-
what is antigen?
substance that is recognized and processed by immune system
-
what is hapten?
- drug or metabolite that must bind to a tissue or protein to serve as a complete antigen
- (too small to be recognized by itself)
-
Is there humoral or cellular immune response in pseudoallergy?
NOPE
-
does anaphylactoic reaction involve immune mediated reaction?
- NOPE
- this is a type of pseudoallergy that mimics anaphylaxis
-
does anaphylaxis involve immune mediated reaction?
- Yes.
- this is the most severe and life threatening form of drug allergy (a form of hypersensitivity)
- histamine mediated
-
what is the mechanism of hypersensitivity?
- Not completely understood
- because difficult to study (many animal models), single drug can have many mechanisms and reactions, and it is difficult to identify the antigen
-
what are the hallmark characteristics of drug hypersensitivity?
- drug is the antigen; "individual drug related"
- 1) onset from 5-21 d after initial exposure (sensitization period)
- 2) associated with usual or standard dose of drug
- 3) presence of histamine related or immune mediated S&S, including eosinophilia
- 4) reversibility of symptoms after d/c of drug
- 5) faster appearance of reaction (within hours to days) after reintroduction of the drug
-
what are the 5 stages of immune response to a drug during hypersensitivity?
- 1) formation of complete antigen
- 2) processing of the complete antigen by antigen presenting cells
- 3) recognition of the antigenic determinants by the T-lymphocytes
- 4) generation of a drug specific antibody or sensitized T cells
- 5) clinical presentation of immune reaction
-
how do haptens form? (part of the first stage of hypersensitivity)
- via metabolism in liver, skin keratinocytes, WBC
- hapten binds with higher weight protein to form a complete antigen
- (note: binding of a drug to plasma protein, like albumin, does not count)
-
what should happen when hapten major histocompatibility complex on the APC surface interact with T-helper cells to induce a clinical reaction? (part of the 3rd stage of hypersensitivity)
- cytokines should be released to differentiate T-helper cells to type 1 and type 2 for a clinical reaction.
- otherwise, cells are just sensitized and no reaction will occur.
-
T helper type 1 cells secrete cytokines favoring ___, ___ and ___. And this is called ____ response. (part of 4th stage of hypersensitivity)
- CD4+, CD8+, memory cells
- cellular response
-
T helper type 2 cells secrete cytokines favoring ___, ___ and ___. And this is called ____ response. (part of 4th stage of hypersensitivity)
- antibodies IgE, IgG, IgM
- humoral response
- (aka delayed immune response becdause makes antibodies)
-
During stage 5 of hypersensitivity, there is clinical presentation of immune reaction. How are these classified?
- classified by mechanism and clinical presentation.
- (note: you must have a clinical response to proceed to stage 5)
-
How long do stages 1-4 for hypersensitivity take?
5-21 days
-
what are the 4 types of immune reaction for hypersensitivity? (this is stage 5)
- type I: immediate hypersensitivity
- type II: cytotoxic reaction
- type III: immune complex reaction
- type IV: delayed and cellular immune response
-
what is type I immune reaction called?
what is the timing?
what antibodies are released?
what are the targeted cells?
what is the presentation?
T helper type 1 cells secrete cytokines favoring ___, ___ and ___. And
this is called ____ response. (part of 4th stage of hypersensitivity)
- immediate hypersensitivity (severe)
- minutes to 2 hour, up to 48 h
- IgE (histamine mediated)
- mast cells (lungs, GI, connective tissue), basophils (blood)
- anaphylaxis, urticaria, angioedema, bronchospasm, CV collapse, resp collapse
-
what is type II immune reaction called?
what is the timing?
what antibodies are released?
what are the targeted cells?
what is the presentation?
- cytotoxic reaction
- 7-21 days
- IgG and IgM
- blood cells
- cytopenia (hemolytic anemia, thrombocytopenia, neutropenia), vasculitis
-
what is type III immune reaction called?
what is the timing?
what antibodies are released?
what are the targeted cells?
what is the presentation?
