22750118 drug allergy part2
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Clinical features of drug hypersensitivity
May be cutaneous,organ-specific,
or systemic
Drug allergy
• Maculopapular exanthem (MPE)
• Bullous exanthem • Stevens-Johnson Syndrom
(SJS), toxic-epidermal necrolysis (TEN)
• Acute generalized exanthematous pustulosis (AGEP)
• Drug induced hypersensitivity syndrome (DiHS), or drug reaction with eosinophilia and systemic symptoms (DRESS)
• (Interstitial) nephritis, pancreatitis, colitis, pneumonitis, hepatitis
• Urticaria, angioedema, anaphylaxis, bronchospasm
• Blood cell dyscrasia, hemolytic anaemia, thrombocytopenia, agranulocytosis
• Vasculitis• Drug induced
autoimmunity (SLE, pemphigus ...)
IgE
IgG&Compl.
T-cell
Antibody mediated hypersensitivity reactions
(I-III) and delayed type hypersensitivity reactions (IV a-d)
Type I Type II Type IIIType IV a Type IV b Type IV c
Type IV d
Immune reactant
IgE IgG IgGIFN, TNFα(TH1 cells)
IL-5, IL-4/IL-13(TH2 cells)
Perforin/GranzymeB
(CTL)
CXCL-8. GM-CSF, IL-17
(?) (T-cells)
Antigen Soluble antigenCell- or matrix-
associated antigen
Soluble antigen
Antigen presented by
cells or direct T cell stimulation
Antigen presented by
cells or direct T cell stimulation
Cell-associated antigen or direct T cell stimulation
Antigen presented by cells or direct T cell stimulation
EffectorMast-cell activation
FcR+ cells (phagocytes, NK
cells)
FcR+ cellsComplement
Macrophage activation
Eosinophils T cells Neutrophils
Example of hypersen-sitivity reaction
Allergic rhinitis, asthma, systemic anaphylaxis
Some drug allergies (e.g., penicillin)
Serum sickness, Arthus reaction
Tuberculin reaction, contact dermatitis (with IVc)
Chronic asthma, chronic allergic rhinitis, maculo-papular exanthema with eosinophilia
Contact dermatitis,maculopapular and bullous exanthema,hepatitis
AGEP,Behçet disease
Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003
Ag
platelets
blood vessel
immune complex
TH1
chemokines, cytokines, cytotoxins
cytokines, inflammatory
mediators
CTL
cytokines, inflammatory
mediators
IFN-TH2
IL-4IL-5 eotaxin PMNCXCL8
GM-CSF
Drug allergy: Heterogeneous clinical manifestations &
pathophysiology• Urticaria, anaphylaxis• Blood cell dyscrasia• Vasculitis• Maculopapular exanthem• Bullous or pustular
exanthems (AGEP)• Stevens-Johnson Syndrome
(SJS), toxic-epidermal necrolysis (TEN)
• Hepatitis, interstitial nephritis, pneumopathy
• Drug induced autoimmunity (SLE, pemphigus ...)
