Allergy

Question 1

What happens in early phase allergic reaction?

Answer 1

• exposure to allergens* leads to the rapid development of symptoms
• this reaction develops within seconds or minutes of exposure
• results from the binding of allergens to pre-formed IgE antibodies on the surface of mast cells and basophils

Question 2

What happens after IgE binding?

Answer 2

• IgE binds its specific allergen
• Cross-linking of IgE antibodies by allergen leads to clustering of FcεR1 receptors
• The intracellular portion of the receptor becomes phosphorylated
• The resulting intracellular cascade leads to cellular activation
• Mast cell ‘degranulates’ releasing histamine, tryptase and other pre-formed mediators

Question 3

Review the Leuokortiene delayed allergy reaction

Answer 3

Question 4

What are the Pharmacological effects of mast cell mediators and leukotrienes

Answer 4

• Wheal and flare on skin
• Discharge and sneezing from the nose
• Red eyes
• wheezing from the lungs

Question 5

What are the general characteristics of allergens?

(4)

Answer 5

• Proteins (there are a few minor exceptions)
• Physical properties that favour transition across mucus membranes
• Biologically active, often enzymes
• Have moderate homology with self-proteins

Question 6

What is Anaphylaxis?

• clinical features seen?
• common triggers

Answer 6

• ‘Generalised allergic’ reaction
• Systemic release of histamine causes generalised vasodilatation & fluid loss from circulation to tissues
  
  • Cutaneous: hives, angioedema
  • Gut histamine release: vomiting, diarrhoea
  • Mucosal histamine release: laryngeal oedema, bronchoconstriction
  • Circulation: vasodilatation, hypotension
• Food, drugs and insect venom commonest triggers in UK
• Cardinal features: typical symptoms, multi-system and dramatic, rapidly follows exposure to allergen and tends to improve fairly quickly thereafter

Question 7

What is Oral allergy syndrome?

• clinical symptoms

Answer 7

• IgE directed against pollen proteins cross-reacts with homologous proteins in plant-derived foods
• Oral itching upon exposure to raw fruit, nuts and vegetables
• In UK:
  
  • Pollen = mainly birch
  • Food = mainly Rosaceae fruits (apples)

Question 8

What is Rhinitis?

Answer 8

• Sneezing, rhinorhoea, blockage due to a type 1 allergy
• Lower airway obstruction
  
  • Wheeze due to type 1 allergy
• Allergens/ symptoms may be:
  
  • Seasonal: pollens, moulds
  • Episodic: occupational, animal dander
• When symptoms are chronic, the inflammation becomes established and cannot be explained simply in terms of mast cell degranulation

Question 9

What happens in late phase allergic reaction?

Answer 9

• The early phase reaction to an allergen is followed some hours later by a second ‘late phase reaction’
• Biopsy of the late phase shows infiltration with inflammatory cells – particularly CD4 T cells, eosinophils and mast cells;
  
  • largely Th2 cells produced
    
    • IL-4,5,9,13

Question 10

Explain the relevance of T cell subsets in allergy and the

Th2 hypothesis

Answer 10

• Th2 responses to allergens have been consistently associated with allergic disease
  
  • Biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines
  • T cells from allergic patients stimulated with allergen in the laboratory produce Th2 cytokines
• Plenty of reasons to believe that Th2 responses may be important in allergy:
  
  • IL-4 is required for B cell class switching to IgE
  • IL-4 and IL-13 promote mucus hypersecretion
  • IL-5 is required for eosinophil survival
• IL-9 recruits mast cells

Question 11

Explain the Hygiene hypothesis in allergy aetiology?

Answer 11

• Low hygiene levels, high pathogen load, helminth infection proposed to:
  
  • Skew immunity from Th2 to Th1
  • Induce regulatory T cells
• High hygiene levels, low pathogen load, absence of helminth infection proposed to:
  
  • Skew immunity towards Th2
  • Reduce production of regulatory T cells

Question 12

How is allergy detected/ tested for?