- immune complex reaction
- 5-21 days
- IgG and IgM
- skin, joint, kidney, liver
- serum sickness illness, morbilliform or maculopapular rash, glomerulonephritis, interstitial nephritis, erythema multiformes, SJS
-
what is type IV immune reaction called?
what is the timing?
what antibodies are released?
what are the targeted cells?
what is the presentation?
- delayed and cellular immune response
- 24-48h
- sensitized T lymphocyte (no Ig)
- skin, liver, lung, kidney
- contact dermatitis, maculopapular rash, bullous or pustular eruptions, SJS, TEN, interstitial pneumonitis
-
which type of immune reaction during stage 5 of hypersensitivity do NOT involve immunoglobulin antibody?
- type IV (delayed and cellular immune response)
- has sensitized T lymphocyte
-
what are the 3 mechanisms of pseudoallergy?
- 1) direct stimulation of mast cells (often in skin) causes histamine release
- 2) non-immunologic activation of complement cascade
- 3) alteration of metabolism or production of inflammatory mediators
- ****does NOT involve the immune system
-
what kind of reaction does opiates cause? (hypersensitivty or pseudoallergy)
what is the mechanism?
- pseudoallergy
- direct stimulation of mast cells to release histamine
-
what kind of reaction does protamine cause (antidote for heparin)?
what is the mechanism?
- pseudoallergy
- direct stimulation of mast cells to release histamine
- also non-immunologic activation of complement cascade
-
what kind of reaction does pentamidine cause?
what is the mechanism?
- pseudoallergy
- direct stimulation of mast cells to release histamine
-
what kind of reaction does polymyxin cause?
what is the mechanism?
- pseudoallergy
- direct stimulation of mast cells to release histamine
-
which 4 medications have pseudoallergy wtih the mechanism of direct stimulation of mast cells to release histamine?
- opiates
- polymixin
- pentamidine
- protamine
- this mechanism is mostly dose related
-
what kind of reaction does contrast media have?
what is the mechanism?
- pseudoallergy
- nonimmunologic activation of complement cascade
-
what 2 medications may have pseudoallergy with mechanism of non-immunologic activation of complement cascade?
-
what kind of reaction does NSAIDs have?
what is the mechanism?
- pseudoallergy
- alteration of metabolism or production of inflammatory mediators
-
what kind of reaction does ACEi have?
what is the mechanism?
- pseudoallergy
- alteration of metabolism or production of inflammatory mediators
-
what two medications have pseudoallergy with mechanism of alteration of metabolism or production of inflammatory mediators?
-
Does psedoallergy have to do with an individual drug or the class of drug?
- the class
- (hypersensitivity has to do with individual drug)
-
what are signs and symptoms of anaphylaxis?
- early: urticaria +/- angioedema, bronchospasm, stridor, elevated tryptase
- late: erythema, laryngeal edema
- general: hypotension, arrhythmia, eosinophilia, reflex tachycardia
- this is medical emergency
-
what are the S&S of urticaria?
- asymmetric, circumscribed erythematous papular lesions of variable size with raised borders, pruritis
- red rim and central cleaning
-
what are s&s of angioedema?
- asymmetric non-pitting edema of head and neck usually
- periorbital edema, laryngeal edema
- difficulty swallowing
- hoarseness and difficulty speaking
- rarely edema of extremities and genitalia
- involves deep dermis
-
what are S&S of blood disorders?
- hemolytic anemia with positive Coombs test
- thrombocytopenia (<100,000), neutropenia
- decreased C3 and C4
- antiplatelet or antineutrophil antibodies
- occurs within 5-21 days
-
what are the S&S of serum like sickness?
- skin rash (urticarial or maculopapular) with prodromal fever and malaise, arthralgia, lymphadenopathy
- elevated ESR, decreased C3 and C4
- rarely glomerulonephritis
-
what are S&S of vasculitis?
