Allergy Flashcards
What is an allergic disorder?
Immunological process that results in immediate + reproducible Sx after exposure to an allergen.
What is an allergen?
Usually a harmless substance that can trigger an IgE mediated immune response + may result in clinical Sx
What is sensitisation?
Detection of specific IgE either by skin prick testing or in vitro blood tests
Occurs more often than allergic disease.
Not sufficient for dx
Which immunoglobulin is clinically significant in allergic disorders?
IgE
IgE mediated Type 1 hypersensitivity
What is the immune response to bateria, viruses and fungi?
- Microbial PAMP
- Recognition of conserved microbial structure
- Th1, Th17 immune response
What is the immune response to helminths, allergens and venoms?
- Recognition by change in function- tissue damage caused by agent- disruption of epithelial barrier (rather than direct recognition of pathogen)
- Th2 immune response
Describe the Th2 response on a cellular level
Stressed/damaged epithelialium releases signalling cytokines: GM-CSF, IL-25, IL-33, TSLP
Signals ILC2 + Th2 to secrete: IL4,5,9,13
These lead to eosinophil elimination of agent + epithelial mucous secretion
Simultaneously IL4 stimulates B cells to produce IgE + IgG4
TSLP + others can cytokines can activate follicular CD4 T cells
What causes degranulation of mast cells? What do mast cells release? What effects can these have?
- Allergen causes high affinity cross-linking of IgE receptor on mast cells
- Release Histamine, Prostaglandins, Leukotrienes + cytokines (further recruitment- eosinophils, CD4+8)
- Act on endothelium- increased permeability, smooth muscle contraction + neuronal itch
- Response acts to expel allergen/ parasite OR will be responsible for Sx of asthma, eczema, hay fever
What are innate lymphoid cells?
Derived from common common lymphoid progenitor
Found at mucosal barriers (skin, respiratory + GIT)
Lack antigen specific receptors.
Respond to inflammatory cytokines + release effector cytokines
What factors promote IgE production?
Antigen dose
Length of exposure
Physical properties of allergen: a/w carrier proteins/ carbohydrate, proteolytic activity, resistance to heat, digestive enzymes
Route of exposure: oral, skin, RT
What is the difference between oral exposure compared to skin and respiratory exposure?
Oral exposure promotes immune tolerance whereas skin + respiratory induces IgE sensitisation.
How does oral exposure promote immune tolerance, whereas skin and RT exposure induce IgE sensitisation?
Ingestion of allergen orally leads to inhibition of IgE synthesis by T regs in GI mucosa
Oral tolerance requires induction of CD4 T regs
T regs inhibit multiple pro-allergic functions e.g. inhibit DC APC function + secretion of IL-10
Which statement is correct?
A. Cutaneous exposure to allergen promote immune tolerance
B. IgE degranulation of mast cells promotes a delayed clinical response
C. IL-4 plays a crucial role in development of Th2 immune responses
D. Targeted drug therapy against IgE has not been useful in the treatment of atopic asthma
E. Secretion of IL-22 by epithelial cells induces Th2 immune responses
C: IL-4 promotes Th2 immune responses
Give 4 theories for the rise in incidence of allergic disease
- Hygiene hypothesis: lack of childhood exposure to infectious agents increases susceptibility to allergic diseases by suppressing natural development of immune system
- Increase in epithelial damaging agents due to industrialisation + urbanisation
- Reduced diversity + alteration in composition of skin, resp + intestinal microbiome
- Dietary: increased processing, delayed intro of eggs/ peanuts, lack of Vit D, fatty fast food
Which theories corresponds with the rise in allergic rhinitis?
Industrialisation: change in farming practices- increased grass for more cows = more exposure to pollen
Hygiene hypothesis: improved water + food, smaller family size, less exposure to animals/ soil
Which theories correspond to the rise in childhood asthma?
Hygiene hypothesis + dietary:
increased exposure to indoor allergen (HDM) as kids played more indoors, exercised less
increased no. vaccines + BS abx
What is the evidence that microbial environment can protect against asthma?
Amish + Hutterite communities share similar genetic background + different lifestyles.
