Allergies

Types of Allergic Reactions

IgE-mediated (Type I Hypersensitivity)

• Mechanism: Involves the production of immunoglobulin E (IgE) antibodies in response to an allergen. Upon re-exposure, the allergen binds to IgE on mast cells and basophils, triggering degranulation and release of histamine and other mediators.
• Common Conditions:
  • Anaphylaxis: Severe, life-threatening systemic reaction.
  • Allergic Rhinitis (Hay Fever): Sneezing, runny nose, itchy eyes.
  • Asthma: Wheezing, shortness of breath, chest tightness.
  • Food Allergies: Hives, gastrointestinal symptoms, anaphylaxis.
  • Urticaria (Hives): Raised, itchy welts on the skin.
  • Atopic Dermatitis (Eczema): Chronic itchy and inflamed skin.
• Symptoms:
  • Stereotypical signs and symptoms develop usually within 60 minutes of ingestion.
  • Rapid onset (minutes to hours) after exposure.
  • Localized or systemic: hives, angioedema, respiratory distress, gastrointestinal symptoms, cardiovascular collapse (in anaphylaxis).

Pathlogy:

1. First Exposure: Sensitization Phase
   • allergic reactions do not occur on first exposure to an allergen. The development of IgE-mediated allergies requires prior sensitization
   • An antigen introduced into the body is recognized as a foreign substance.
   • The body produces immunoglobulin E (IgE) antibodies to combat the antigen.
   • IgE antibodies attach to mast cells (found in connective tissue) and basophils (immature mast cells in the blood).
   • These antibodies can remain attached for varying durations (seconds to years).
   • As long as the antibodies are attached, the patient is sensitized and primed for a reaction upon re-exposure.
2. Re-exposure Mechanism:
   • When the person is re-exposed to the same allergen, the allergen binds to the IgE antibodies on the surface of the mast cells and basophils.
   • This binding triggers the degranulation of these cells, releasing chemical mediators like histamine, leukotrienes, and prostaglandins.
   • The release of these mediators causes the symptoms of an allergic reaction, such as hives, itching, swelling, respiratory distress, and in severe cases, anaphylaxis.
3. Chemical Mediators:
   • Common mediators: histamine, leukotriene, prostaglandin, tryptase.
   • These mediators are absorbed by capillaries, enter the blood, and circulate throughout the body, producing systemic multi-organ signs and symptoms.
4. Severity of Reaction:
   • The systemic and multi-organ response requires a sufficient release of mediators from mast cells and basophils.
   • Small amounts of mediators cause minor symptoms.
   • The extent of signs and symptoms depends on the response of organs and vascular structures to the mediators.
5. IgE Antibodies
   • Abundance: Extremely low compared to other antibody classes.
   • Distribution: Approximately 50% free, 50% bound to IgE receptors on effector cells (mast cells, basophils).
   • Half-Life:
     • Free IgE: Few days.
     • Cell-bound IgE: About 2 months.
   • Activation: Cross-linking of cell-bound IgE by allergen leads to release of histamine and other inflammatory mediators.
   • Sensitivity: Cross-linking of about 1% of IgE molecules is sufficient for half-maximal activation.

Common Aeroallerens implicated in IgE-mediated allergy

• Dust mite
• pollens (grass, tree, weed)
• animal epithelia
• moulds
  • Mediates: Allergic rhinitis and allergic asthma.
  • Symptoms: Sneezing, rhinorrhoea, itchy/watery eyes, bronchospasm.
  • Trigger Clues: Seasonal rhinitis (pollen), exacerbation from lawn mowing, animal exposure.

The commonest foods implicated in IgE-mediated allergy are: 

• Peanut
• tree nuts
• shellfish
• fish
• milk
• egg
• wheat
• soy
• sesame

Common

• Insect stings (most commonly honeybee, ants, wasps)
  • Honey bee venom (Apis mellifera)
  • Paper wasp venom (Pollistes spp)
  • Common wasp (Vespula spp)
  • Fire Ant (whole-body allergen extract)
  • Jumper Ant (Myrmecia pilosula) –
• Medications (most commonly antibiotics, non-steroidal anti-inflammatory drugs, contrast-induced anaphylactoid reactions, immunotherapy)
• Unidentified (no cause found, more than 50% of cases)

Uncommon

1. Physical triggers (exercise, heat, cold, UV light)
2. Biological fluids (transfusions, immunoglobulin, antivenoms, semen)
3. Latex
4. Tick bites
5. Hormonal changes (breastfeeding, menstrual factors)
6. Dialysis membranes (haemodialysis-associated anaphylaxis)
7. Hydatid cyst rupture
8. Aeroallergens (domestic/laboratory animals, pollen)
9. Food additives (monosodium glutamate, metabisulfite, preservatives, colours, natural food chemicals)
10. Topical medications (antiseptics)