(also known as Churg Strauss syndrome)
- purpuric or maculopapular rash with prodromal fever, arthralgia, sore throat
- nausea, abdominal pain, synovitis, proteinuria with casts and RBCs, hemoptysis, wheezing, pleuritic pain, infiltrate and CXR
-
what are the S&S of SJS and TEN?
- prodrome of nausea, vomiting, sore throat, cough, arthralgia, myalgia, fever, burning sensation of skin, facial edema, mucosal lesions, epidermal detachment (<10% with SJS, >30% with TEN), + Nikolsky's sign
- organ failure and metabolic abnormality in TEN
- iris lesion
- dermatologic EMERGENCY
-
what are the risk factors for hypersensitivity?
- prior reaction is the most reliable risk factor
- antigenicity (drug related): increased MW (>4000Da), chemical composition including proteins or polypeptides, ability of drug or metabolite for covalenty binding to carrier protein
- patient related: route, dose, frequency, age, gender, genetics, concurrent viral infection
- atopy is NOT implicated as a risk factor
-
Which has more risk for developing hypersensitivity?
continuous dosing vs single dosing
continuous dosing
-
is atopy a risk factor for increased hypersensitivty?
- no
- however, due to high IgE response in atopic patient, once allergy develops, it would be more severe
-
what are the risk factors for pseudoallergy?
- prior reaction to drug is most reliable risk factor
- more dependent on specific causative drug
-
Pseudoallergy.
Increased risk anaphylactoid reaction from contrast agents in ___, ____, ___ and ___.
- women
- atopy
- asthma
- BB therapy
-
Pseudoallergy.
Increased risk of angioedema from ACEi in ___, ___, and ___.
- black american
- hx angioedema
- longer acting ACEi
-
Pseudoallergy.
increased risk of aspirin induced asthma due to aspirin in ___.
hx asthma
-
Pseudoallergy.
increased risk of urticaria or angioedema from NSAIDs in ___.
atopic pt with previous hx
-
what is the mechanism of penicillin hypersensitivity?
- rapidly hydrolyzed to major and minor determinants and either may elicit IgE mediated response (penicillin itself does not cause)
- side chain specific reactions may occur with aminopcn and piperacillin (not related to b-lactam ring)
- skin test to rule out b-lactam allergy
-
how do you rule out b-lactam allergy for penicillin hypersensitivity?
- 1) scratch skin with lancet
- 2) administer pre-pen (major determinant) and penicillin G. also use histamine and saline controls)
- 3) wait 15 min and see if itching, erythema, or wheal are present.
- 4) if negative, perform intradermal test. wait 15 min for symptoms
- 5) if none, tolerate penicillin; if yes, do not continue high risk IgE response with pcn re-exposure
4) if positive, do not continue high risk IgE response with pcn re-exposure
-
is there a cross reactivity between pcn and aztreonam?
NOPE
-
is there a cross reactivity between pcn and carbapenem?
- unknown
- if confirmed IgE mediated allergy with pcn via skin test, avoid carbapanem as wel
- cross sensitivity within the carbapenem class is unknown.
-
is there a cross reactivity between pcn and cephalosporin?
- low risk (<10%), especially with 2nd and 3rd generation cephalo so may use these if pcn-associated maculopapular rash
- 1st generation has a higher sensitivity due to similar substitution group
- however, if IgE mediated reaction history, avoid cephalo!
-
when is penicillin medically necessary?
if type I hypersensitivity is suspected for these patients, what should you do?
- treatment of syphilis in pregnant women
- patient with cystic fibrosis and pneumonia
- can perform epicutaneous skin test to assess likelihood of anaphylaxis reaction on re-exposure (IgE mediated response)
-
what is the limitation of skin test for penicillin?
- it does not indicate IgG, IgM or cell mediated
- only IgE is indicated
-
when should you NOT skin test for penicillin? why not?