Answer 12

• in vivo: skin testing
• in vitro: ELISA
• this tests for allergen-specific IgE antibodies

Question 13

What are treatments for allergy: Symptom relievers

Answer 13

• B2 agonist
  
  • Eg salbutamol
  • Act on lung B2 adrenoreceptors, cause smooth muscle relaxation
• Nasal decongestion
  
  • eg oxymetazoline
  • Act on α1 adrenoreceptors to cause vasoconstriction
  • Only for short-term use (can cause physiological dependence)
  • Topical and systemic
• Epinephrine
  
  • Systemic adrenergic effects oppose vasodilatation and bronchoconstriction

Question 14

What are treatments for allergy: Drugs acting on early-phase mediators

Answer 14

• H1 Antihistamines
• Leukotriene receptor antagonists
• Mast cell stabilisers

Question 15

What are Mast cell stabilisers?

• how do they work
• efficacy

Answer 15

• Eg sodium cromoglycate
• Reduce mast cell degranulation by unknown mechanism
• Not orally absorbed – topical use only
• Short half-life requires frequent dosing
• Main benefit is steroid-free, but efficacy very poor

Question 16

What are H1 Antihistamines?

• how do they work
• efficacy?

Answer 16

• Inverse agonists at H1 histamine receptor
• Best used before exposure to allergen
• 1st generation eg chlorpheniramine
  
  • Considerable sedation, drug interactions
• 2nd generation eg cerizine, loratidine, desloratidine, fexofenadine
  
  • No/ minimal sedation, once-daily

Question 17

What are Leukotriene receptor antagonists?

• how do they work
• efficacy?

Answer 17

• Only UK drug is montelukast
• Effective in reducing early allergic responses, but inferior to H1 antihistamines
• Unlike anti-histamines, beneficial in chronic asthma, which is the main indication for their use

Question 18

What are other treatments for allergic diseases?

Answer 18

• Corticosteroids
  
  • inhaled/nasal
  • topical preparations may cause local and systemic effects
• Omalizumab
• Allergen-specific immunotherapy

Question 19

What is Omalizumab
- how does it work

• used in?

Answer 19

Omalizumab is a monoclonal antibody directed against IgE, used for atopic asthma (amongst other things)

Question 20

Explain the use of Allergen-specific immunotherapy

• what are the 5 main immunological effects

Answer 20

• Allergen doses administered by subcutaneous injection or sublingually
• Provide long-term protection
• Mainly venom allergy and rhinitis
• Multiple immunological effects:
  
  • Induce regulatory T cell responses to allergens
  • Reduce Th2 responses
  • Induce allergen-specific IgG antibodies
  • Reduction in mast cell responsiveness
  • Reduce allergen-specific IgE levels

Question 21

What is the difference between contact dermatitis (Type IV sensitization) and type 1 allergy?

Answer 21

Question 22

What is the difference between Skin prick testing vs patch testing?

Answer 22

Question 23

What are the WHO classification for adverse drug reactions?

Answer 23

• Type A
  
  • Related to Pharmacology of drug
  • Predictable
  • Usually dose-dependent
  • High morbidity, Low mortality
• Type B: anything that resembles an allergic or immunological reaction
  
  • Not (directly) related to the pharmacology
  • Unpredictable
  • (Often) dose-independent
  • High mortality

Question 24

What is defined as immediate drug-related hypersensitivity?

Answer 24

• Within 1 hour of drug administration
• Skin: urticaria, angioedema
• Respiratory: rhinitis, bronchospasm, laryngeal oedema
• Cardiovascular collapse
• The result of mast cell activation
• May be IgE-mediated, or a form of non-allergic immediate DHR
• NOT part of the ‘atopic’ phenotype of asthma, eczema, rhinitis and food allergy: risk is similar in atopic and non-atopic individuals (only exception is NSAIDS in asthma – see later)

Question 25

What is the time course of an immediate drug hypersensitivity reaction?

