Allergy

Question 1

What is an allergic disorder?

Answer 1

Immunological process that results in immediate and reproducible symptoms after exposure to an allergen.

Question 2

What is sensitisation?

Answer 2

Sensitisation is the detection of specific IgE either by skin prick testing or in vitro blood tests: OCCURS MORE OFTEN THAN ALLERGIC DISEASE

Question 3

How does the body respond to allergens?

Answer 3

In clinical practice immunological process usually involves an IgE mediated type 1 hypersensitivity reaction

Allergen is usually a harmless substance that can trigger an IgE mediated immune response and may result in clinical symptoms

Question 4

When is the Th1/ Th17 immune response elicited?

Answer 4

Microbial PAMP and structural feature recognition

Question 5

What elicits a Th2 immune response?

Answer 5

Helminthes/ allergens/ Venoms

Question 6

What can the immune system recognise?

Answer 6

Immune system recognizes enzymatic activities of allergens and multicellular parasites: no direct recognition as seen for example with bacteria, viruses and fungi

Considerable overlap in immune pathways that detect tissue damage and allergens which have extensive protease activity and the capacity to damage epithelial barriers.

Question 7

Summarise Th2 immune responses

Answer 7

Epithelial cells and mast cells detect allergens, venoms, and worms

Stressed or damage epithelial cells secrete IL-25, IL-33 and TSLP to act on memory CD4 T cell subsets, innate lymphoid cells and other lymphoid cells to promote secretion of IL-4, IL-5, IL-9, IL-13

Cytokines secreted by tissue lymphocytes act on effector cells (eosinophils, basophils, epithelial cells, B cells, sensory neurons endothelium and smooth muscle cells) to eliminate and expel pathogens allergens, and repair tissue damage

Epithelial and mast cells can both detect and eliminate pathogens and allergens.

Question 8

How is Th2 responses induced?

Answer 8

Not really well understood in humans

Defects in skin epithelial barrier ( atopic dermatitis) are a significant risk factor for development of IgE antibodies

Skin dendritic cells (DC) [Langerhans cells and dermal DC] promote secretion of Th2 cytokines much more efficiently than other DC subsets which suggest that different DC subsets may prime Th2 immune responses in humans

IL-4 secretion is only induced following peptide-MHC presentation to TCR to either naïve and/or memory Th2 cells

Question 9

Which allergic diseases do children get?

Answer 9

Atopic dermatitis 
Food allergy (milk, egg, nuts)

Question 10

Which allergic diseases do children get?

Answer 10

Asthma
Allergic rhinitis

Question 11

Which allergic diseases do adults get?

Answer 11

Drug allergy
Bee allergy
Oral allergy syndrome
Occupational allergy

Question 12

Which one of the following proteins/cytokines is NOT a drug target for current drugs and/or biologics used to treat allergic disorders?

A. IL-13

B. Histamine

C. IL-33

D. IgE

E. IL-5

Answer 12

C. IL-33

Question 13

What is the prevalence of asthma, allergic rhinitis, atopic dermatitis and food allergy in adults?

Answer 13

Asthma 10%

Allergic rhinitis 20%

Atopic dermatitis 5%

Food allergy 3.7%

Question 14

How has the prevalence of allergic rhinitis changed over the 20th century?

Answer 14

Increased

Question 15

Why have allergic disorders risen over the last 50 years?

Answer 15

Hygiene hypothesis: lack of childhood exposure to infectious agents increases susceptibility to allergic diseases by supressing natural development of immune system.

Lack of Vitamin D in infancy is a risk factor for development for food allergy

Dietary factors: reduced omega and linoleic fatty acids, delayed introduction of peanuts in children with egg allergy and atopic dermatitis

Rise in food allergy may be associated with high concentration of dietary advanced glycation end products and pro-glycating sugars which immune system mistakenly detects as causing tissue damage; fast food and soda

Question 16

Which systems are affected in IgE responses?

Answer 16

Skin

Respiratory Tract

GI tract

Vasculature/ CNS

Question 17

How are systems affected in IgE responses?

Answer 17

Occurs within minutes or up to 3 hours after exposure to allergen and symptoms can include:

Skin: angioedema (swelling of lips, tongues, eyelids) , urticaria ( wheals or ‘hives’), flushing and itch

Respiratory tract: cough, SOB wheeze, sneezing, nasal congestion and clear discharge, red itch watery eyes

Gastrointestinal tract: nausea, vomiting and diarrhoea

Vasculature and CNS: symptoms of hypotension (faint, dizzy, blackout) and a sense of impending doom

Question 18

What are the clinical features of an allergic response?