• Drug induced hypersensitivity syndrome (DiHS/DRESS)
Sub-classification of drug allergy
• According to – Timing of onset
• Symptoms start <1hr after administration (immediate) vs
• >1hr (often 6hr) after application (delayed) - Immune mechanism
• Gell & Coombs classification, type I-IVa-d- Combined
• Immediate and IgE mediated• Delayed and T-cell mediated (rarely IgG)
• Correlating the clinical manifestations with the immununological mechanisms
Timing of onset
Within 1(-2)* hrs: immediate reactions, mainly IgE mediated; Urticaria, angioedema, bronchospasm, anaphylaxis, and anaphylaxis related symptoms
After 1(-2)** hr (often > 6hrs - weeks): delayed reactions, mainly T cell, occasionally IgG mediated: often, but not always skin symptoms *) the onset of IgE mediated reactions can occasionally occur later, particularly with oral drugs
**) the onset of T-cell mediated reactions can occasionally occur early, particularly with previous exposure to the drug
Appearance of symptoms in immediate or delayed type
drug allergyImmediate type:“silent” sensitization, well tolerated; at re-exposure quick development of symptoms(urticaria, anaphylaxis)
Delayed type: Sensitization and symptoms often at 8th – 10th day of therapy (exanthema)
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Allergic vs non-allergic drug hypersensitivity
Allergic
Immune reactions (T-cells, IgE,IgG against a drug/metabolitewith exanthema, urticaria, etc.) • Highly specific • Dependent of structure• Can be dangerous, severe
(IgE & T cell reactions!)• Cross-reactions to
structurally related compounds
• IgE to drug occasionally detectable (skin tests, IgE-serology)
Non-allergic
No immune reaction against thedrug detectable, symptoms canoccur at the first contact• Activation of immunological
effector cells (mast-cells, basophil leukocytes, etc)
• Cross-reactions due to function of drug, not structure
• Skin tests and serology negative
Drug provocation tests can be positive in allergic and non allergic reactions
Allergic or Non-allergic drug hypersensitivity
Drug-specific IgE with: • penicillin/cephalosporin, pyrazolones*
quinolones*, (recombinant) proteins
Non-immune hypersensitivty reaction with:
• NSAID (acetylsalicylic acid, diclofenac*, .…)radio contrast media*, muscle relaxants*, gelatine-infusions*
Histamine, LT, TNF,Tryptase,....
hapten-carrier
MC
* Both IgE and non-immune mediated mechanisms possible
Type I (IgE mediated) Allergy or non-immune hypersensitivity reaction
• rapidly appearing urticaria• rapidly appearing angioedema, mostly periorbital, oral, genital swellings, with moderate pruritus, in association with generalized urticaria• gastrointestinal symptoms: cramps, diarrhoea, vomiting• anaphylaxis and anaphylactic
shock
Clinical symptoms and signs
Anaphylaxis and anaphylactic shock
Delayed reactions
• Due to drug specific T cells• T-cells secrete different cytokines• The cytokines activate and recruit distinct
effector cells• Cytotoxic mechanisms are always involved,
in some severe reactions (SJS/TEN) even dominating the clinical symptoms
• Similar mechanism in skin as in internal organs (e.g. interstitial nephritis)
ExanthemsT-cells recognize the drug and exert, depending on their
function, a specific pathology
BullousExanthem
Acute generalized exanthematous pustulosis (AGEP)
Maculopapular exanthem(MPE)
Acute Generalized Exanthematous Pustulosis
(AGEP)
Clinical manifestations• Generalized, sterile
pustules• Fever (>38°C)• Leukocytosis
Aetiology• Mainly drugs (~90%)• Rapid onset (3-4d)• Mercury (~10%)• Acute enteroviral infection
Acute Generalized Heterogeneous
Exanthematous Pustulosis (AGEP) - Patch Tests
• Patch tests are frequently positive
• The patch test reaction at 48 hrs
imitates the early phase of the
disease with T-cell infiltration
• After 96 hrs, pustule formation
can be observed
Delayed reactions: danger symptoms and signs
• Extensive, confluent infiltrated exanthema • Bullae, pustules• Nikolsky sign• Erythrodermia• Painful skin• Mucosal affection• Facial oedema• Lymphadenopathy• Constitutional symptoms (higher fever, malaise,
fatigue): Look carefully if any of these signs is present. Stop all ongoing drugs. Do liver, renal and blood tests.
Serious drug allergies
Both immediate and delayed reactions may be potentially life-threatening
Anaphylaxis (immediate reaction) is not the only life-threatening reaction
Mortality in severe, delayed drug hypersensitivity
reactions• Stevens - Johnson Syndrome (SJS) & toxic
epidermal necrolysis (TEN): bullous exanthema and mucosal affection
• DRESS (DHiS): Drug reaction with eosinophilia and systemic symptoms (often hepatitis, sometimes pancreatitis, interstitial lung disease, colitis, myocarditis, pleuritis, pericarditis, nephritis …)
• AGEP (acute generalized exanthematous pustulosis)
• Isolated hepatitis, interstitial nephritis, interstitial lung disease, pancreatitis
Mortality
10 – 30 %
10 %
5 %
?