Children with IgE-mediated food allergy frequently have other atopic disease, such as

• Asthma, Eczema, allergic rhinitis

Anaphylactoid Reactions vs. Anaphylactic Reactions

Anaphylactoid reactions (now often referred to as non-IgE-mediated anaphylaxis or non-allergic anaphylaxis) are similar to anaphylactic reactions but occur without prior sensitization and IgE antibody involvement. Here’s a detailed comparison and explanation:

Anaphylactoid Reactions (Non-IgE-Mediated)

• Mechanism:
  • Direct release of chemical mediators (histamine, leukotrienes, prostaglandins, tryptase) from mast cells and basophils without the involvement of IgE antibodies.
  • Can be triggered on first exposure to certain substances.
• Common Triggers:
  • Medications: Vancomycin, opiates, NSAIDs, local anesthetics, monoclonal antibodies, chemotherapeutic agents.
  • Contrast Agents: Used in imaging studies.
  • Others: Exercise, temperature changes, certain foods, and preservatives.
• Symptoms:
  • Similar to IgE-mediated anaphylaxis and include:
    • Skin: Hives, flushing, itching.
    • Respiratory: Wheezing, shortness of breath, throat tightness.
    • Gastrointestinal: Nausea, vomiting, diarrhea.
    • Cardiovascular: Hypotension, tachycardia, dizziness.
    • Severe cases: Anaphylactic shock with multiple organ involvement.
• Diagnosis:
  • Based on clinical presentation and history of exposure to known anaphylactoid triggers.
  • No need for prior sensitization; can occur on first exposure.
• Treatment:
  • Identical to the treatment of IgE-mediated anaphylaxis.
  • Immediate administration of intramuscular epinephrine.
  • Supportive care: Antihistamines, corticosteroids, bronchodilators, intravenous fluids.
  • Close monitoring for severe reactions.

Anaphylactic Reactions (IgE-Mediated)

• Mechanism:
  • Involves prior sensitization to an allergen, leading to the production of IgE antibodies.
  • Upon re-exposure, the allergen binds to IgE on mast cells and basophils, causing degranulation and release of chemical mediators.
• Common Triggers:
  • Food Allergens: Peanuts, tree nuts, shellfish, milk, eggs.
  • Insect Stings: Bees, wasps, hornets.
  • Medications: Penicillin, other antibiotics.
  • Environmental Allergens: Pollen, pet dander.
• Symptoms:
  • Similar to those of anaphylactoid reactions and include:
    • Skin: Hives, angioedema, itching.
    • Respiratory: Wheezing, shortness of breath, throat tightness.
    • Gastrointestinal: Nausea, vomiting, diarrhea.
    • Cardiovascular: Hypotension, tachycardia, dizziness.
    • Severe cases: Anaphylactic shock with multiple organ involvement.
• Diagnosis:
  • Based on clinical presentation and history of prior exposure and sensitization.
  • Confirmed by allergen-specific IgE testing or skin prick testing.
• Treatment:
  • Immediate administration of intramuscular epinephrine.
  • Supportive care: Antihistamines, corticosteroids, bronchodilators, intravenous fluids.
  • Avoidance of known allergens.
  • Biphasic Reaction
    • the recurrence of anaphylaxis symptoms soon after the initial episode
    • occur about 5-20% of the time
    • an average of 4 to 8 hours after the original episode, even with adequate treatment
    • may occur >24 hours after the initial episode
    • usually less severe than the initial episode
    • possible risk factors include:
      • delayed administration of adrenaline
      • slow response to adrenaline
      • need for repeated doses of adrenaline
      • need for IV fluids

Key Points:

• Indistinguishable Presentation: Both anaphylactic and anaphylactoid reactions present with similar signs and symptoms, making them clinically indistinguishable without history.
• Treatment: Both conditions are treated identically with immediate administration of epinephrine and supportive measures.
• Mechanism: Anaphylactic reactions require prior sensitization and are IgE-mediated, whereas anaphylactoid reactions can occur on first exposure and are not IgE-mediated.

Non-IgE-mediated

Mechanism: Does not involve IgE antibodies. Reactions can be mediated by other immunologic mechanisms such as T-cells or immune complexes.

Pathophysiology

• Antigen Presentation:
  • Antigens are taken up by antigen-presenting cells (APCs) like dendritic cells.
  • APCs process the antigen and present it to T-cells.
• T-cell Activation:
  • In many non-IgE-mediated reactions, T-cells play a central role.
  • T-helper cells (Th1 or Th2) release cytokines that mediate inflammation and recruit other immune cells.
• Immune Response:
  • The activated T-cells and recruited immune cells (e.g., macrophages, eosinophils) release various inflammatory mediators.
  • These mediators can cause tissue damage and inflammation directly or indirectly.
• Chronic Inflammation:
  • Persistent exposure to the antigen can lead to chronic inflammation and tissue remodeling.

