Allergy Flashcards
Allergic disorder
Immunological process that results in immediate and reproducible symptoms after exposure to an allergen.
In clinical practice the immunological process usually involves an IgE mediated type 1 hypersensitivity reaction
Allergen
Usually a harmless substance that can trigger an IgE mediated immune response and may result in clinical symptoms
Sensitisation
Detection of specific IgE either by skin prick testing or in vitro blood tests
Occurs more often than allergic disease
Two main types of TH2 immune responses
Microbial PAMP –> structural features recognition –> TH1, TH17 immune response
Helminthes, allergens, venoms –> functional feature recognition –> TH2 immune response
Immune system recognises enzymatic activates of allergens and multicellular parasites - no direct recognition as seen with bacteria, viruses and fungi
Pathway for TH2 immune response to allergens, worms, venoms
Allergens, Worms, venoms –> Stressed or damaged epithelium –> IL1alpha, IL15, IL33, TSLP –> TH2, TH9, ILC2 –> IL4, IL5, IL9, IL13 –> eosinophils, basophils –> worm and allergen expulsion, mucous secretion
Allergens, Worms, venoms –> Stressed or damaged epithelium –> IL1alpha, IL15, IL33, TSLP –> TFH2 –> IL4, IL21 –> B cells –> IgE, IgG4
Worms, Allergens, Venoms –> mast cell activation –> histamine, prostaglandins, leukotrines, proteases –> endothelium, smooth muscle, neurons –> worm and allergen expulsion, enhanced epithelial barrier function
What are the signalling cytokines in allergic reactions
IL-1alpha
IL15
IL33
TSLP
What are the effector cytokines in allergic reactions
For eosinophils/basophils: IL4, IL5, IL9, IL13
For B cells: IL4, IL21
What are the biological and drug targets in allergic disorders
Histamine Leukotrines IL4 IL5 IL13 IgE IgG4
TH2 immune response features
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.
What route promotes immune tolerance
Oral
What route promotes IgE sensitisation
Skin
What are risk factors for development of IgE antibodies
Defects in skin epithelial barrier (e.g. atopic dermatitis)
What skin features predispose to allergic reactions
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 reponses in humans
What causes IL4 secretion
IL-4 secretion is only induced following peptide-MHC presentation to TCR to either naïve and/or memory Th2 cells
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
IL33
What allergies onset in infancy
Atopic dermatitis Food allergy (milk, egg, nuts)
What allergies onset in childhood
Asthma (HDM, pets) Allergic rhinitis (HDM, grass, tree pollens)
What allergies onset in adulthood
Drug allergy
Bee allergy
Oral allergy syndrome
Occupational allergy
Most common allergic disorder in adults
Asthma - 10%
What are the theories for why allergic disorders have risen over the last 50-100 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 proglycating sugars which immune system mistakenly detects as causing tissue damage; fast food and soda
What is the hygiene hypothesis
Lack of childhood exposure to infectious agents increases susceptibility to allergic diseases by supressing natural development of immune system.
Clinical features of IgE allergic 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
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.
What is used to select what allergens should be tested by skin prick and/or blood tests
Clinical history
What symptoms are NOT associated with IgE allergic reactions
Fatigue
Migraine
Recurrent episodes of abdominal pain, diarrhoea, constipation, bloating
Hyperactivity
Depression
Symptoms may vary over time, with antigen dose and source
Elective investigations of allergic disease
Skin prick tests
Laboratory measurement of allergen specific IgE
Component-resolved diagnostics
Challenge test - supervised exposure to the putative antigen
Investigations of allergic disease during an acute episode
Evidence of mast cell degranulation - serum mast cell tryptase levels
How is a skin prick test carried out
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
What indicated a positive skin prick test
A positive test is indicated by a wheal ≥ 3mm greater than the negative control.
What should be discontinued before a skin prick test
Antihistamines should be discontinued for at least 48 hours beforehand
What is the considered to be the most sensitive and specific test for allergy
Skin prick testing is considered to be more sensitive and specific than blood tests to diagnose allergy in routine clinical practice
Advantages of skin prick tests
Rapid (read after 15 minutes)
Cheap and easy to do
Excellent negative predictive value ( > 95%)
Increasing size of wheals correlates with higher probability for allergy
Patient can see the response
Disadvantages of 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
How is a serum specific IgE blood test carried out
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.