Drugs with potential for serious allergies
• Immediate reactions (anaphylaxis) -lactam-antibiotics, pyrazolone, neuromuscular
blocking agents, radiocontrast media
• Delayed reactions (drug-induced hypersensitivity syndromes)– Antiepileptics: carbamazepine, lamotrigine,
phenobarbital– Allopurinol – Sulfonamide/Sulfasalazine– Nevirapine, Abacavir– Certain quinolones– Minocyclin, diltiazem
Diagnosis of drug allergy
1. Can it be a drug hypersensitivity ? If so, allergic or non-allergic?
1. Documentation of acute stage:
• Documentation of the case (semiology, chronology, all drugs taken)
• Documentation of the severity of symptoms, including laboratory analysis (suspected serious reactions)
• Establish temporal relationship of drug intake to appearance of symptoms
• Risk factors (underlying disease)• Rule out possible differential diagnosis
2. Identifying the responsible drug
Identifying the responsible drug
1. History
2. Experience with the drug: books indicating specific side effects of drugs
3. Definition of presumed pathomechanism (IgE, T-cell, IgG)
4. Skin tests with non toxic preparations of the drug – Skin prick test (SPT); Intradermal test (IDT) – Late reading IDT and patch tests
5. Serology/specific IgE– Drug specific IgE (available for few drugs only) – Basophil activation tests (in theory available for many drugs) – Coombs-test in the presence of drug in hemolytic anaemia
6. Lymphocyte transformation/activation test
7. Drug provocation tests (where 4-6 not available/ not validated)• The responsible drug is identified by a combination of history, clinical experience of
drug imputability and targeted tests
• Skin and laboratory tests are performed 6 weeks after the acute stage
• Type of test depending on whether diagnosing immediate or delayed reactions
Laboratory testsfor serious reactions
Immediate reactions• Serum tryptase• Serum histamine
Delayed reactions• Complete blood count:
eosinophilia and lymphocytosis, leukocytosis
• Liver function tests: ALT, AST, GT, ALP
Serum creatinine• Urine microscopy and
dipstick: nephritis, proteinuria
• ( CRP )
In late reactions certain laboratory tests are recommended to assess severity
Immediate reactionsSerum tryptase
0 30 60 90 120 150 180 210 240 270 300 330
Plasma histamine
Serum tryptase
24-hr Urinary histamine metabolite
An elevated level supports a diagnosis of anaphylaxis.Normal levels do not exclude anaphylaxis.
Immediate reactionsSkin prick and intradermal
tests• For IgE-mediated reactions• Skin prick test (SPT), Intradermal test (IDT)• Sensitive & specific
– Sensitivity• 70% if penicilloyl polylysine (PPL), minor
determinant mix (MDM), amoxicillin (AX) and ampicillin (AMP) all tested
– Specificity for most -lactams 97-99%• E.g. -lactam penicillins, cephalosporins,
anaesthetic agents.
Skin Prick Test (SPT)
• Specific• Sensitive• Simple to perform• Rapid (result in 15-20
min)• Educational for patient
Intradermal Skin Test (IDT)
• More sensitive than skin prick test
• May induce false positive reactions
• May induce systemic reactions• Should be done only if skin prick
test is negative and allergen is highly suspect.
Immediate reactionsDrug specific IgE Tests• Commercially available
– Phadia CAP®/ ImmunoCAP (fluorescent enzyme immunoassay, FEIA)
– Penicilloyl G, penicilloyl V, suxamethonium
• Less sensitive and more expensive compared to skin testing– Sensitivity for penicillins/ amoxycillin from 38-54%– Specificity for penicillins/ amoxicillin from 87-100%
• Results– Reported as kU/L– Positive ≥ 0.7 kU/L (Class 2)
Patient IgE
Allergen coupled toImmunoCAP
Conjugate;Enzyme Anti-IgE
Patient IgE ab bound toImmunoCAP allergen
Fluorogenic substrate
Conjugate bound topatient IgE
Conjugate enzyme reacts withsubstrate forming a fluorescent product
Illustration of a Widely Used Assay (ImmunoCAP® System) for Allergen Specific IgE Quantification
Immediate reactions Flow – CAST
• Flow cytometric basophil activation test (FAST, FLOW-CAST or BASOTEST) – Based on the flow cytometric evaluation of CD63 on
blood basophils, an activation molecule appearing following incubation of blood basophils with drugs or other allergens in vitro
-lactams:• Sensitivity 50%, specificity 93% when compared
with FEIA• Greater sensitivity and specificity than FEIA
(37.9% and 86.7% respectively)• Combination of FAST and FEIA allows
identification of 65-80% of penicillin allergic individuals.