- if reaction hx is SJS (type 4), TEN (type 4), or exfoliative dermatitis (type 4), serum-like sickness (type 3), cytopenia (type 2), hepatitis, nephritis
- because these are NOT type 1
-
if you have a late forming nonpruritic maculopapular rash, should you skin test?
not necessary b/c low risk of severe reaction
-
regarding penicillin,
what should you do when type 1 hypersensitivity is suspected?
what should you do when type 2-4 are suspected?
how about you late forming nonpruritic maculopapular rash?
- type 1: skin test
- type 2-4: avoid test and avoid drug
- late rash: can try test dose
-
what is the general desensitization guide?
- only if medically necessary
- closely monitored setting with epinephrine, antihistamine, NS, O2, large bore IV
- discontinue beta blockers (b/c hypotension so interfere with epinephrine)
- use oral route for lower risk
- administer two-fold dose every 15-30 min starting with a very low dose (0.05mg) and observe. 15-20 doses given to escalate to therapeutic range
-
what should you d/c when you use epinephrine for penicillin anaphylaxis or in close monitoring due to desensitization of pcn?
beta blockers
-
what is the mechanism of cephalosporin hypersensitivity?
- caused by the beta-lactam ring or side chains
- all generations share a common b-lactam ring and as with pcn
- groups of cephalo share structurally similar side chains and this predict risk of cross reactivity
-
groups of cephalo share structurally similar side chains. what does this predict?
risk of cross reactivity
-
how do you prevent cephalo hypersensitivity?
- if the previous reaction was potentially IgE mediated, pcn skin test may be performed. if negative, may be due to the side chain. if positive, follow skin test algorithm.
- alternative cephalo use should be clinically decided. think about severity of allergic rxn, availability of equally effective non b-lactam abx, side chain structure of choice agents
-
what is the first definition of "sulfa" medication?
what does it include?
- refers to medications containing a sulfamoyl moiety (SO2NH2)
- includes sulfonamide antibiotic,
- oral sulfonylurea hypoglycemia,
- carbonic anhydrase inhibitor, metolazone, loop diuretic, thiazide
- celecoxib, sumatriptan, zonisamide
-
what is NOT a sulfa drug?
- sulfate salts
- sulfites
- sulfides
- (i.e morphine sulfate, atropine sulfate)
-
what is the second definition of sulfa drug?
what are the drug examples?
what kind of reaction may these have?
- aromatic amine at N4 position
- sulfonamide antibiotics (i.e. sulfadiazine, sulfamethoxazole, sulfapyridine)
- associated with more severe and IgE-mediated reactions (type 1 reaction)
-
Is the risk of cross reactivity between the sulfa subclasses high?
considered low
-
how do you prevent sulfa hypersensitivity?
- depends on history and medication
- history of allergy to sulfa abx seems to have slight increased risk of allergy to sulfa non-abx.
- poor ability to predict hypersensitivity risk and cross reactivity. no reliable agent for skin testing
-
do you have a risk for sulfa non-abx if you have a hx of allergy for sulfa abx?
- just slight increase
- unless you have an anaphylaxis reaction to sulfa, you can give other medications
-
which medications cause hypersensitivity? (that we learned in Hugh's class)
- penicillin
- cephalosporin
- sulfa drugs
- salicylate
-
which medications cause pseudoallergy that we learned in Hugh's class?
- ACEi
- salicylate
- contrast media
-
which one can you pretreat and which one can you not?
hypersensitivity vs. pseudoallergy
- hypersensitivity: cannot pretreat
- pseudoallergy: can pretreat (because you can expect)
-
how do you prevent angioedema by ACEi?
- this is pseudoallergy
- Avoid all ACEi in the future (re-exposure can cause more severe reaction)
-
can you get angioedema with ARB?
- yes there are reports
- however, not contraindicated so use with caution
-
what are the mechanisms of salicylate reaction?