Prevalence of asthma + sensitisation much lower in Amish than in Hutterites.
Increase in LPS in dust samples collected from Amish than Hutterites. Increased secretion of innate immune cytokine by PBMC exposed to LPS in Amish than Hutterites.
Which theories correspond with the rise in food allergies?
Dietary:
Early oral exposure protect against peanut allergy.
Sensitisation to peanut + wheat can occur from skin exposure
Differences in preparation of peanuts (roast promotes IgE whereas boiled IgG).
Which statement is correct?
A. Incidence of all allergic disorders has significantly increased in the last 20 year.
B. Increased outdoor activities by children is believed to be linked to rising hospitalisation for asthma.
C. Hospitals in London are seeing increased cases of delayed anaphylaxis to red meat.
D. Increased secretion of pro-inflammatory innate cytokines by PBMC following exposure to environmental microbial product may protect against development of asthma.
D. Increased secretion of pro-inflammatory innate cytokines by PBMC following exposure to environmental microbial products may protect against development of asthma.
What are appropriate investigations for allergic disease?
Allergen specific IgE (Sensitisation) Tests
Functional allergen tests
What are the allergen specific IgE tests?
Skin prick + intradermal test
IgE blood tests
What are the functional allergen tests?
In vitro:
Basophil activation
Serial mast cell tryptase
Ex vitro:
Open or blinded allergen challenge
Which allergic diseases are most likely to be present in infants?
Atopic dermatitis
Food allergy (milk, egg, nuts)
Which allergic diseases are most likely to be present in children?
Asthma (HDM, pets)
Allergic rhinitis (HDM, grass, tree pollens)
Which allergic diseases are most likely to be present in adults?
Drug allergy
Bee allergy
Oral allergy syndrome e.g. tingling tongue after eating apple
Occupational allergy
Describe the onset of an IgE allergic response
Occurs within minutes or up to 3h after exposure to allergen
Give 4 signs or symptoms that can arise in the skin in an allergic response
Angioedema: swelling of lips, tongue, eyelids
Urticaria: wheals or hives
Flushing
Itch
Give 6 signs or symptoms of the respiratory tract that can arise in allergic response
Cough
SOB
Wheeze
Sneezing
Nasal congestion + clear discharge
Red, itchy, watery eyes
Give 3 gastrointestinal symptoms that can arise in an allergic response
Nausea
Diarrhoea
Vomiting
What vascular or CNS symptoms can arise in an allergic response?
Sx of hypotension (faint, dizzy, blackout)
Sense of impending doom.
What are the features of IgE mediated allergic responses?
>, 2 organ systems usually involved.
Reproducible: occurs after every exposure.
Allergic Sx may be triggered by cofactors
Link between exposure + onset Sx may not be obvious.
Clinical hx used to select allergens to be tested by skin prick +/- blood tests.
Give 4 co-factors that can trigger an allergic response
Exercise
Alcohol
NSAIDs- disrupt GIT
Viral infection in kids
Give 3 exposures that may not be obvious prior to onset of symptoms in an allergic response
- House Dust mite
- Fungal + Staph skin colonisation
- Red meat ingestion
List 6 symptoms NOT associated with an IgE allergic response?
Fatigue
Migraine
Recurrent episodes of abdo pain, diarrhoea, constipation, bloating
Hyperactivity
Depression
Sx which vary over time, with antigen dose + source
When are sensitisation tests more likely to be associated with an allergic disorder?
In the context of an appropriate hx, large skin wheals, higher specific blood IgE values are more likely to be a/w allergic disorder.
Results of skin prick or serum specific IgE do NOT predict SEVERITY of reaction.
Why is presence of IgE not sufficient for diagnosis of allergic disease?
Presence of IgE is NECESSARY but NOT SUFFICIENT for dx of allergic disease.
Sensitisation is FAR more common than allergic disease, hence detection of IgE is best considered a RF for an allergic disorder.
Clinical hx is used to select what allergens should be tested.
What is a skin prick test?
Expose patient to standardised solution of allergen extract through a skin prick to the forearm.
Use standard skin test solutions, +ve control (histamine) and -ve control (diluent).