– NSAIDs: sensitivity 71-76%– Positive Test: > 15% CD63+ (Stimulation Index ≥ 2)
Immediate reactionsCAST
• Cellular Allergen Stimulation test (CAST)-ELISA– Sulphidoleukotrienes (LTC4 and its metabolites
LTD4 and LTE4) produced upon in vitro stimulation of blood leukocytes (predominantly basophils) by drugs are quantitatively measured
-lactams:• Sensitivity 46% (range 35–80%)• Specificity between 79 and 89%.
Delayed reactionsLymphocyte transformation
test (LTT)• Measures the proliferation of T cells to a drug in vitro• Advantage:
– Applicable to many different drugs with different immune reactions, as drug-specific T cell are almost always involved in drug hypersensitivity reactions
• Disadvantages:– Test per se is rather cumbersome and technically
demanding– Sensitivity is limited
Picher WJ, et al. Allergy 2004: 59: 809–820
LTT LTT frequently positive (>50%)• Generalized maculopapular exanthema• Bullous exanthema• Acute generalized exathematous pustulosis (AGEP)• DHS/drug hypersensitivity syndrome with eosinophilia and systemic
symptoms (DRESS)• Anaphylaxis (generalized, severe symptoms)
LTT occasionally positive• Hepatitis (dependent on type of drug)• Nephritis (dependent on type of drug)• Urticaria, angioedema• Interstitial lung disease*• Pancreatitis*
LTT rarely positive (<10%)• Toxic epidermal necrolysis (TEN)• Vasculitis• Macular exanthema (without T-cell infiltration)• Guillain-Barre syndrome• Blood dyscrasia-like idiopathic thrombocytopenic purpura (ITP)• Haemolytic anaemia• Fixed drug eruption.
Picher WJ, et al. Allergy 2004: 59: 809–820
Delayed reactionsPatch tests
• Drug patch tests are positive in 32–50% of patients who have developed a cutaneous drug eruption
• Advantages– Usually positive in AGEP, maculopapular rash,
photodermatoses, lichenoid rash, fixed drug eruption– Frequently positive for betalactam antibiotics,
especially amoxicillin, cotrimoxazole, corticosteroids, heparin derivatives, pristinamycin, carbamazepine, diltiazem, diazepam, hydroxyzine, pseudoephedrine, tetrazepam
• Disadvantages– Low sensitivity (at best 50%)– Lack of standardized test reagents.
Barbaud A, et al. Contact Dermatitis, 2001, 45, 321–328Barbaud A. Toxicology 2005; 209:209–216
Acute Generalized Exanthematous Pustulosis
(AGEP) - Patch Tests
• Patch tests are frequently positive
• The patch test reaction at 48 hrs
imitates the early phase of the
disease with T-cell infiltration
• After 96 hrs, pustule formation
can be observed.
Courtesy: Pichler WJ
Drug Provocation Tests (DPT)• Indications
– Exclude hypersensitivity in non-suggestive history or non-specific symptoms ( SBDC,DBPCDC)
– Provide safe pharmacologically and/or structurally non-related drugs in proven hypersensitivity e.g. beta-lactam antibiotics
– Exclude cross-reactivity of related drugs in proven hypersensitivity e.g. cephalosporin in a penicillin allergic
– Definitive diagnosis in suggestive history with negative, non-conclusive or non-available allergological tests
• Contraindications– Pregnant women– Co-morbidity where DPT may provoke situation beyond
medical control e.g. • Acute infection• Uncontrolled asthma• Underlying cardiac, hepatic, renal disease
– Immunobullous drug eruptions– Severe systemic initial reaction.
