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Flashcards in Asthma and allergy Deck (49)
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Compare innate vs. adaptive immune system


- non specific response

- exposure -> immediate maximal response

- cellular & humoral (antibody, molecules) components

- NO immunological memory

- found in nearly all forms of life



- pathogen & antigen specific

- lag time b/w exposure and maximal response

- cellular & humoral componentswith specific antigen-antibody responses 

- exposure leads to immunological memory

- found only in jawed vertebrates


Describe allergy

- definition (compared to hypersensitivity)

- pathophys

- ix

- mx

- prevention

  • Hypersensitivity = objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects.
  • Allergy = hypersensitivity reaction initiated by immunologic mechanisms
  • c.f. Non-allergic hypersensitivity = NOT a/w immunologic mechanisms 
  • Allergy itself can be further divided to: 
    • IgE mediated; non atopic (e.g. drug allergy) & atopic (can be symptomatic or asymptomatic)
    • Non-IgE mediated: 
      • T-cell e.g. contact dermatitis
      • Eosinophil e.g. gastro-enteropathy
      • IgG mediated e.g. allergic alveolitis
  • Pathophys: Th2 respones (IgE, mast cells, eosinophils)
  • Ix: 
    • serum tryptase: peak 60-90 minutes, persists up to 5h. may not be elevated with food anaphylaxis. 
    • plasma histamine: NOT helpful
    • skin prick testing. note contraindications in: 
      • pts unable to take steroids/anti-histamine
      • severe eczema
      • Relative contraindication: anaphylaxis to allergen, pregnancy, poorly controlled asthma 
  • Mx: Adrenaline 1: 1000 0.01mg/kg (max 0.5mg) IM Q15-20 min PRN if anaphylaxis. Corticosteroids, antihistamine. 
  • Prevention: 
    • Allergen specific immunotherapy: for anaphylaxis caused by insect stings/venom. NOT recommended for food
      • Exposure to allergen in either the subcutaneous or sublingual form, then give higher doses each time to build tolerance -> switch immune response from Th2 to Th1 -> Production of IgG, IgG4, IgA (instead of IgE) & induction of Treg response (IL10, TGFB)
      • Grass pollen immunotherapy: 3 years of immunotherapy effective in inducing sustained benefit following cessation
      • House dust mites (subling desens) in adult allergic asthma: delays time to severe asthma exacerbation
      •  **Contraindicated in pregnancy and patients with uncontrolled asthma 
    • Desensitisation of medications:
      • give higher doses each time to build tolerance -> switch immune response from Th2 to Th1 -> Production of IgG, IgG4, IgA (instead of IgE) & induction of Treg response (IL10, TGFB)
      • need to then be uninterrupted course of medication 
    • Monoclonal antibody in asthma: 
      • Anti-IgE: Omalizumab. bind IgE -> down regulate down stream inflammation
      • IL-5 antagonist: benralizumab (antibody that blocks IL-5R), mepolizumab (antibody that blocks IL-5)
      • IL-4 R antagonist: Dupilumab 
      • TSLP-antagonist: Tezepelumab


Types of allergy based on pathogenesis

1. IgE mediated (target of allergy desensitisation)

- non atopic (insect venom, drugs, other)

- atopic 

2. Non-IgE mediated (does not work with allergy desensitisation)

- T cell; contact dermatitis

- eosinophi: gastro-enteropathy

- IgG: allergic alveolitis

- other


Define atopy

  • Immunological reactivity in which immunoglobulin E (IgE) is readily produced in response to:
    • ordinary exposure (skin contact, ingestion, inhalation)
    • common allergens of the subjects’ environment.
  • In itself, atopy does not imply the presence of disease but is a reflection of the immunological state of the individual
  • usually improves with aging 


Describe immunology of allergy

- sensitisation


  1. Allergen exposure -> antigen presented by APC (dendritic cells, macrophages) via MHC II to T cell receptor on CD4+ helper cells.
  2. Costimulatory signals B7 to CD28 activate T cell (absence of this interaction leads to anergy)
  3. CD4+ helper T cells differentiate to 3 major sbsects of effector cells -> produce distinct sets of cytokines 
    • Th2 subset important in tissue homeostasis, repair. barrier immunity (elimination of microbes at epithelial barriers & development of allergy)
  4. IgE class switching & production by B cells/plasma cells
  5. IgE binding to receptors on tissue mast cells