Much more expensive than SPT
Advantages of serum specific IgE test
May help diagnosis of allergy in someone with appropriate clinical history
Higher values are more likely to be associated with allergic disorder and can be used to triage patients who do not need oral food challenges
Results of serum specific IgE do not predict severity of reaction
Very good negative predictive value however lot of false positive ( > 80% of patients with peanut specific IgE are asymptomatic)
Concentration of specific IgE can be used to predict which children may outgrow allergy and should proceed to oral food challenge
Can be used to monitor response to anti-IgE therapy
Indications for specific IgE blood test
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
Blood test to detect IgE to single protein components
What is component resolved diagnostics useful for
Diagnosis of peanut and hazelnut allergy
How does a component resolved diagnostic test work
IgE sensitisation to birch pollen homologue peanut and hazelnut allergen component target heat and proteolytic labile protein and usually associated with minor or no symptoms
IgE sensitisation to seed storage peanut and hazelnut allergen components target heat and proteolytic stable protein and are usually with severe allergic reactions
What is a good biomarker for anaphylaxis
Mast cell tryptase
What is mast cell tryptase
Pre-formed protein found in mast cell granules
Why is mast cell tryptase a good biomaker for anaphylaxis
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
What is a challenge test used for
Test ofr food and drug allergy
What is the gold standard for food and drug allergy
Challenge test
How is a challenge test carried out
Increasing volumes of the offending food/drug are ingested
Double blind placebo or open challenge
Food challenges take place under close medical supervision.
Disadvantages of challenge tests
Very expensive in terms of clinical staff time.
Can be difficult to interpret mild symptoms
Risk of severe reaction
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?
A. Component allergen test
B. Skin prick test
C. IgE blood test
D. Mast cell tryptase
E. Food challenge
Component allergen test
A 60 year old female with hypotension and skin rash under general anaesthesia What is the most appropriate test to diagnose anaphylaxis?
A: Skin prick
B. Drug challenge
C. Blood histamine
D. Serial mast cell tryptase
E. Urine prostaglandin D2
Serial mast cell tryptase
What is 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
What organ systems are involved in anaphylaxis
Skin is most frequent organ involved (84%), cardiovascular symptoms (72%) and respiratory 68%.
Respiratory symptoms occur more often in children and cardiovascular in adults
What is the clinical criteria for diagnosis of anaphylaxis
- Acute onset of illness (minutes to several hours) with involvement of skin, mucosal tissue or both (hives, itch, swollen lips, tongue, uvula) AND AT LEAST ONE OF THE FOLLOWING
A) Respiratory compromise, (SOB, wheeze, stridor, fall in PEF, hypoxemia)
B) Reduced BP or associated symptoms (collapse, syncope, incontinence) - Reduced BP after exposure to known allergen for specific patient (minutes to several hours)
A) Infants and children low specific BP (age specific) or more than 30% decrease in systolic BP
B) Adults systolic BP <90mmHg or more than 30% decrease from baseline - Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours)
A) Involvement of skin, mucosal tissue or both (hives, itch, swollen lips, tongue, uvula)
B) Respiratory compromise, (SOB, wheeze, stridor, fall in PEF, hypoxemia)
C) Reduced BP or associated symptoms (collapse, syncope, incontinence)
D) Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)
Summarise diagnosis criteria for anaphylaxis
NO know or unknown allergen exposure + acute onset of skin signs (urticaria, angioedema) + AT LEAST ONE OF
respiratory signs OR decreased BP, collapse, syncope, incontinence.
Likely allergen exposure + AND LEAST TWO OF:
Skin changes OR respiratory signs OR low BP OR GI signs
Known allergen exposure AND low BP
What age group is anaphylaxis more common in
More common in children aged 0-4 years than any other age group
What is the most common cause of anaphylaxis in children
Food
What is the most common cause of anaphylaxis in children
Venom
What is the cause of idiopathic anaphylaxis
Seen in 20% of cases: hidden causes include shrimp, wheat and anisakis
What are the components of IgE anaphylaxis
Mast cells and basophils
Histamine and PAF
What are the components of IgG anaphylaxis
Macrophages, neutrophils
Histamine and PAF
What are the components of complement anaphylaxis
Mast cells and macrophages
PAF and histamine
What are the components of pharmacological anaphylaxis
Mast cells
Leukotrines and histamine
What are the different types of anaphylaxis
IgE
IgG
Complement
Pharmacological
What are some causes of IgE anaphylaxis
Food
Insect venom
Ticks
Penicillin
What are some causes of IgG anaphylaxis
Biologicals
Blood
IgG transfusions
What are some causes of complement anaphylaxis
Lipid excipients
Liposomes
Dialysis membranes
PEG
What are some causes of pharmacological anaphylaxis
NSAIDs including aspirin, opiates, neuromuscular and quinolone drugs
Skin reactions that can mimic anaphylaxis
Chronic urticaria
Angioedema (ACE inhibitors)
Cardiovascular reactions that can mimic anaphylaxis
MI
PE
Respiratory reactions that can mimic anaphylaxis
Very severe asthma
Vocal cord dysfunction
Inhaled FB
Neuropsychiatric conditions that can mimic anaphylaxis
