Respiratory Immunology 3: Allergic Disease

Question 1

Hypersensitivity reactions definition?

Answer 1

Immune response that results in bystander damage to self (exaggeration of normal immune mechanisms), inc. allergic disease and autoimmunity

Question 2

Classifications of hypersensitivity reactions?

Answer 2

Type 1: Immediate sensitivity (allergic diseases)

Type II: Direct cell killing

Type III: Immune complex mediated

Type IV: Delayed type hypersensitivity

Question 3

Allergy definition?

Answer 3

IgE-mediated antibody response to an external antigen (although, not all allergic-type diseases are mediated by IgE reactions)

NOT ALL ADVERSE REACTIONS ARE ALLERGIC REACTIONS

Question 4

Allergic conditions?

Answer 4

Asthma
Allergic rhinitis (hayfever)
Allergic conjunctivitis
Urticaria - raised itchy rash on skin, i.e: hives, welts, nettle rash
Angioedema - self-limited; localised, rapid swelling of subcutaneous tissues/mucous membranes (non-pitting oedema, often with clear demarcation and is usually not itchy, unless associated with urticaria)
Atopic eczema
Food allergy - many believe they have this and do not
Drug allergy
Diarrhoea and vomiting
Anaphylaxis

Question 5

Risk factors for allergic disease?

Answer 5

Genetic susceptibility to allergic disease - unlikely to be cause of increasing prevalence

ENVIRONMENTAL FACTORS:
“Westernised”/industrialised countries
Small family size - later child less likely to have allergy than earlier

Question 6

Factors causing immune system maturation?

Answer 6

Infections (bacterial/viral) contracted from siblings/peers enhance maturation and so protect against allergy and asthma

Question 7

Clinical features of Type I allergic disease?

Answer 7

Generic feature:
Occurs QUICKLY AFTER EXPOSURE (exception - food allergies) and can be associated with > 1 organ system
Presentation is influenced by SITE OF CONTACT
THRESHOLD for reactions may be influences by co-factors, e.g: EXERCISE, ALCOHOL, INFECTION

Question 8

Allergen examples?

Answer 8

House dust mite
Pollen and animal dander
Foods
Drugs
Latex
Bee and wasp venom 

Many are soluble proteins that function as enzymes

Question 9

Cells involved with allergic disease and their role?

Answer 9

B lymphocytes - recognise antigen and produce antigen-specific IgE antibody

T lymphocytes - provide B lymphocytes with help to make IgE antibody

Mast cells - inflammatory cells releasing VASOACTIVE SUBSTANCES

Question 10

Where do mast cells reside?

Answer 10

In tissues, esp. at interface with external environment; do not circulate in large numbers

Question 11

What do mast cells do in allergic disease?

Answer 11

Produce vasoactive substances:
Preformed- HISTAMINE, TRYPTASE (can be measured), HEPARIN
Synthesised on demand - LEUKOTRIENES, PROSTAGLANDINS, CYTOKINES, like IL4 and TNF

Orchestrate INFLAMMATORY CASCADE - increase blood flow, contraction of smooth muscle, increase vascular permability and secretions at mucosal surfaces

Question 12

Mast cell receptors?

Answer 12

Express Fc receptors on their surface, for Fc region of IgE antibody

Question 13

How do allergies arise, specifically due to mediation by mast cells?

Answer 13

On encounter with allergen, B cells produce antigen-specific IgE antibody; allergen is cleared on first encounter

Residual IgE antibodies bind to circulating mast cells via Fc receptors and there is no significant consequence

After RE-ENCOUNTER with antigen:
Allergen binds to IgE-coated mast cells and disrupts cell membrane
Degranulation of mast cell releases vasoactive substances
Cytokine & LT transcription is increased

Question 14

3 types of asthma classifications?

Answer 14

Early onset/late onset
Atopic/non-atopic
Extrinsic/intrinsic

Question 15

What is extrinsic asthma?

Answer 15

AKA allergic asthma that is in response to external allergen and is IgE mediated
Associated with other allergic diseases

Question 16

Release of histamine and other inflammatory mediator consequences?

Answer 16

Muscle spasm - causes bronchoconstriction (producing wheeze)
Mucosal inflammation - causes mucosal oedema and increases secretions (producing sputum)
Inflammatory cell infiltrate - infiltration of lymphocytes and eosinophils into bronchiole (produces yellow sputum); associated with chronicity

Question 17

Clinical features of anaphylaxis?

Answer 17

Feeling of impending doom and loss of consciousness
Angioedema of lips and mucous membrances
Laryngeal obstruction and stridor 
Conjunctival injection
Flushing/sweating
Wheeze, bronchoconstriction
HYPOTENSION
Cardiac arrhythmias
Urticaria
Diarrhoea, abdominal pain
Itching of palms, soles of feet and genitalia

Question 18

Non-allergic causes of mast cell degaranulation?

Answer 18

AKA SPONTANEOUS MAST CELL DEGRANULATION - mast cells are hypersensitive and “twitchy”

Drugs - morphine and other opiates, aspirin and NSAIDs

Thyroid disease
Idiopathic
Physical urticaria - in response to heat or pressure

Question 19

Describe aspirin induced asthma and causes?

