Allergy Flashcards
What is an allergic disorder?
Immunological process that results in immediate and reproducible symptoms after exposure to an allergen.
What is sensitisation?
Sensitisation is the detection of specific IgE either by skin prick testing or in vitro blood tests: OCCURS MORE OFTEN THAN ALLERGIC DISEASE
How does the body respond to allergens?
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
When is the Th1/ Th17 immune response elicited?
Microbial PAMP and structural feature recognition
What elicits a Th2 immune response?
Helminthes/ allergens/ Venoms
What can the immune system recognise?
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.
Summarise Th2 immune responses
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.
How is Th2 responses induced?
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
Which allergic diseases do children get?
Atopic dermatitis Food allergy (milk, egg, nuts)
Which allergic diseases do children get?
Asthma
Allergic rhinitis
Which allergic diseases do adults get?
Drug allergy
Bee allergy
Oral allergy syndrome
Occupational allergy
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
C. IL-33
What is the prevalence of asthma, allergic rhinitis, atopic dermatitis and food allergy in adults?
Asthma 10%
Allergic rhinitis 20%
Atopic dermatitis 5%
Food allergy 3.7%
How has the prevalence of allergic rhinitis changed over the 20th century?
Increased
Why have allergic disorders risen over the last 50 years?
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
Which systems are affected in IgE responses?
Skin
Respiratory Tract
GI tract
Vasculature/ CNS
How are systems affected in IgE responses?
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
What are the clinical features of an allergic response?
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
Which symptoms are not associated with IgE allergic reactions?
Fatigue
Migraine
Recurrent episodes of abdominal pain, diarrhoea, constipation, bloating
Hyperactivity
Depression
Symptoms which vary over time, with antigen dose and source
What are the elective investigations of allergic diseases?
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
What investigations do you do during an acute episode?
Evidence of mast cell degranulation
Serial mast cell tryptase
Blood and/or urine histamine
What can specific IgE tests tell you?
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.
What is the skin prick test?
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
What’s a positive skin prick test?
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
What are the advantages of the skin prick test?
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
What are the disadvantages of the skin prick test?
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
What is the serum sprecific IgE blood test?
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.
Why should we use serum specific IgE tests?
- May help diagnosis of allergy
- Concentration of specific IgE predict who will outgrow allergy (should do oral food challenge)
- Higher values = more likely allergic disorder (triage patients who do not need oral food challenges)
- Very good NPV but not PPV
- Can be used to monitor response to anti-IgE therapy
Results of serum specific IgE do not predict severity of reaction
What are the indications for serum specific IgE tests?
Patients who can’t stop anti-histamines
Patients with dermatographism
Patients with extensive eczema
History of anaphylaxis
Borderline/equivocal skin prick test results
What is Component Resolved Diagnostics (CRD)?
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
What are Indications for allergen component testing ?
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
Why is mast cell tryptase important?
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
Why are challenge tests good?
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
What is the Basophil activation test?
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
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?
Skin prick
A 60 year old female with hypotension and skin rash under general anaesthesia What is the most appropriate test to diagnose anaphylaxis?
Serial mast cell tryptase
What is anaphylaxis?
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)
What is epi/ cause of anaphylaxis?
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
Reactions that can mimic anaphylaxis
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
Laboratory diagnosis of anaphylaxis
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
What is the most important treatment of anaphylaxis and why?
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
What is the emergency management of anaphylaxis?
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)
What is the Further management of anaphylaxis?
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
What is in a Emergency community anaphylaxis kit?
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
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
A: Intramuscular adrenaline
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
E: ACE inhibitor induced angioedema
Summarise food allergies
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
What are the adverse reaction to foods?
Food intolerance
Food aversion
Food allergy
describe the adverse reaction to foods?
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)
Which allergies can be outgrown and what is related to food allergies?
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)
What might you find in the clinical history of food allergy?
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)
What investigations would you do for food allergy?
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
What is the management of food allergy?
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
What is the IgE mediated food allergy syndromes?
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
What is oral allergy syndrome?
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
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
B: Cross reactive IgE sensitisation between hay fever and apple allergens
What is Type 1 and Type 2 inflammatory allergic reactions?
What is involved in Th2 immune responses? (Label the picture below)
What is involved in a Th2 reaction?
What can cause reactions?
Defects in skin are RFs for IgE antibodies
Il-4 plays a crucial role in memory cells/ basophils/ mast cells
Which 3 allergic diseases saw a sequential rise?
Exam style Question on Innate lymphoid cells:
- Where are innate lymphoid cells found?
- What do Innate Lymphoi cells respond to?
- How are CD4 innate lymphoid cells classified?
- What does ILC2 secrete?
- Which diseases is ILC2 implicated in?
- What does Amphiregulin do?
Exam style question:
What is an eosinophil?
What does it do?
What is the key cytokine for development?
What are eosinophils implicated in?
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?
Opiates and quinolones directly stimulate mast cells.
How does mast cell degranuation occur?
What factors promote IgE production?
Summarise the Th2 Immune response
Why does allergic rhinitis exist?
How do microbes protect against asthma?
How can you diagnose allergies?
Why is IgE sensitisation important?
How and when are intradermal tests used?
What are sensitisation tests?
What is the risk profile of specific IgE blood tests?
What are the indications for blood sensitisation tests?
Summarise component resolved/ molecular testing?
What tests can you use for nuts, wheata, egg/ mil and fish/ shellfish?
Summarise the diagnosis of anaphylaxis
60 year old hypotension and rash: test to diagnose anaphylaxis?
Seriel mast cell tryptase
What can you identify from specific IgE testing?
We can identify:
- Risk Profile
- Concentration of IgE (positive correlation with symptoms)
- Affinity of IgE (Positive correlation with risk)
- Ability of IgE to induce degranulation
- Identification of molecular target