Common Conditions:

• Contact Dermatitis: T-cell-mediated response causing skin rash after contact with allergens like nickel or poison ivy.
• Celiac Disease: Autoimmune response to gluten involving T-cells, leading to gastrointestinal and systemic symptoms.
• Food Protein-Induced Enterocolitis Syndrome (FPIES): Non-IgE gastrointestinal reaction to foods in infants.
• Drug Reactions: Non-IgE-mediated hypersensitivity reactions to medications.

Symptoms:

• Delayed onset (hours to days) after exposure.
• Localized or systemic: dermatitis, gastrointestinal distress, respiratory symptoms, systemic symptoms depending on the condition.

Examples and Specific Pathophysiology

1. Celiac Disease:
   • Trigger: Gluten (a protein found in wheat, barley, and rye).
   • Pathophysiology:
     • Gluten peptides are presented by APCs to T-cells in the gut.
     • T-cells release cytokines, leading to inflammation and damage to the intestinal mucosa.
     • This results in villous atrophy, crypt hyperplasia, and malabsorption.
   • Symptoms: Diarrhea, abdominal pain, bloating, weight loss, fatigue.
2. Contact Dermatitis:
   • Trigger: Metals (nickel), chemicals (cosmetics, detergents), plants (poison ivy).
   • Pathophysiology:
     • Allergen penetrates the skin and binds to proteins, forming a complex recognized as foreign.
     • Langerhans cells (a type of APC) process the allergen and present it to T-cells.
     • T-cells release cytokines and chemokines, leading to local inflammation and skin rash.
   • Symptoms: Red, itchy rash, blisters, swelling at the site of contact.
3. Food Protein-Induced Enterocolitis Syndrome (FPIES):
   • Trigger: Certain foods (e.g., cow’s milk, soy, grains).
   • Pathophysiology:
     • Ingestion of the trigger food leads to activation of T-cells in the gut.
     • T-cells release inflammatory cytokines, causing inflammation and damage to the intestinal lining.
   • Symptoms: Vomiting, diarrhea, dehydration, lethargy.
4. Hypersensitivity Pneumonitis:
   • Trigger: Inhaled organic dusts (mold, bird droppings).
   • Pathophysiology:
     • Inhaled antigens are engulfed by macrophages and presented to T-cells.
     • T-cells release cytokines, leading to recruitment of other immune cells and granuloma formation in the lungs.
     • Chronic exposure leads to fibrosis and reduced lung function.
   • Symptoms: Cough, shortness of breath, fatigue, fever.

Treatment and Management

• Avoidance: Identifying and avoiding the trigger is crucial.
• Medications:
  • Anti-inflammatory drugs (corticosteroids) to reduce inflammation.
  • Immunosuppressive agents in severe cases.
  • Non-IgE-mediated reactions often involve other inflammatory mediators and cells, such as T-cells, cytokines, and immune complexes. Histamine may play a minimal role in these reactions. therefore Anti-histamines might not be effective
• Dietary Management: In conditions like celiac disease, strict adherence to a gluten-free diet.

Mixed IgE and Non-IgE-mediated

1. Mechanism: Involves both IgE-mediated and non-IgE-mediated mechanisms.
2. Common Conditions:
   • Eosinophilic Esophagitis: Chronic immune-mediated esophageal disease with both IgE and T-cell involvement.
   • Atopic Dermatitis: In some cases, involves both IgE and non-IgE mechanisms.
3. Symptoms:
   • Vary depending on the condition, can include a combination of IgE-mediated and non-IgE-mediated symptoms.

Other Hypersensitivity Reactions

1. Type II Hypersensitivity (Cytotoxic)
   • Mechanism: IgG or IgM antibodies directed against cell surface or extracellular matrix antigens, leading to cell destruction.
   • Common Conditions:
     • Hemolytic Anemia: Destruction of red blood cells.
     • Goodpasture Syndrome: Autoantibodies against basement membrane in lungs and kidneys.
   • Symptoms:
     • Hemolysis, tissue-specific damage.
2. Type III Hypersensitivity (Immune Complex)
   • Mechanism: Formation of antigen-antibody complexes that deposit in tissues and cause inflammation.
   • Common Conditions:
     • Systemic Lupus Erythematosus (SLE): Immune complexes deposit in various organs causing systemic inflammation.
     • Serum Sickness: Reaction to foreign proteins in sera.
   • Symptoms:
     • Vasculitis, arthritis, nephritis.
3. Type IV Hypersensitivity (Delayed-type)
   • Mechanism: T-cell-mediated response causing inflammation and tissue damage.
   • Common Conditions:
     • Contact Dermatitis: Skin reaction to allergens like poison ivy.
     • Tuberculosis (TB) Skin Test: Delayed reaction to tuberculin antigen.
   • Symptoms:
     • Delayed onset (48-72 hours), localized inflammation, granuloma formation.