Measure local wheal + flare response to controls + allergens.
IgE crosslinking on skin mast cells, leads to degranulation + release of histamine + other inflammatory mediators.
What is a positive response on a skin prick test? What must be done prior to testing?
Wheal ≥ 3mm > the -ve control.
Antihistamines + some anti-depressants should be discontinued for 48h beforehand.
What are advantages of the skin prick test?
Rapid (read after 15-20m)
Cheap + easy to do
Excellent -ve predictive value, usually >95%
Increasing size of wheals correlates with higher probability for allergy
Patient can see the response
What are disadvantgaes of the skin prick test?
Requires experience to interpret.
Risk of anaphylaxis: 1 in 3000
Poor +ve predictive value: high false +ve rate
Limited value in patients with dermato-graphism or extensive eczema
False -ve results with labile commercial food extracts
What are intradermal tests? What are the advantages and disadvantages?
Application of allergens, +ve and -ve controls into skin
More sensitive but less specific than SPT
Best used to follow up -ve venom + drug allergy test (better than blood tests)
Can be used if SPT to allergen is -ve but convincing hx
Labour intensive, greater risks of anaphylaxis.
What are sensitisation (IgE antibody) blood tests?
Detection of IgE to whole allergen extract or to individual protein component within an allergen extract
Automated assays can detect individual or multiple allergens.
What are 4 limitations to sensitisation (IgE antibody) blood tests?
May detect IgE antibody with little clinical relevance
Allergen in low abundance may lead to reduced sensitivity
Expensive
Limited understanding of role outside that for specialists
What are indications for sensitisation blood tests?
No access to SPT +/- IDT
Pt who can’t stop anti-histamines
Pt with a hx of dermatographism/ extensive eczema
Pt with a hx of anaphylaxis
Decision on who needs food challenge
Prediction for resolution of egg, milk, wheat allergy
Monitor response to anti-IgE therapy
What must be remembered when interpreting allergen specific IgE sensitisation tests (skin + blood)?
Risk profile of serum IgE for prediction of allergic Sx
Detection of IgE is necessary but not sufficient for dx of allergic disease
Dx must integrate epidemiology, hx, exam, SPT, lab + challenge testing
What contributes to the risk profile of serum IgE for prediction of allergic symptoms?
Concentration: higher levels more likely a/w Sx
Molecular target within whole extract or even individual epitope can be linked to Sx
Affinity to target: higher affinity a/w risk
Capacity of IgE antibody to induce mast/ basophil degranulation
What is component resolved/molecular allergen testing?
Blood test to detect IgE to single protein components within allergen extract
Abundance + stability of protein contributes to risk of allergic disease
Diagnostic use:
- Food allergy (nuts, egg, milk)
- Insect allergy (wasp + bees)
- Guide to immunotherapy (grass + HDM)
What is mast cell tryptase?
Tryptase: Pre-formed protein in mast cell granules.
Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase.
Peak conc. 30m-2h; returns to baseline by 6-12h.
What may failure of tryptase to return to baseline after anaphylaxis indicate?
Systemic mastocytosis + hereditary alpha tryptasaemia
When is measurement of tryptase useful?
If dx of anaphylaxis is not clear (hypotension + rash during anaesthesia).
What does tryptase measurement have reduced sensitivity for?
Food induced anaphylaxis.
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.
Where are basophil activation tests being increasingly used? What difficult has been encountered with this?
In dx of food + drug allergy: surrogate marker for challenge tests.
Difficult to standardise test, some have basophils refractory to responding to allergens
Describe food and drug challenge tests
Gold standard for food + drug allergy dx.
Increasing volumes of offending food/ drug are ingested.
Double blind placebo or open challenge.
What are the disadvantages of food and drug challenge tests?
Performed under close medical supervision. Very expensive in terms of clinical staff time.
Can be difficult to interpret mild Sx.
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?
Skin prick test
(Cheap, quick, + easy
Had skin reaction- no suggestion of anaphylaxis)
Give 3 features commonly emphasised in anaphylaxis
Acute onset of Sx/ signs (mins- 6h)
Severe/ life-threatening ABC problems
Skin + mucosal signs/ Sx
What is the most frequently involved organ in anaphylaxis?