Answer 25

* Within 1 hour of last dose * Often much quicker, particularly iv treatments * NSAIDS may be a little delayed, but still usually within 1 hour * Soon after initiation, usually 1^st dose * Sensitisation typically during an earlier course * Usually takes about 14 days to class switch to IgE * Doesn’t always follow the rules – possibly activation of previously primed response * Key question to ask is the time between the LAST dose and symptom onset

Question 26

What are examples of immediate drug-related hypersensitivity that is non-IgE mediated?

Answer 26

* Non-specific mast cell activation * Opiates, myorelaxants, radiocontrast media, vaccines * But note IgE-mediated also possible for these medications * More likely in people with underlying ‘spontaneous urticaria’ (untriggered itchy skin/ hives on most days) * ACEi angioedema – not immediate, but can appear * Also inhibit de-activator of bradykinin * 1 in 1000 patients develop angioedema * Timing of symptoms not related to dosing (in this respect not a good example of an immediate reaction)

Question 27

What is the test when suspecting a drug hypersensitivity reaction?

Answer 27

Mast cell tryptase * Tryptase released from mast cells during anaphylaxis; easier to measure in laboratory compared to histamine * Serum tryptase levels recommended to confirm acute anaphylaxis * Take blood 1-2 hours after onset of symptoms and again after 24 hours * Increase followed by normalisation in correct context confirms anaphylaxis * Sensitivity said to be around 70%

Question 28

What are the key features of non-immediate drug hypersensitivity reaction?

Answer 28

* Not directly related to a drug dose, although may appear to be so by chance * Typically during treatment course * 3-5 days if treated with drug before * 5-8 days if first sensitisation * Taken together, clinical features not in keeping with mast cell degranulation * Typically continue for some time after drug is stopped * Antimicrobials = biggest group

Question 29

What is Steven Johnson Syndrome/ TENS?

Answer 29

* affects skin, mucous membranes, genitals and eyes * Fever, cough, conjunctivitis, mucosits * Men\>greater women, mostly 30 years or under * Typically 3-8 days after dose * _Antibiotics, and anticonvulsants most common culprit drugs_ * Can also be infection-induced * Very high mortality and gets worse with each exposure

Question 30

What is the management of SJS/TENS syndrome

Answer 30

* involving other specialities such as burns unit * Topical antibiotics * warm compress to promote drainage of boils * Oral and IV antibiotics

Question 31

What is the epidemiology of beata lactam Allergy?

Answer 31

* Reported by 10% of UK population, and a much higher proportion of hospital inpatients * True prevalence closer to 1-2% * Over-reported because * Sensitisation lost at a rate of 10% per year, but label persists * Rash was caused by something else eg infection, primary dermatological disorder such as spontaneous urticaria

Question 32

How do we test for a Beta-Lactam allergy?

Answer 32

* The only situation where the antigens are known and commercially available for testing * First-line test is skin prick testing with B Lactams and B Lactam reagents * Negative results have high negative predictive value – usually confirm tolerance with brief challenge test * When positive, perform **challenge** with alternative to demonstrate tolerance

Question 33

How is a challenging testing carried out?

Answer 33

* Hospital-based procedure for higher risk patients; may be done at home in some cases * Oral challenge wherever possible * Gradually increasing doses every 30 minutes or so, until therapeutic dose is reached * Eg amoxycillin 25mg, 100mg, 250mg, 500mg * Cons: very time-consuming, risk of allergic reactions and doesn’t pick up type IV hypersensitivity * Pros: large majority of patients can be ‘de-labelled’

Question 34

What is the criteria to refer to immunology in the face of a drug allergy?

Answer 34

* Not needed if: * Drug unlikely to be needed again * Minor reaction (eg maculo-papular rash) * Alternatives readily available * Nothing more to add (eg TENS) * May be helpful if: * Drug will be needed again * Choice restricted * Cross-reactivity questions * Diagnostic doubt

Question 35

What are examples of Beta- lactams?

Answer 35

**penicillins, cephalosporins**