Answer 18

At least 2 organ systems are usually involved.

Reproducible: occurs after every exposure

Allergic symptoms may be triggered by cofactors such as exercise, alcohol, and possibly infection.

Clinical history is used to select what allergens should be tested by skin prick and/or blood tests

Not always obvious e.g.:

House dust mite

Fungal skin colonisation

Red meat ingestion

Question 19

Which symptoms are not associated with IgE allergic reactions?

Answer 19

Fatigue

Migraine

Recurrent episodes of abdominal pain, diarrhoea, constipation, bloating

Hyperactivity

Depression

Symptoms which vary over time, with antigen dose and source

Question 20

What are the elective investigations of allergic diseases?

Answer 20

Skin prick and intradermal tests
Laboratory measurement of allergen specific IgE
Component-resolved diagnostics
Basophil activation test
Challenge test
Supervised exposure to the putative antigen

Question 21

What investigations do you do during an acute episode?

Answer 21

Evidence of mast cell degranulation
Serial mast cell tryptase
Blood and/or urine histamine

Question 22

What can specific IgE tests tell you?

Answer 22

Skin prick and blood test are used to detect presence/absence of IgE antibody against external proteins.

Diagnosis of allergic disease is made by the clinician; integrates data obtained from epidemiology, history, examination, SPT, laboratory, and challenge testing.

A positive IgE test only demonstrates sensitisation (risk of allergic disease) NOT CLINICAL ALLERGY. Detection of IgE is necessary but not sufficient to make a diagnosis of allergic disease.

Question 23

What is the skin prick test?

Answer 23

Expose patient to standardised solution of allergen extract through a skin prick to the forearm.

Use standard skin test solutions and positive control (histamine) and negative control (diluent)

Measure local wheal and flare response to controls and allergens

Looking for crosslinking and degranulation

Question 24

What’s a positive skin prick test?

Answer 24

A positive test is indicated by a wheal ≥ 3mm greater than the negative control.

Antihistamines should be discontinued for at least 48 hours beforehand

Skin prick testing is considered to be more sensitive and specific than blood tests to diagnose allergy in routine clinical practice

Question 25

What are the advantages of the skin prick test?

Answer 25

Rapid (read after 15-20 minutes) Cheap and easy to do Excellent negative predictive value usually more than \> 95% Increasing size of wheals correlates with higher probability for allergy Patient can see the response

Question 26

What are the disadvantages of the skin prick test?

Answer 26

Requires experience to interpret Risk of anaphylaxis: 1 in 3000 Poor positive predictive value: high false positive rate Limited value in patients with dermatographism or extensive eczema False negative results with labile commercial food extracts

Question 27

What is the serum sprecific IgE blood test?

Answer 27

Allergen bound to sponge in a plastic cap and patient’s serum is added. Specific IgE (if present) binds to allergen. Anti-IgE antibody tagged with a fluorescent label is added. Amount of IgE/Anti-IgE is measured by fluorescent light signal. Blood test are very reliable but can be expensive.

Question 28

Why should we use serum specific IgE tests?

Answer 28

1. May help diagnosis of allergy 2. Concentration of specific IgE predict who will outgrow allergy (should do oral food challenge) 3. Higher values = more likely allergic disorder (triage patients who do not need oral food challenges) 4. Very good NPV but not PPV 5. Can be used to monitor response to anti-IgE therapy ## Footnote *Results of serum specific IgE do not predict severity of reaction*

Question 29

What are the indications for serum specific IgE tests?

Answer 29

Patients who can’t stop anti-histamines Patients with dermatographism Patients with extensive eczema History of anaphylaxis Borderline/equivocal skin prick test results

Question 30

What is Component Resolved Diagnostics (CRD)?

Answer 30

Blood test to detect IgE to single protein components: abundance and stability of protein contribute to risk of allergic disease Useful for diagnosis of peanut and hazelnut allergy: may reduce the needs for food challenges IgE sensitisation to heat labile and proteolytic susceptible birch pollen homologue peanut and hazelnut allergen component target heat are usually associated with minor or no symptoms IgE sensitisation to heat and proteolytic stable seed storage peanut and hazelnut allergen components are usually with severe allergic reactions

Question 31

What are Indications for allergen component testing ?