Skin
(Hives, itch, swollen lips, tongue, uvula)
Give 2 systems that may be compromised in anaphylaxis and the corresponding symptoms
Cardiovascular: collapse, syncope, incontinence, drop in BP
Respiratory: SOB, wheeze, stridor, fall in PEF, hypoxaemia
Which system is more commonly affected in adults and children in anaphylaxis?
Children: Respiratory
Adults: Cardiovascular
Give 4 epidemiological facts about anaphylaxis
Most common age group: 0-4y
Food more in kids
Drug + venom more in adults
Idiopathic in 20-30% cases- hidden causes inc. shrimp, wheat, red meat
What cells, mediators and aetiological causes are involved in the IgE mediated mechanism of anaphylaxis?
Cells: Mast cells + Basophils
Mediators: Histamine + PAF
Aetiology: Food, Insect venom, Ticks, Penicillin
What cells, mediators and aetiological causes are involved in the IgG mediated mechanism of anaphylaxis?
Cells: Macrophages + Neutrophils
Mediators: Histamine + PAF
Aetiology: Biologicals, Blood + IgG transfusions
What cells mediators and aetiological causes are involved in the complement mediated mechanism of anaphylaxis?
Cells: Mast cells + Macrophages
Mediators: PAF + Histamine
Aetiology: Lipid excipients, liposomes, dialysis membranes + PEG
What cells, mediators and aetiological causes are involved in the pharmacological mediated mechanism of anaphylaxis?
Cells: Mast cells
Mediators: Leukotrienes + Histamine
Aetiology: NSAIDs inc. Aspirin, Opiates, neuromuscular + quinolone drug
Give 8 differentials to the symptoms/ signs of reactions that can mimic anaphylaxis
Skin: Chronic urticaria + Angioedema (ACEi)
Throat swelling: C1 inhibitor deficiency
Cardio: MI + PE
Resp: Severe asthma, vocal cord dysfunction, inhaled FB
Neuropsychiatric: anxiety/ panic disorder
Endocrine: carcinoid + phaeochromocytoma
Toxic: Scromboid toxicity (Histamine poisoning)
Immune: Systemic mastocytosis
Which laboratory measurements support retrospective diagnosis of anaphylaxis?
Serial measurement of serum tryptase at 30m-2h, then at least 24h after onset of anaphylaxis
Conc > 1.2x baseline tryptase + 2ug/L
Failure to detect elevation does not exclude anaphylaxis
By what mechanism does adrenaline act on receptors in treatment of anaphylaxis?
Alpha1: causes peripheral vasoconstriction, reverses low BP + mucosal oedema
Beta1: increases HR + contractility + BP
Beta2: relaxation of bronchial smooth muscle + reduces release of inflammatory mediators from mast cells/ basophils
What is the emergency management of anaphylaxis?
Call for help
Position supine, raise legs
IM adrenaline, repeat if no response
IV crystalloid
Antihistamines only after airway, breathing + circulation corrected
NO steroids
What are the aspects of follow up management post-anaphylaxis?
Referral to allergy clinic
Ix cause
Info sheet on Sx, avoidance of triggers, Epipen
Prescribe emergency kit to manage
Copy of management plan + training for pt, carer, school + GP
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 a food allergy?
Adverse health effect arising from specific immune response that occurs reproducibly on exposure to a given food
Affect ~5% adults + ~8% kids
What are food intolerances?
Non-immune reactions which include metabolic, pharmacological + unknown mechanisms
Give 3 examples of food intolerances
Food poisoning: Bacterial, Scromboid Toxin
Enzyme deficiency: Lactase
Pharmacological: Caffeine, Tyramine
Give 2 examples of food aversions
Fads
Eating disorders
Give 4 mechanisms of food allergy
IgE mediated: Anaphylaxis, OAS
Mixed IgE + cell mediated: Atopic dermatitis
Non IgE mediated: Coeliac- type IV hypersensitivity
Cell mediated: Contact dermatitis
Which allergies are commonly outgrown and which usually persist?