Anxiety or panic disorder
Endocrine disorders that can mimic anaphylaxis
Carcinoid and phaechromocytoma
Toxic reaction that can mimic anaphylaxis
Scromboid toxicity (histamine poisoning)
Immune reaction that can mimic anaphylaxis
Systemic mastocytosis
Laboratory diagnosis of anaphylaxis
Serial measurement of serum tryptase (highly specific marker for mast cell degranulation)
Samples taken at 1, 3 and 24 hours post episode of anaphylaxis
The rise in tryptase concentration is directly proportional to fall in BP
What is the treatment for anaphylaxis
IM adrenaline into outer aspect of thigh and repeat if needed
Adjust body position: sit up, supine, lie on side
100% O2
Fluid replacement
Inhaled bronchodilators
Hydrocortisone 100mg IV (prevent late phase response)
Chlorpheniramine 10mg IV (skin rash)
What is the MOA of adrenaline in anaphylaxis
alpha1 receptors: causes peripheral vasoconstriction, reverses low BP and mucosal oedema
beta1 receptor: increase heart rate and contractility and BP
beta2 receptor: relaxation bronchial sooth muscle and reduce release of inflammatory mediators
Further management of anaphylaxis
Referral to allergy/immunology clinic
Investigate cause of anaphylaxis
Written information on: recognition of symptoms, avoidance of identifiable triggers, indications for self treatment with an epipen
Prescription of emergency kit to manage anaphylaxis
Copy of management plan and training for patients, carers, school staff and GP
Implement patient’s management plan in nursery and school
Venom immunotherapy and drug desensitisation as appropriate
Refer patient with food induced anaphylaxis to a qualified dietician
Advice patients to acquire a medic alert bracelet
Review patients to ensure that they understand their disease and can use their Epipen
Utilise patient support group (i.e. anaphylaxis campaign)
What is in an emergency community anaphylaxis kit
Epipen: preloaded adrenaline syringe
Prednisolone 20mg OD
Antihistamine table (cetirizine 10mg) OD
What is in an Epipen
300ug adrenaline for adults, 150ug for children
What must be done after using an anaphylaxis emergency kit
Must call ambulance and attend A&E after using the 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
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
What is a food allergy
Adverse health effect arising from specific immune response that occurs reproducibly on exposure to a given food
What is food intolerance
Non immune reactions which include metabolic, pharmacological and unknown mechanisms
What proportion of adults and children are affected by food allergies
8% of children
5% of adults
What are the features of food intolerance
Food poisoning (bacterial, scromboid toxin) Enzyme deficiencies (lactase) Pharmacological (caffeine, tyramine )
Features of food aversion
Fads
Eating disorders
Features of food allergy
IgE mediated reactions (anaphylaxis, OAS)
Mixed IgE and cell mediated (atopic dermatitis)
Non IgE mediated (coeliac disease)
Cell mediated (contact dermatitis)
What food allergies do children often outgrow
Milk and egg
What food allergies do children tend to not outgrow
Peanut and tree nut allergy
What is a risk factor for food allergy
Moderate/severe atopic dermatitis
What route of allergen exposure is most associated with allergy development
Oral exposure more likely to develop tolerance
Cutaneous exposure more likely to develop allergy
What are some important questions to include in an allergy history
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 are the investigations for food allergy
Clinical history
SPT/specific IgE blood test
Skin prick test
Individual allergen protein component
What is the gold standard to diagnose a food allergy
Double blind oral food challenge
What does a positive SPT/specific IgE blood test do (food allergy)
Useful to confirm a clinical history of food allergy.
A negative test excludes IgE mediated allergy
What can testing for individual allergen protein components help to distinguish
Between IgE sensitisation and IgE mediated allergy
Skin prick test in food allergy
Fruit and vegetable skin prick test solutions are labile and it is often better to use actual fruit or vegetable
A positive test (and specific IgE blood test indicated sensitisation but not necessarily allergy.
Increasing high food-specific IgE levels or larger skin tests wheal size indicate a higher chance of allergy.
What are the principles of management of food allergy
Avoidance
Emergency management
Prevention
What are the principles of allergen avoidance in food allergy
Education about food labelling, interaction with restaurants, school
Nutritional input for dietary balance, growth in children
Acknowledge anxiety, potential bullying: mental health support if needed
What are the principles of allergen prevention in food allergy
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 are the IgE mediated food allergy syndromes
Anaphylaxis
Food associated exercise induced anaphylaxis
Delayed food-induced anaphylaxis to beef, pork, lamb
Oral allergy syndrome
What are the features of 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
Most common food causes of anaphylaxis
Peanut Tree nut Shellfish Milk Eggs
Features of food associated exercise induced anaphylaxis
Food induces anaphylaxis if individual exercises within 4-6 hours of ingestion
Common food triggers are wheat, shellfish, celery
Features of 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
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