Describe roles of Th1, Th2, Th17 & Folicular T helper cells

- defining cytokines

- target cells

- host defense

- role in disease

Th1 activate macrophages to target intracellular pathogens. a/w autoimmunity, chronic inflammation. IFN gamma is responsible

Th2 activates eosinophils to target parasites. a/w allergy. IL 4, 5, 13 are responsible

Th17 activates neutrophils, to target extracellular pathogens. a/w autoimmunity. IL 17, 22 are responsible

Follicular T helper cells activate B cells to target extracellular pathogens. a/w autoimmunity. IL-21 is responsible


Describe potential roles of naive CD4+ T helper cell


Roles of Th2 cells

tissue homeostasis and repair

barrier immunity; eimination of microbes at epithelial barriers

Th2 response drives allergy! 


Role of immunoglobulin E

iniaition of allergic inflammatory response 

Short serum half life of 2 days (c.f. IgG of 20 days)

Usually bound to mast cells/receptors on inflammatory cells in tissues

detect antigens by cross linking with adjacent IgE molecules on FceRI. Receptors are brought into juxtaposition -> activates mast cell medators; preformed (histamine, heparin, tryptase, chymase), newly synthesised (eicosanoids. prostaglandins, leukotrienes) and cytokines (IL4, IL13 for IgE switching. IL5 & GM CSF for eosinophil recruitment. TNF alpha for priming leukocytes for mediator secretion). 


Cytokines responsible for IgE switching

IL4, IL13


What is the main effector cell of chronic allergic inflammation?



Mechanisms of immunotherapy

High dose allergen exposure during immunotherapy -> deviation of Th2 responses to Th0/Th1 response. 

promotes generation of IL-10 & TGF beta -> produce T regulatory cells -> induce B cells switch to IgG and IgG4 antibodies (rather than IgE)

during subsequent natural environmental allergen exposure, Th2 response is inhibited

Decrease in mast cell & basophil activity for degranulation & systemic anaphylaxis

T cell tolerance induces T reg cells & suppress Th2 cells

Early to late effects: basophils, mast cell desensitisation -> regulation of T cells -> regulation of B cells and antibodies


Classifications of asthma

1. allergic vs. non allergic

2. intrinsic vs. extrinsic

3. non atopic vs. atopic

4. type 2 low, type 2 high - this is the most important as it guides immunotherapy

Type 2 high asthma indicates eosinophillic or high IgE or both. (includes non atopic eosinophilic). It involves mast cells, epithelium, Th2, NKT, ILC2 (type 2 innate lymphoid cell which can also mediate eosinophils via IL-5 independent of adaptive immune system)

Type 2 high asthma are eligible for immunotherapy e.g. monoclonal antibody against IL-5, IL-5 receptor, IgE. 


Monoclonal antibody therapy in asthma

  • anti-IgE antibody; omaliumab. effective 
  • anti-IL5 antibody; mepolizumab. reduced rate of exacerbations, increase FEV1
  • anti-IL5 receptor antibody; benralizumab. reduced rate of exacerbations. increased FEV1. Glucocorticoid sparing effect  

Can be used in type 2 high asthma. (not type 2 low asthma given there is low IgE & no eosinophilic involvement). Note that IL-5 is involved in eosinophils. 




Role of house dust mite sublingual allergen immunotherapy

Effective in adults with allergic asthma in a randomised clinical trial

reduced moderate or severe exacerbations during steroid reduction

absolute reduction of exacerbations at 6 months


Describe types of adverse drug reactions

Type A (80%): pharmacological

  • SE
  • toxic
  • secondary (e.g. antibiotic changing microbes induced diarrhoea)
  • drug interactions

Type B (10-15%): hypersensitivity

  • imune mediated/allergic 5-10%:
    • IgE mediated: small amount. Immediate. <1 hour. urticaria, angiooedema, bronchospasm, anaphylaxis. 
    • T cell mediated: majority. Non-immediate >1hour. maculopapular, mobiliform, severe skin reactions (SJS).  
    • others (e.g. immne complex, cytotoxic reactions)
  • non immune mediated/non-allergic 5-10%