Answer 31

A Detect primary sensitization Confirm cross reactivity B Define risk of serious reaction for stable allergens C. Improve diagnostic sensitivity on addition of components which are poorly represented in whole food extracts D Improve diagnostic sensitivity for unstable molecules in whole food extracts

Question 32

Why is mast cell tryptase important?

Answer 32

Tryptase: pre-formed protein found in mast cell granules Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase Peak concentration at 1-2 hours; returns to baseline by 6-12 hours Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia Reduced sensitivity for food induced anaphylaxis

Question 33

Why are challenge tests good?

Answer 33

Gold standard for food and drug allergy diagnosis Increasing volumes of the offending food/drug are ingested Double blind placebo or open challenge Food challenges take place under close medical supervision. Very expensive in terms of clinical staff time. Can be difficult to interpret mild symptoms Risk of severe reaction

Question 34

What is the Basophil activation test?

Answer 34

Measurement of basophil response to allergen IgE cross linking Activated basophils increase the expression of CD63, CD203, CD300 protein on cell surface Increasing use in diagnosis of food and drug allergy: surrogate marker for challenge tests Efforts to this standardise test to use n diagnostic laboratories to reduce need fro challenge tests

Question 35

A 15 year old with a history of asthma and hayfever who notices an urticarial and angioedema skin rash shortly after eating peanuts. What is the most appropriate initial diagnostic test?

Answer 35

Skin prick

Question 36

A 60 year old female with hypotension and skin rash under general anaesthesia What is the most appropriate test to diagnose anaphylaxis?

Answer 36

Serial mast cell tryptase

Question 37

What is anaphylaxis?

Answer 37

Anaphylaxis: a severe potentially systemic hypersensitivity reaction. Rapid onset, life threatening airway, breathing and circulatory problems which is usually but not always associated with skin and mucosal changes Incidence: 1.5-8/100,000 persons years with studies from UK showing increase in hospital admissions over last 20 years Estimated prevalence based on European studies is 0.3% Skin (hives, itch, swollen lips, tongue, uvula) is most frequent organ involved (84%), then cardiovascular system (collapse, syncope, incontinence symptoms, drop in BP) in 72% cases and respiratory compromise (SOB, wheeze, stridor, fall in PEF, hypoxemia in 68%. Respiratory symptoms occur more often in children and cardiovascular in adults Acute onset of symptoms and/or signs (minutes to several hours)

Question 38

What is epi/ cause of anaphylaxis?

Answer 38

Prevalence of anaphylaxis 0.3% of population More common in children aged 0-4 year than other age groups Food more common in children, drug and venom diagnosed more often in adult Idiopathic anaphylaxis seen in 20% cases: hidden causes include shrimp, wheat, and red meat

Question 39

Reactions that can mimic anaphylaxis

Answer 39

SKIN: Chronic urticaria and angioedema (ACE inhibitors) THROAT SWELLING: C1 inhibitor deficiency CARDIOVASCULAR: Myocardial infarction and PE RESPIRATORY: Very severe asthma, vocal cord dysfunction, inhaled FB NEUROPSYCHIATRIC: Anxiety or panic disorder ENDOCRINE: carcinoid and phaechromocytoma TOXIC: Scromboid toxicity (Histamine poisoning ) IMMUNE: Systemic mastocytosis

Question 40

Laboratory diagnosis of anaphylaxis

Answer 40

Serial measurement of serum tryptase (a highly specific marker for mast cell degranulation) Samples taken 1 hour, 3 hours and 24 hours post episode of anaphylaxis The rise in tryptase concentration is directly proportional to fall in BP Persistent rise in tryptase 24 hours after allergic reaction suggestive of systemic mast cell disease

Question 41

What is the most important treatment of anaphylaxis and why?

Answer 41

Adrenaline Mechanism of action adrenaline α1 receptors: causes peripheral vasoconstriction, reverses low BP and mucosal oedema β1 receptor: increase heart rate and contractility and BP β2 receptor: relaxation bronchial sooth muscle and reduce release of inflammatory mediators

Question 42

What is the emergency management of anaphylaxis?

Answer 42

IM adrenaline into outer aspect of thigh and repeat if needed Adjust body position: sit up, supine, lie on side Oxygen 100% Fluid replacement Inhaled Bronchodilators Hydrocortisone 100mg IV ( prevent late phase response) Chlorpheniramine 10mg IV ( skin rash)

Question 43

What is the Further management of anaphylaxis?