- true hypersensitivity reaction (i.e anaphylaxis, interstitial nephritis) (reacting to a specific NSAID and not a structurally dissimilar NSAID)
- pseudoallergy reaction (i.e. asthma exacerbation, urticaria, angioedema) due to COX-1 inhibition that shift AA metabolism towards LT path
-
how do you prevent salicylate hypersensitivity reaction?
avoid structurally similar NSAIDs (due to risk of cross reactivity)
-
how do you prevent NSAID-induced asthma? (pseudoallergy mechanism of salicylate)
- avoid all COX-1 inhibitor
- COX-2 inhibitor may be used
- low dose APAP (<1g) may be an alternative
-
what is the mechanism of contrast media?
- anaphylactoid reaction
- non immunologic activation of complement cascade
-
how do you prevent anaphylactoid reaction by contrast media?
- use low osmolar agent
- pretreat: (PED)
- prednisone 50mg po 13, 7, 1 hr before admin
- ephedrine 25mg po 1 hr before procedure (avoid if unstable angina, HTN, arrhythmia)
- diphenhydramine 50mg po/iv/im 1 hr before procedure
- in emergency, hydrocortisone 200mg iv STAT and q4h and diphenhydramine
-
how do you generally manage acute hypersensitivity? (provide adult doses)
- avoid suspected medication if possible
- establish and maintain airway
-
are the hypersensitivity and pseudoallergy treated differently?
they are treated similary
-
how do you manage anaphylaxis?
place in recumbent position and elevated lower extremities
- O2 4-10L/min
- if hypotensive, IV fluid
- Epinephrine 0.2-1mg/dose SC/IM q10-15min
- diphenhydramine 25-50mg/dose IM/IV then q4-6h (max 400mg/d)
-
what do you use for anaphylaxis for preventing late phase and those also with asthma and angioedema?
- methylprednisolone 1-2 mg/kg IV q6-8h for 24h (max 125 mg q6h)
- then 1-2mg/kg/day IV or PO
-
what do you use if anaphylaxis is not responsive to diphenhydramine and epinephrine?
ranitidine 50mg in 20ml D5W IV q6-8h
-
If the patient is beta-blocked, epinephrine may not work as well for hypersensitivity. what can you use instead?
- glucagon 1-5mg IV followed by 5-15mcg/min
- this is a positive inotrope
-
what can you use for urticaria?
- combination of antihistamine
- 1st line: nonsedating H1 blockers (cetirizine 5-20mg qd, loratidine 5-10mg qd, fexofenadine 180mg qd or 60mg tid)
- 2nd line: hydroxyzine 10-00mg qd or div, diphenhydramine 12.5-100mg q46h prn
- 3rd line: doxepin 25-100mg/d (off label)
-
how do you manage angioedema?
- H1 blocker
- epinephrine
- corticosteroids
- nebulized B2 agonsit
-
how do you manage vasculitis?
- H1 blocker
- corticosteroids (prednisone 1mg/kg) in div doses x 7-14d
-
how do you manage SJS/TEN?
- nutrition support (b/c high metabolic rate due to a lot of calorie burning to recover)
- pain control, intranasal saline, oral hygiene (for mucosal lesion)
- topical antiseptic and wound care
- surgical debridement
-
what should you avoid in SJS/TEN management? why?
steroids due to infection risk
-
Epinephrine autoinjector direction for use:
1) grasp pen with black tip pointing down and form a fist
2) with other hand, pull off gray safety release
3) hold black tip near outer thigh
4) swing arm and jab firmly at ___ angel with outer thigh
5) hold in place for ___.
6) remove and massage for ___
7) seek immediate medical attention and notify that you have taken this injection.
- 4) 90 degree
- 5) 10 seconds
- 6) 10 seconds
-
abacavir
hypersensitivity or pseudoallergy?
hypersensitivity
-
anticonvulsants
hypersensitivity or pseudoallergy?
allergy
-
azathioprine
hypersensitivity or pseudoallergy?
allergy
-
allopurinol
hypersensitivity or pseudoallergy?
allergy
-
amphotericin B
hypersensitivity or pseudoallergy?
allergy
-
anesthetics
hypersensitivity or pseudoallergy?
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