Questions to ask to assess allergic drug hypersensitivity

1. Was this reaction on first exposure to the drug?

  • need previous exposure for sensitisation for an allergy
  • first dose previously tolerant unless cross reactivity 

2. What was the nature of the reaction?

  • mast cell activation + IgE: urticaria, angiooedmea, bronchospasm, anaphylaxis. mast cell activation
  • mast cell activation without IgE: above symptoms in setting of radiocontrast, vancomycin 
  • T cells: maculopapular exanthems. morbiliform, fixed drug eruptions. 

3. What was the time course of the reaction?

  • <1 hour: immediate reaction. IgE medaited with preformed IgE antibodies
  • accelerated 1-72h, or delayed >72h: drug sepcific T-cell 


immunological mechanisms responsible for urticaria, angiooedmea, bronchospasm, anaphylaxis


mast cell activation + IgE

Can occur in certain settings e.g. radiocontrast, vancomycin with mast cell activation however without IgE involvement 



immunological mechanism responsible for maculopapular exanthems. morbiliform, fixed drug eruptions. 

T cells


Types of hypersensitivity

Type I (IgE mediated): immediate reaction. mast cell activation. a/w allergy, allergic rhinitis, asthma, systemic anaphylaxis

Type II (cytotoxic antibody mediated): IgG. Mediates phagocytes, NK cells. a/w haemolytic anaemia, thrombocytopaenia. 

Type III (immune complex mediated): mediates complement. a/w serum sickness, vasculitis.

Type IV (T cell mediated): delayed reaction. Various subtypes a/w different effector cells. A/w tuberculin reaction, contact dermatitis, chronic asthma, SJS/TEN, chronic allergic rhinitis, maculopapular exanthem, Behcett's disease. 


Types of Hypersensitivity tests

1. skin testing

  • e.g. skin prick or intradermal (only for insect stings)
  • positive if >3x3mm at 15 minutes
  • predictive value for only a limited group of IgE mediated drug allergic reactions (note only 10% of allergy is IgE mediated)
  • not highly sensitive with food. not specific in eczema pts (wheal easily with skin trauma)
  • limitation: vast majority of allergic drguc reactions are not IgE mediated. the relevant immunological epitopes are not known for most drugs 
  • Avoid skin prick testing 4-6 weeks post an anaphylactic reaction due to false positives
  • Absolute contraindications: antihistamines (ineffective test), tricyclie antidepresssants, topical steroids (<72h), severe eczema, poor cooperation, dermatographism 
  • Relative contraindications: pregnancy, persistent/unstable asthma, severe anaphylaxis to particular allergen
    • Unstable asthma is a stronger contraindication than stable asthma 
    • Beta-blocker use is a relative contraindication-risk of anaphylaxis and poor response to adrenaline. Stronger contraindication if patient is a higher risk of anaphylaxis 

2. in vitro tests. e.g. RAST/ELISA to detect serum specific IgE antibodies

  • only available for some betalactam antibiotics
  • can be used if skin prick test contraindicated for allergic rhinitis
  • immunogenic epitopes unknown for many drugs
  • more specific but less sensitive than skin tests -> better positive predictive values. poor negative predictive values
  • i.e. even if you test negative, doesn't mean that you don't have an allergy. if you test positive, likely you have an allergy. 
  • use in conjunction with clinical evaluation AND skin tests 

3. lymphocyte transformation test

  • detect drug specific T cells involved in some delayed allergic hypersensitivity reactions 
  • more for research purposes. limited clincial application. low sensitivity  

4. Skin patch testing 

  • limited role for diagnosing delayed drug hypersensitivity reactions 
  • low sensitivity 

5. Oral food challenge

  • gold standard investigation for food allergy diagnosis
  • helpful if clinically suspicious of food allergy but negative skin prick test and negative IgE

6. Drug provocation test 

  • to exclude hypersensitivity when hx not suggestive (e.g. vasovagal with local anesthetic)
  • to confirm diagnosis when skin prick test and SpIgE negative (penicillin)


Describe immediate hypersensitivity in penicillins & cephalosporins

If immediate hypersensitivity to: 

- beta lactam ring; cross reactivity occurs. allergic to both penicillins and cephalosporins

- side chain: only allergic to that specific cephalosporin or penicillin. no cross reactivity to beta lactams in general 


Dx & Mx of drug allergy based on clinical suspicion

- low probability

- indeterminate probability

- high probability

1. low probability; challenge to eliminate suspicion

2. intermediate probability: if need to use drug, use a validated test (e.g. skin prick test in IgE mediated certain medications). If positive then desensitise. If negative, challenge with medication. 

