hypersensitivity and anaphylaxis

block 2 week 2 ctb

hypersensitivity

• one of 3 ways in which immune responses can be harmful to the body overall

• includes:

  • allergy: relatively localised, mild-moderate reactions

  • anaphylaxis: systemic, life-threatening reactions

epidemiology/risk factors

• 7% of children in UK develop allergies during childhood

• many do not persist into adulthood

• common food allergies:

  • milk

  • eggs

  • bananas

  • nuts

  • sesame seeds

  • fish

  • shellfish

• possible reasons

  • improved hygiene and less parasitic infections

  • vit D deficiency

  • dietary changes (later introduction of food items)

hypersensitivity

• inappropriate and excessive immunological reaction to an external antigen due to dysfunctional control of the immune system

• allergy = local reaction (mucous membranes, skin, lungs)

• anaphylaxis = systemic reaction (shock and death)

• allergen = antigen that induces hypersensitivity reaction

autoimmunity

inappropriate immune response to self‑antigens (autoantigens).

most relevant cells in hypersensitivity

• mast cells

• eosinophils

• basophils

innate and adaptive immunity diagram

hypersensitivity involves both innate and adaptive immune responses

innate immune system

• Rapid, non‑specific, no memory.

• Cellular and humoral components.

adaptive immune responses

• Slower onset, highly specific.

• Generates immunological memory.

type I hypersensitivity: immediate/IgE mediated

• mediators:

  • IgE

  • mast cells

  • basophils

  • eosinophils

• examples:

  • allergies

  • anaphylaxis

  • asthma

  • atopy

type II hypersensitivity: AB-dependent

• mediators:

  • IgM

  • IgG

• examples:

  • autoimmune haemolytic anaemia

  • Goodpasture’s Syndrome

  • myasthenia gravis

  • Graves

type III hypersensitivity: immune complex mediated

• mediators:

  • immune complex

• examples:

  • serum sickness

  • extrinsic allergic alveolitis (EAA)

  • rheumatoid arthritis

  • systemic lupus erythematosus

type IV hypersensitivity: delayed/cell-mediated

• mediators:

  • T lymphocytes

  • macrophages

• examples:

  • allergic contact dermatitis

  • chronic transplant rejection

  • multiple sclerosis

  • tuberculin skin test

type I hypersensitivity

• mast derived mediators (vasoactive amines, lipid mediators, cytokines)

• cytokine mediated inflammation (eosinophils, neutrophils)

type II hypersensitivity

• complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils and macrophages)

• opsonisation and phagocytosis of cells

• abnormalities in cellular function (eg hormone receptor signalling)

type III hypersensitivity

• complement and Fc receptor mediated recruitment and activation of leukocytes

type IV hypersensitivity

1. macrophage activation, cytokine-mediated inflammation

2. direct target cell lysis, cytokine mediated inflammation

epidemiology of type I hypersensitivity

• ~20% of people in developed countries experience allergy at some point.

• Atopy:

  • Genetic/familial predisposition to allergy (e.g. eczema, asthma).

  • Environmental factors also important.

common allergens/presentations of type I hyoersensitivity

• Environmental:

  • Pollens → hay fever

  • House dust mites

  • Animal dander

• Insect venoms:

  • Bee stings, wasps (risk of anaphylaxis)

• Food and drugs:

  • Higher risk of systemic exposure and anaphylaxis.

pathology of type I hypersensitivity

mast cell degranulation of hype I hypersensitivity

clinical features of type I hypersensitivity

• Sensitisation occurs first (IgE production & binding to mast cells)

• Thereafter exposure generates immediate response (degranulation)

• Airway & eye mucous membranes → pruritus & sneezing

    rhinorrhoea & lacrimation

• Skin → pruritus & urticaria (also seen in Type IV reactions)

• Oral & intestinal mucous membranes → pruritus & angioedema

• Systemic exposure → anaphylaxis =  local swelling, flushed, faint, dyspnoea, peri-oral paraesthesia, throat/chest tightness, wheeze, pale, sweaty, hypotensive

pathophysiology of type I hypersensitivity in depth

Sensitisation Phase (First Exposure)

• Allergen recognised by:

  • B cells

  • T helper 2 (Th2) cells

• B cells differentiate into plasma cells producing IgE.

• IgE binds via Fc region to receptors on:

  • Mast cells

  • Eosinophils

  • Basophils

• No clinical symptoms at this stage.

Activation Phase (Second Exposure)

• Allergen binds to IgE on mast cell surface.

• Triggers mast cell activation and degranulation.

Mast Cell Degranulation

• Release of:

  • Preformed granules:

    • Vasoactive amines (e.g. histamine)

    • Proteases

  • Lipid mediators:

    • Prostaglandins

    • Leukotrienes

  • Cytokines:

    • Recruit additional immune and inflammatory cells

type IV hypersensitivity

• Pathology = usual T cytotoxic cell response (slow & specific), but still inappropriate & excessive (as per definition)

• So unlike Type 1 (immediate/IgE-mediated) hypersensitivity,

• Type IV (delayed/cell-mediated) = slower & more specific/localised

• Various allergens causing few diseases :

   eg. nickel, other metals, latex

   → allergic contact dermatitis (slowly developing, pruritic, localised)

• Other examples not truly “inappropriate & excessive” (eg. chronic organ rejection) or else autoimmune (eg. MS) or diagnostic (eg. TST)

• Clinical features = slowly developing, localised immune reactions

investigations for hypersensitivity

Laboratory Markers

• Tryptase:

  • Released from mast cells

  • Elevated in Type I reactions

• IgE: often raised

• Eosinophil count: may be raised

Skin Testing

Skin Prick Testing

• Small drops of allergens applied to skin.

• Skin pricked with stylet.

• Read at ~15 minutes.

• Positive if lesion is ≥3 mm larger than negative control.

• Controls:

  • Negative: saline

  • Positive: histamine

Patch Testing

• Used for multiple allergens.

• No skin pricking.

• Patches left in place for 2–3 days.

• Useful for Type IV reactions.

hypersensitivity treatments

Avoidance

• Avoid known allergens where possible.

Pharmacological Treatment

• Mast cell stabilisers:

  • Prevent degranulation

  • Often t

  • opical (eye drops, nasal sprays)

• Antihistamines:

  • Block histamine receptors

  • Topical or systemic

• Steroids:

  • Reduce inflammation and immune response

  • Topical or systemic

• Leukotriene receptor antagonists:

  • Block inflammatory mediators

  • Systemic tablets

• De-sensitisation :  also called “allergen immunotherapy”

    relies on creating tolerance to allergens

    by exposure to gradually increasing doses

    delivered sublingually or subcutaneously

    small risk of anaphylaxis during therapy

    requires weekly/monthly treatment for ~3 years

ABC treatment of hypersensitivity

• Airway – Breathing – Circulation

  • Lie patient down

  • High-flow oxygen

  • IV fluids

• Adrenaline (epinephrine) 500 mcg IM (0.5 ml of 1mg/ml)

  • IV chlorphenamine (anti-histamine)

  • IV hydrocortisone (steroid)

  • Nebulised salbutamol (bronchodilator)

• Repeat adrenaline IM if no improvement after 5 minutes