Answer 43

CONSERVATIVE **Onward Referral**: Referral to an allergy/immunology clinic, Investigate the cause of anaphylaxis, Refer patients with food induced anaphylaxis to a qualified dietician, Review patients to ensure that they understand their disease and can use their Epipen CONSERVATIVE **Education**: Recognition of symptoms, Avoidance of identifiable triggers, Indications for self treatment with an Epipen, Copy of management plan and training for patient, carers, school staff and GP, Advise patients to acquire a Medic Alert bracelet, Utilise patient support groups ie Anaphylaxis Campaign **MEDICAL**: Prescription of emergency kit to manage anaphylaxis, Venom immunotherapy and drug desensitisation as appropriate

Question 44

What is in a Emergency community anaphylaxis kit?

Answer 44

Epipen: preloaded adrenaline syringe Contains 300ug adrenaline for adult patients and 150ug adrenaline for children AND Prednisolone 20mg OD Antihistamine tablet Cetirizine 10mg OD Must call for ambulance and attend A&E after using emergency kit

Question 45

24 year female with rapid onset of a skin rash, breathless, loss of consciousness shortly after eating shellfish. What is the most appropriate initial treatment? A. Intramuscular adrenaline B. Intravenous adrenaline C. Intravenous fluids D. Intravenous hydrocortisone E. Nebulised salbutamol

Answer 45

A: Intramuscular adrenaline

Question 46

A 55 year old man who attends A&E with angioedema involving lips and tongue which has developed over previous hours. He has a history of hypertension and is taking an ACE inhibitor and calcium channel blocker. Clinical examination show a pulse of 75bpm, blood pressure 150/90, respiratory rate of 18/min and oxygen saturation 78% on air. What is the most likely diagnosis? A. C1 inhibitor deficiency B. Acute anxiety attack C. Systemic Mastocytosis D. Idiopathic Anaphylaxis E. ACE inhibitor induced angioedema

Answer 46

E: ACE inhibitor induced angioedema

Question 47

Summarise food allergies

Answer 47

Food allergy: adverse health effect arising from specific immune response that occurs reproducibly on exposure to a given food Food intolerance: non immune reactions which include metabolic, pharmacological and unknown mechanisms Food allergy likely affect up to 5% of adults and 8% of children

Question 48

What are the adverse reaction to foods?

Answer 48

Food intolerance Food aversion Food allergy

Question 49

describe the adverse reaction to foods?

Answer 49

1) Food intolerance Food poisoning (bacterial, scromboid toxin) Enzyme deficiencies (lactase) Pharmacological (caffeine, tyramine ) 2) Food aversion Fads, eating disorders 3) Food allergy IgE mediated reactions (anaphylaxis, OAS) Mixed IgE and cell mediated (atopic dermatitis) Non IgE mediated (coeliac disease) Cell mediated (contact dermatitis)

Question 50

Which allergies can be outgrown and what is related to food allergies?

Answer 50

Most children outgrow milk and egg allergy but rarely outgrow peanut and tree nut allergy Moderate/severe atopic dermatitis is an important risk factor for food allergy (indication for allergy testing even in absence of clinical history)

Question 51

What might you find in the clinical history of food allergy?

Answer 51

What does the patient mean by allergy. Distinguish between IgE and non IgE mediated symptoms. Dose, how food is prepared and co-factors can influence clinical symptoms Does the patient have any history of atopic disease Enquire about previous investigations for food allergy ie SPT, IgE blood tests and complementary medical tests Has elimination of food made any difference to symptoms Consider other differential diagnoses (food intolerance, eating disorders, coeliac disease)

Question 52

What investigations would you do for food allergy?

Answer 52

Clinical history is used to estimate prior probability of allergy, identify culprit foods and decide what diagnostic allergen tests are used to achieve a post test probability of allergy A positive SPT/specific IgE blood test is useful to confirm a clinical history of food allergy. A negative SPT/specific IgE blood test essentially excludes IgE mediated allergy (Negative predictive value NPV = 95%). Fruit and vegetable skin prick test solutions are labile and it often better to useful use actual fruit or vegetable. Testing for individual allergen protein component can distinguish between IgE sensitisation and IgE mediated allergy

Question 53

What is the management of food allergy?