3. High probability. Desensitise without testing with validated test, if the drug is needed. If severe systemic non immediate reaction (SJS/TEN), this is NOT desensitisable -> avoid and use alternatives, even if the said drug is required. 


How do T cells recognise drugs in delayed hypersensitivity?

T cell receptor binds to: 

  • hapten: small chemically reactive molecule stable covalent binding to protein or peptide
  • prohapten: drug not chemically reactive but becomes reactive during metabolism
  • direct pharmacologic interaction by drug to the T cell with immune receptor (pharmacologic-immune concept)


Criteria for anaphylaxis

1. individual has skin symptoms or swoollen lips and either: 

• Difficulty breathing or

• Reduced blood pressure (< 100 mmHG systolic or > 30% decrease)


Or if known allergen, just blood pressure instability alone on exposure to the known allergen can be anaphylaxis. 


2. An individual had exposure to a suspected allergen and two or more of the following:

• Skin symptoms or swollen lips

• Difficulty breathing

• Reduced blood pressure

GI symptoms with suspected food allergy (such as vomiting, diarrhoea, cramping)


Is anaphylaxis always an allergy?

No. It can be mediated by non immunologic mechanisms (i.e. independent of IgE. direct mast cell activation) in physical factors (exercise, cold, heat, sunlight), ethanol, medications (e.g. opioids)


although medications can also cause immunologic mechanisms (IgE) for anaphylaxis


Mx of anaphylaxis


Adrenaline 1:1000

• adults 0.4mg deltoid or thigh

• children 0.01mg/kg, max 0.4 mg

• repeat 15 to 20 minutes as necessary

• Should be in ED if any life-threatening features or adrenaline used


Mild reactions: antihistamine +/- prednisolone, medical consultation


Laboratory Dx of anaphylaxis

serum tryptase: ideally 60-90 minutes (peak) post exposure. most specific diagnostic test for mast cell activation. indicative of anaphylaxis. Lasts up to 4 hours

Plastma histamine; peaks <30 minutes, lasts 1 hour

24h urinary histamine metabolite peaks later. Lasts >4 hours. 




Describe irritant contact dermatitis

- due to what

- pathophys

- how is it different from allergic contact dermatitis

- px

- ix

 - mx 


  • due to direct contact with the causative agent 
  • May be acute or chronic (persistent)
  • higher incidence in younger Pts
  • Irritants include: prolonged water exposure, detergents and surfactants, solvents, oxidising agents, acids, alkali. wood, fibreglass, dust 
  • Pathophys of irritant contact dermaittis: Non-immunologic process that results from direct contact with an irritant. does not need prior sensitisation (c.f. allergic contact dermaitits),
    • disruption of the epidermal layer due to chemical or physical irritants 
    • Cytotoxic effect on keratinocytes & induces release of preformed cytokines such as IL-1, IL-1 beta and TNF
    • Activation of innate immunity 
    • Chronic dermatitis: Characterised by hyperkeratosis, parakeratosis, hypergranulosis and acanthosis
  • Px: onset of symptoms within minues-hours of exposure
    • pain, burning, stinging, discomfort exceeding itching especially early in the course
    • Macular erythema, hyperkeratosis, or fissuring predominating over vesicular change
    • Glazed, parched, or scalded appearance of the epidermis
    • Commonly involved sites: hands, fingertips and finger webs 
    • chronic: erythema, scaling, lichenification, hyperkeratosis and fissuring 
  • Ix: patch testing (testing patches of skin on the back with irritants to find causative irritants), skin biopsy 
  • Mx: 
    • Avoid the offending irritant 
    • Avoid soap- use pH balanced cleansers 
    • Rashes can be treated with a short course of topical steroid screams and emollients 
    • Severe contact dermatitis: systemic corticosteroids such as oral pred
    • For chronic contact dermatitis phototherapy may be used or methotrexate, cyclosporine or azathioprine 