Drug Provocation Tests (DPT)
• Risks/benefits explained to patient• Informed consent• Cessation of antihistamine
– short-acting (chlorpheniramine, hydroxyzine) 3 days
– long-acting (cetirizine, loratidine, fexofenadine) 7 days
• Fasted overnight• Careful observation with resuscitation
equipment.
Aberer W, et al. ENDA, the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003; 58:854-63
Allergy to drugs
Certain drugs cause hypersensitivity reactions more frequently
than others:
• Anticonvulsants
• Anti-infectious agents
• Radiocontrast media
• Neuromuscular blocking agents (NMBA)
• NSAID (pyrazolones, diclofenac,..)
Special cases: corticosteroids, heparins, antineoplastic drugs
Anti-convulsants
Carbamazepine, lamotrigine, phenobarbital • Anticonvulsants can cause mild to very severe mainfestations like
DHiS/DRESS and SJS/TEN• Anti-convulsant hypersensitivity syndrome can occur in 1:3000
treated persons• Immunogenetic risk factors were defined in Han-chinese (HLA-
B*1502) • Symptoms differ from drug to drug: exanthema, hepatitis, nephritis,
fever, signs of capillary leak syndrome, similar to symptoms observed in a cytokine storm (compare TGN-1412 incident)
• Laboratory tests: lymphocytosis and high eosinophils in >70%, high cytokines (IL-5, IFN ) in serum, ALT/AST ↑ ↑, (serum creatinine ↑)
• Often in the third week re-appearance of symptoms in the absence of drug intake: due to re-activation of HHV-6 and other herpes viruses (CMV, EBV, HHV-6,7)
• Treatment: corticosteroids for hepatitis; use of high dose Ig-replacement therapy (IVIG) - controversial
Anti-infectious agents-lactams:
• 2-8% of hospitalized patients develop allergies (MPE > urticaria > anaphylaxis > SJS)
• Are haptens, able to cause all forms of drug allergies (type I – IVa-d)
• Cross-reactivity between penicillins and cephalosporins ?
– 4-11% in immediate reactions with documented type I allergy
– Predominantly in earlier studies for 1st generation cephalosporins (cephalothin, cephaloridine)
– Very rare and negligible in delayed reactions
– Recommendation for skin testing to penicillins and suspected cephalosporin
Cross-reactivity within -lactam group
amoxicillincefadroxil
Same side chains: IgE cross-reactivity possible*T-cell cross-reactivity extremely rare
Same core structureT-cells§ + IgE
* Blanca M, et al: Allergy 2001 §Padovan E. et al. Eur J Immunol 1996
Mauri-Hellweg D et al J.I. 1996
Anti-infectious agents
Sulfonamides: e.g. sulfamethoxazole (SMX)– Mainly given in combination with trimethoprim
(cotrimoxazole)– ~ 2-4% of hospitalized patients develop allergies,
but up to 50% of HIV infected patients treated for Pneumocystis jirovecii prophylaxis (MPE > urticaria > anaphylaxis > SJS)
– SMX can become a hapten (SMX-NO), able to cause all forms of drug allergies (type I - IVd)
– T-cell reactions (exanthema IVa-IVd) mainly due to p-i concept, namely a direct stimulation of TCR by SMX
NSAID sensitivity• Incidence of aspirin hypersensitivity
– General population 0.6-2.5%– Adult asthmatics 4.3-11%
• Clinical phenotypes– NSAID/Asprin exacerbated respiratory disease (AERD) or aspirin
induced asthma (AIA)• Underlying asthma, sinusitis, nasal polyposis (Widal/Samter’s
triad)– Aspirin induced urticaria/angioedema (AIU)
• Underlying chronic idiopathic urticaria (CIU)– NSAID induced urticaria/angioedema/anaphylaxis
• No underlying risk factors– NSAID single reactors
• Genetic risk factors– HLA associations and genetic polymorphisms in aspirin-sensitive
asthma and urticaria/angioedema in certain populations
NSAID sensitivity• Diagnosis
– Inhalational lysine aspirin challenge– Oral aspirin drug provocation test– Search for an alernative by DPT– Not validated/investigational
• Skin tests• Specific IgE tests• Flow-CAST (Cellular antigen stimulation
tests)• Treatment
– Aspirin “Desensitization” for AERD• Prevention
– Education on potentially cross-reacting NSAID– Use of selective COX-2 inhibitors as alternative
Peri-operative anaphylaxis