Answer 53

Conservative Education: Avoidance, Education about food labelling, interaction with restaurants, school, Anaphylaxis guidelines Diet advice: Nutritional input for dietary balance, growth in children Reassurance: Acknowledge anxiety, potential bullying: mental health support if needed Ensure allergic asthma is well controlled Prevention Breast feeding: strong family of allergy, LEAP study: early rather than delayed introduction of peanut in high risk children (moderate/severe AD and egg allergy) significantly reduces development of peanut IgE sensitisation and allergy

Question 54

What is the IgE mediated food allergy syndromes?

Answer 54

Anaphylaxis: Peanut, tree nut shellfish, fish, milk and eggs are most common Natural history dependent on food Food associated exercise induced anaphylaxis Food induces anaphylaxis if individual exercises within 4-6 hours of ingestion Common food triggers are wheat, shellfish, celery Delayed food-induced anaphylaxis to beef, pork, lamb Symptoms occur 3-6 hours after eating red meat and gelatin IgE antibody to oligosaccharide alpha-gal (α1, 3-galactose) found in gut bacteria Induced by tick bites which should be avoided

Question 55

What is oral allergy syndrome?

Answer 55

Limited to oral cavity, swelling and itch: only 1-2% cases progresses to anaphylaxis Sensitisation to inhalant pollen protein lead to cross reactive IgE to food Onset after pollen allergy established: affect adults \> young children Respiratory exposure to pollen (birch) results in IgE directed to homologous proteins in stone fruits (apple, pear) vegetables (carrot) and nuts (peanut, hazelnut) Cooked fruits, vegetables and nut cause no symptoms: heat labile allergens detected by component allergen tests

Question 56

A 35 year old man with tree pollen hayfever and immediate lip tingling and swelling immediately after eating apples. What is the most likely explanation for IgE hypersensitivity ? A. IgG4 subclass deficiency B. Cross reactive IgE sensitisation between hay fever and apple allergens C. Apple-hay fever immune complex disease D. Increased Th17 immune response to apple allergen E. Food aversion disorder

Answer 56

B: Cross reactive IgE sensitisation between hay fever and apple allergens

Question 57

What is Type 1 and Type 2 inflammatory allergic reactions?

Answer 57

Question 58

What is involved in Th2 immune responses? (Label the picture below)

Answer 58

Question 59

What is involved in a Th2 reaction?

Answer 59

Question 60

What can cause reactions?

Answer 60

Defects in skin are RFs for IgE antibodies Il-4 plays a crucial role in memory cells/ basophils/ mast cells

Question 61

Which 3 allergic diseases saw a sequential rise?

Answer 61

Question 62

Exam style Question on Innate lymphoid cells: 1. Where are innate lymphoid cells found? 2. What do Innate Lymphoi cells respond to? 3. How are CD4 innate lymphoid cells classified? 4. What does ILC2 secrete? 5. Which diseases is ILC2 implicated in? 5. What does Amphiregulin do?

Answer 62

Question 63

Exam style question: What is an eosinophil? What does it do? What is the key cytokine for development? What are eosinophils implicated in?

Answer 63

Question 64

Exam question: What are the 2 types of mast cells? What is mast cell degranulation triggered by? What is the role of mast cells? What are the key mast cell receptors? Do opiates and quinolones involve basophils/ IgE?

Answer 64

Opiates and quinolones directly stimulate mast cells.

Question 65

How does mast cell degranuation occur?

Answer 65

Question 66

What factors promote IgE production?

Answer 66

Question 67

Summarise the Th2 Immune response

Answer 67

Question 68

Why does allergic rhinitis exist?

Answer 68

Question 69

How do microbes protect against asthma?

Answer 69

Question 70

How can you diagnose allergies?

Answer 70

Question 71

Why is IgE sensitisation important?

Answer 71

Question 72

How and when are intradermal tests used?

Answer 72

Question 73

What are sensitisation tests?

Answer 73

Question 74

What is the risk profile of specific IgE blood tests?

Answer 74

Question 75

What are the indications for blood sensitisation tests?

Answer 75

Question 76

Summarise component resolved/ molecular testing?

Answer 76

Question 77

What tests can you use for nuts, wheata, egg/ mil and fish/ shellfish?

Answer 77

Question 78

Summarise the diagnosis of anaphylaxis

Answer 78

Question 80

60 year old hypotension and rash: test to diagnose anaphylaxis?

Answer 80

Seriel mast cell tryptase

Question 81

What can you identify from specific IgE testing?

Answer 81

We can identify: 1. Risk Profile 2. Concentration of IgE (positive correlation with symptoms) 3. Affinity of IgE (Positive correlation with risk) 4. Ability of IgE to induce degranulation 5. Identification of molecular target