Answer 19

Characterised by WHEEZE o.5-3 hrs after ingestion
Triggered by aspirin, NSAIDs (like ibuprofen)
Paracetamol and COX-2 generally alright

Question 20

Samter’s triad meaning and treatment?

Answer 20

Asthma, nasal polyps and salicylate sensitivity (severe end of the aspirin sensitivity spectrum)
Dietary modification can reduce high prevalence of salicylates in some foods

Question 21

4 steps in diagnosing allergic disease?

Answer 21

Confirm diagnosis
Identify causative agent - pinpoint specific allergen and target measure to reduce exposure and encourage lifestyle modification
Determine risk of future severe reaction
Determine therapy appropriateness

Question 22

Specific investigations for allergic disease?

Answer 22

Elective investigations:
Skin prick tests (“gold standard” to support an allergy diagnosis)
Quantitative specific IgE to putative allergen
Challenge test - supervised exposure to putative antigen

During acute anaphylactic episode, look for mast cell degranulation evidence (serum mast cell TRYPTASE levels)

Question 23

Skin prick test procedure and reaction?

Answer 23

Expose patient to standardised allergen solution and extract through a skin prick to the forearm
Positive reaction = local wheal and flare response

Question 24

Skin prick test cautions?

Answer 24

Drugs can influence response:
Anti-histamines should be discontinued for at least 48 hrs before testing
Corticosteroids have no influence

Very rarely, may induce anaphylaxis

Question 25

Skin prick tests advantages and disadvantages?

Answer 25

Advantages - cheap, quick, unrivalled sensitivity for majority of allergens (part. aeroallergens) and PATIENT CAN SEE THE RESULT

Disadvantages - requires experience for interpretation Indiscriminate testing (for too many allergens with too many skin prick tests) NOT RECOMMENDED, as it will yield false positives and may cause anaphylaxis

Question 26

Specific IgE tests and advantages?

Answer 26

Measure amount of IgE in serum directed against specific allergen
Useful when skin prick test unavailable and sensitivity and specificity are about 70-75% compared with skin prick tests

Question 27

Why is total IgE level not useful?

Answer 27

Many causes of an elevated IgE (vasculitis, lymphoma, drugs, etc) and significant allergic disease can occur without elevated IgE

Total IgE not a useful routine test in diagnosis of allergic disease

Question 28

How to test for anaphylaxis acutely?

Answer 28

Detection of MAST CELL DERIVED MEDIATORS of anaphylaxis:
Mast cell TRYPTASE - product of mast cell granules; widespread degranulation of mast cells during anaphylaxis results in increase in serum tryptase (peak conc. at 1-2 hrs and then returns to baseline by 6 hrs)

Question 29

Why are tryptase tests for anaphylaxis useful?

Answer 29

RISE IN TRYPTASE LEVELS (often proportional to drop in BP) ONLY OCCURS IN ANAPHYLAXIS, and not in local reactions:
Useful if diagnosis of anaphylaxis is not clear

Question 30

Managing IgE mediated allergic disorders?

Answer 30

Avoidance of allergen
Block mast cell activation
Prevent effects of mast cell activation
Anti-inflammatory agents
Management of anaphylaxis
Immunotherapy

Question 31

How to block mast cell activation?

Answer 31

Mast cell STABILISERS - SODIUM CROMOGLYCATE:
Poor oral absorption and used as topical spray when allergen exposure is predictable (like hayfever or exercise-induced asthma)

Question 32

How to prevent effects of mast cell activation?

Answer 32

Anti-histamines - H1 receptor antagonists that block histamine effects (mainstay treatment of allergic disease); useful prophylactically and to control symptoms

Leukotriene receptor antagonists - block LT effects (synthesised by activated mast cells), e.g: Montelukast

Question 33

Corticosteroids in allergic disease?

Answer 33

Based upon naturally occurring steroids and are anti-inflammatory:
Inhibit formation of many different inflammatory mediators:
Platelet activating factor
Prostaglandins
Cytokines

Question 34

Summary of potential drugs for allergic disease?

Answer 34

Antihistamines
LT receptor antagonists
Mast cell stabiliser
Inhaled corticosteroid

Question 35

Management of anaphylaxis?

Answer 35

Self-injectable ADRENALINE in a pre-loaded syringe (acts on β2 adrenergic receptors to constrict arterial smooth muscle - increases BP, limiting vascular leakage, and dilates bronchial smooth muscle, to decrease airflow obstruction)

Investigate trigger and write info sheet (avoid identifiable triggers and indications for self-treatment with adrenaline)

Provide additional info - include family, patient support groups, etc

Advise patients to acquire a MEDIC ALERT BRACELET

Question 36

What is immunotherapy and how does it work?

Answer 36

Controlled exposure to increasing amounts of allergen - subcutaneous injections of tiny amounts of allergen, followed by gradual increase in dose
Mechanisms of action is unknown and may lead to inhibition of anaphylaxis

Question 37

Risk of immunotherapy?

Answer 37

Anaphylaxis (only done in controlled, clinical environment)

Question 38

What can immunotherapy be used for?

Answer 38

For venom anaphylaxis and grass pollen allergies