Outgrow: Milk + Egg
Persist: Peanut + tree nut
What is an important risk factor for food allergy and indication for allergy testing even in absence of clinical history?
Moderate-severe atopic dermatitis
What aspects should be ascertained in a clinical history of food allergy?
IgE v non IgE mediated Sx
Dose, food preparation + co-factors
Hx of atopic disease
Previous Ix for food allergy e.g. SPT, IgE blood
Has elimination of food impacted on Sx
How are skin prick tests and specific IgE blood tests informative in food allergy?
+ve: indicate sensitisation, useful to confirm clinical hx of food allergy
-ve: excludes IgE mediated allergy
Why are fruit and vegetable skin prick solutions not preferential?
They are labile
Better to use actual fruit/ veg
What is the gold standard test for diagnosis of food allergy?
Double blind oral food challenge
What is the avoidance aspect of management for food allergies?
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 is the emergency management aspect of management for food allergies?
Anaphylaxis guidelines
Ensure allergic asthma is well controlled
What is the prevention aspect of management for food allergies?
Breast feeding: Strong FH allergy
LEAP study: Early intro of peanut in high risk children (moderate/ severe AD + egg allergy) significantly reduces development of peanut IgE sensitisation + allergy.
What are IgE mediated food allergy syndromes?
Anaphylaxis:
Peanut, tree nut shellfish, fish, milk + eggs most common.
Natural hx dependent on food.
Food associated exercise induced anaphylaxis:
Delayed food-induced anaphylaxis to beef, pork, lamb
Oral allergy syndrome
Describe food associated exercise induced anaphylaxis
Food induces anaphylaxis if individual exercises within 4-6h ingestion
Common triggers: Wheat, Shellfish, Celery
Describe food-induced anaphylaxis to beef, pork and lamb
Sx occur 3-6h after eating red meat/ gelatin
IgE antibody to oligosaccharide alpha-gal in gut bacteria
Induced by Tick bites
Describe Oral allergy Syndrome
- Limited to oral cavity, swelling + itch: 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 > kids
- Respiratory exposure to pollen (birch) results in IgE directed to homologous proteins in stone fruits (apple, pear) vegetables (carrot) + nuts (peanut, hazelnut).
- Cooked fruits, vegetables + nut cause no Sx: 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 ?
Cross reactive IgE sensitisation between hay fever and apple allergens
Which cytokine plays a crucial role in development of Th2 immune responses? When is this induced?
IL4
Only induced following peptide-MHC presentation to naive/ memory Th2 cells
Which is the characteristic antibody of allergic sensitisation?
IgE
Why do delayed symptoms occur in Th2 immune responses?
Result from CD4 Th2 cytokine secretion (IL4, 5, 13) + eosinophilic related tissue damage
What are PBMC?
Peripheral blood mononuclear cells- lymphocytes, monocytes, DC
What is PAF?
Platelet Activating Factor
Mediator in anaphylaxis
What are the main cytokines secreted by CD4 Th2 cells?
IL4: Helps B cells produce IgE
IL5: Expands + activates eosinophils
IL13: Stimulate mucous secretion
What do eosinophils secrete to eliminate pathogens? What are they implicated in?
Cytotoxic granules
RNAse proteins
Extracellular traps
Implicated in late stage tissue damage in atopic dermatitis, asthma, eosinophilic oesophagi’s + granulomatous disease
What high and low affinity receptors do IgE bind to?
High: Mast cells, Basophils, Eosinophils + DC
Low: Above + B cells, Respiratory + GI epithelial cells
What is IgE induction of mast cell and basophil degranulation associated with?
Immediate hypersensitivity (allergic) reactions
What does cross linking of bound IgE by antigen result in?
Release of pre-formed inflammatory mediators from granules (histamine)
Release + synthesis of lipid mediators (leukotrienes + prostaglandins)
Synthesis of pro-inflammatory cytokines
What does mast cell degranulation lead to?
Recruitment of soluble proteins + inflammatory cells to site of infection
Increase in rate of lymphatic flow back to regional lymph nodes
Smooth muscle contraction in lungs+ gut (may help expel pathogens) + activation of sensory neurones (itch, sneeze)
