromise). The immediate action is administration of intramuscular epinephrine (0.15 mg for a ~15 kg child) into the anterolateral thigh. Adjunctive measures would include supplemental oxygen, albuterol nebulization for persistent wheeze, and possibly H₁-antihistamine and corticosteroids. Following stabilization, the diagnosis of peanut allergy is highly probable. Confirmation would involve referral to an allergist for testing (skin prick test and/or specific IgE to peanut) and, if indicated and safe, a supervised oral food challenge. Prior to discharge, the family must be prescribed an epinephrine auto-injector, trained in its use, and given a written emergency action plan. Counseling on strict peanut avoidance is initiated.

Case Scenario 2: Anaphylaxis in a Patient on Confounding Medications

A 65-year-old woman with a known shellfish allergy, hypertension treated with lisinopril (an ACE inhibitor), and coronary artery disease accidentally consumes a soup containing shrimp stock at a restaurant. She rapidly feels throat tightness, lightheadedness, and collapses. Emergency medical services find her hypotensive (70/40 mmHg) with diffuse urticaria and stridor.

Clinical Reasoning and Management: This is severe anaphylaxis with hypotension and upper airway involvement. Epinephrine remains the first-line treatment, but its vasopressor effects may be blunted or the hemodynamic response may be unpredictable in patients on ACE inhibitors, which inhibit the compensatory renin-angiotensin system. Furthermore, beta-blocker therapy (not present here but a common co-medication) can blunt the response to epinephrine and potentially lead to severe hypertension from unopposed alpha effects. Aggressive volume resuscitation with normal saline is critical. Repeated doses of epinephrine may be required. Advanced airway management may be necessary for laryngeal edema. This case underscores the importance of reviewing a patient’s medication list as part of allergy risk assessment and the potential for more complicated treatment courses in comorbid adults.

Case Scenario 3: Long-Term Management and Immunotherapy

A 7-year-old girl with a history of anaphylaxis to cashew nut desires to begin oral immunotherapy (OIT). Her current reaction threshold is less than one-quarter of a cashew nut. She has well-controlled asthma.

Clinical Reasoning and Approach: OIT is not a decision taken lightly. A thorough discussion of goals, risks, and commitments is required. The family must understand that OIT aims primarily to provide protection against accidental ingestion (desensitization), not a cure. The process involves months of updosing under clinical supervision, where reactions are common, followed by a long-term daily maintenance dose at home. The risk of anaphylaxis during treatment is present. Contraindications include poorly controlled asthma, which would increase the risk of severe respiratory reactions. Shared decision-making is essential. If pursued, the protocol would start with a minuscule, sub-threshold dose of cashew protein in a supervised clinic, with gradual increases every 2-4 weeks until a target maintenance dose (e.g., the equivalent of 1-2 cashew nuts) is reached. The patient must continue to carry epinephrine at all times, as reactivity can vary. This case illustrates the application of an emerging therapy within a rigorous risk-benefit framework.

6. Summary and Key Points

The management of food allergy and anaphylaxis is a dynamic field requiring integration of immunology, pharmacology, and clinical medicine.

Summary of Main Concepts

• Food allergy is an immune-mediated adverse reaction, distinct from food intolerance. IgE-mediated mechanisms underlie most acute and anaphylactic reactions.
• Anaphylaxis is a clinical diagnosis of a severe, systemic hypersensitivity reaction. It is characterized by rapid onset and involvement of two or more organ systems (skin, respiratory, cardiovascular, gastrointestinal).
• The central pathophysiological event is mast cell and basophil degranulation, releasing histamine, tryptase, leukotrienes, and other mediators that cause vasodilation, increased permeability, bronchoconstriction, and tissue inflammation.
• Intramuscular epinephrine is the first-line, life-saving treatment for anaphylaxis. Its alpha-agonist effects reverse shock, and its beta-agonist effects reverse bronchospasm and may stabilize mast cells. Delays in administration are associated with poor outcomes.
• Adjunctive therapies (antihistamines, bronchodilators, corticosteroids) are secondary and should not delay epinephrine.
• Long-term management hinges on strict allergen avoidance, patient education, and preparedness with an epinephrine auto-injector and emergency action plan.
• Oral immunotherapy is an emerging treatment that can induce desensitization but carries significant risk and is not yet considered standard first-line care for all patients.

Clinical Pearls

• The dose of epinephrine for anaphylaxis is 0.01 mg/kg (max 0.5 mg adult, 0.3 mg child) of 1:1000 solution IM in the mid-outer thigh. It can be repeated every 5-15 minutes as needed.
• Skin symptoms are absent in up to 20% of anaphylactic reactions, particularly in cases of profound hypotension (“anaphylaxis without urticaria”). Do not withhold epinephrine due to lack of skin findings if other systemic criteria are met.
• Biphasic reactions, where symptoms recur 1-72 hours after the initial event without re-exposure, occur in less than 5% of cases but warrant observation. The utility of corticosteroids in preventing this is unproven but commonly practiced.
• Measurement of serum tryptase can support the diagnosis of anaphylaxis if a sample is obtained 1-2 hours after symptom onset and compared to a baseline level. A markedly elevated level is suggestive of mast cell activation.
• Patients and caregivers must understand that antihistamines are not a treatment for anaphylaxis; they only mitigate mild cutaneous symptoms. Reliance on antihistamines alone in a systemic reaction is dangerous.
• Pharmacists are critical in ensuring patients filling epinephrine auto-injector prescriptions receive appropriate counseling on storage (not in extreme heat or cold), expiration dates, and, ideally, training with a demonstration device.

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