N.B. contact dermatitis includes chemical burns, irritant contact dermatitis (most common. non-immunologic), allergic contact dermatitis, contact stomatitis and systemic contact dermatitis


C.f. allergic contact dermatitis: 

  • Antigen specific, lymphocyte mediated hypersensitivity reaction: type IV or delayed type hypersensitivity reaction
  • Reaction occurs in the epidermis and is mediated primarily via CD8+ T cells with a Th1-type cytokine profile 
  • Common triggers: Nickel, Neomycin etc.


Describe hereditary angioedema

- definition

- mediated by what

- pathophys

- px

- ix

- mx

- 3 types 

  • 1:30,000-50,000
  • angioedema without urticaria 
  • Hereditary or acquired angiooedema is mediated by bradykinin
  • pathophys: 
    • 300 mutations known. Most common defects:
      • Single base-pair mutation (commonest)
      • Larger gene rearrangement (partial gene deletions & duplications) ~ 20% 
      • De novo mutations ~25% 
    • due to hemizygous C1INH deficiency/dysfunction -> increased classical complement pathway (activation of C4, C2 but not C3) & activation of contact pathway of coagulation (Factor XIIa, Kallikrein) -> excess bradykinin production (7x higher than normal during acute attack) -> increase vascular permeability -> angioedema
    • autosomal dominant (type 1 & 2): need 2 normal copies of the SERPING1 gene (coding C1INH) for normal function
  • Px: onset usually school age. self limited symptoms. usually last 2-3 days
    • Recurrent angioedema (limb, trunk, face, genital) without urticaria, painless
    • skin: oedema
    • abdominal/bowel wall oedema: Nausea/Vomiting/recurrent self-limited, colicky abdominal pain -> mimics acute abdomen. Mx with C1INH concentrate (NOT surgery)
    • laryngeal oedema: may need intubation 
    • does not respond to epinephrine, antihistamines, or glucocorticoids. 
  • Triggers: 50% spontaneous, ACEi (overproduction of bradykinin), oestrogen, trauma/psychological stress
  • Ix: 
    • low C4 level (best screening test, 95%)
    • C1INH antigenic levels, C1INH functional levels
    • C1q antigen  
    • Genotyping for mutations in C1INH gene (SERPING1)
  • Mx: replacement of C1-INH that is deficient or dysfunctional in this disease or by inhibiting the production or function of bradykinin
    • 1st line: 
      • Human plasma-derived C1-INH concentrate (pdC1-INH)
      • Recombinant human C1-INH (rhC1-INH)
      • Icatibant, a bradykinin B2-receptor antagonist
      • Ecallantide, a kallikrein inhibitor (only in the US)
    • 2nd line: solvent-detergent-treated plasma or FFP (if 1st line not available and not severe attacks) 
    • ineffective: Androgens, tranexamic acids, treatments for histaminergic angioedema (e.g. glucocorticoids, antihistamine)
  • risk of death from laryngeal angiooedema 


3 types: Types I, II and III

  • Type 1 (85%): C1 inhibitor (C1INH) deficiency
    • autosomal dominant
    • C1INH protein level/quantity: Low (< 30%)
    • C1INH activity: Low (< 30%) 
    • C4 level: Low
    • C3 level: Normal
    • C1q level: Normal between attacks and reduced during attacks (c.f. reduced C1q level in acquired angiooedema; B-cell lymphoproliferative disorders (e.g. lymphoma, MGUS), autoimmune disease or idiopathic)
  • Type 2 (15%): C1INH dysfunction  
    • autosomal dominant
    • C1INH protein level/quantity: Normal/High
    • C1INH activity: Low (< 30%) 
    • C4 level: Low
    • C3 level: Normal
    • C1q level Normal between attacks and reduced during attacks
  • Type 3: HAE with normal C1INH. due to FXII mutation defect
    • F>M. a/w pregnancy, use of OCP
    • demonstrate FXII mutation 
    • normal C1INH protein level/activity. normal C4, C3, C1q level