• Occur in 1 : 10,000-20,000 anesthetic procedures and in 1:6500 administrations of neuromuscular blocking agents (NMBAs)
• Symptoms reach from mild urticaria to death due to anaphylactic shock (3-10% of peri-operative death are due to such reactions)
• The severe reactions may involve only one system, most commonly the cardiovascular system
• About 60% of the immediate hypersensitivity reactions occurring during anesthesia are IgE-mediated
• But 16-50% occur in persons not previously exposed to anaesthesia
• 28% have recurrent symptoms in the following 8 hrs
Causes of perioperative anaphylaxis
• NMBAs* 50 – 70 %
• Latex 16.7 - 22.3 %
• Antibiotic 10 – 20 %
* Neuromuscular blocking agents likesuxamthonium, pancuronium, vecuronium,atracurium, cis-atracurium
• Colloids (albumin, dextran, gelatin, hetastarch 1-2%
• Aprotinin (polypeptide serine protease inhibitor) 0.5 - 5%
• Protamine < 0.5%• Antiseptics (chlorhexidine,
povidone) < 0.5%• Dyes (patent blue, Isosulfan)
and RCM: < 0.5%
Skin tests in peri-operative anaphylaxis
• Approximately 6 weeks after event
• All drugs (diluted ~1:1000), i.d. & serology, if available
– The sensitivity of skin tests for NMBAs is approximately 94%
• Latex skin prick test & serology
Iomeprol, a non ionic monomer
Iohexola non ionic monomer
Iobitridola non ionic monomer
Iodixanol, non ionic dimer
Differentiate between the older ionic and the newer, and better tolerated non-ionic CM, and between monomers (e.g. iohexol) and dimers (iodihexanol)
Radiocontrast Media
Radiocontrast media• Contrast media are widely applied (> 70 million
applications/yr)• They are triiodinated phenyl ring structures, rapidly excreted
by the urine• They cause immediate, sometimes even lethal reactions. These
were more frequent with ionic CM. The newer non-ionic dimers cause less side effects (<1%), but delayed, mostly mild reactions occur with them as well (mainly with non-ionic dimers, 2-4%)
• About 50% of CM induced immediate and delayed reactions appear upon the first exposure
• Intradermal skin tests with a battery of CM can be positive with immediate and delayed reactions. The highest sensitivity is seen 2-6 months after the reaction
• Cross-reactivity is very common in delayed, less common in immediate reactions. Skin tests may help in the identification of an alternative (tolerated) CM.
Chemotherapeutic agents• Hypersensitivity reactions are not common except with
– Platinum compounds (cisplatin, carboplatin)– Epipodophyllotoxins (teniposide, etoposide)– Asparaginase – 6-mercaptopurine– Taxanes (paclitaxel)– Procarbazine– Doxorubicin
• Mechanisms– Not known, as they have generally not been evaluated– Some cases may be due to non-immune mediated release of histamine or
cytokines, as many patients can subsequently tolerate re-exposure after pretreatment with steroids and antihistamine, and slow readministration of the drug
– Some cases are immune mediated– Reaction rates may vary with different forms of the drugs, e.g. pegylated
• Graded re-challenge– Generally successful for taxanes, less so for platinum compounds
Corticosteroids
• Topical application of corticosteroids (CS) to the skin can lead to sensitization to the CS (contact dermatitis)
• Subsequent nasal or bronchial administration of the same or structurally related CS as well as oral application can lead to appearance of symptoms like flush, urticaria, exanthema; anaphylaxis to i.m. applied CS has been reported, but may be due to methyl-cellulose
• Patch skin tests with a battery of CS can pinpoint the relevant CS; often delayed reading (7d) is necessary, due to the immuosuppressive effect of CS
• In most cases a CS of another group is tolerated and can be given without problems
Corticosteroid allergy: common cross-reactivities
• Structurally related CS can be grouped according to their structural similarity into groups and can also cause allergic reactions in already sensitized individuals:
• Budesonide may result in allergy to fluocinolone, triamcinolone, hydrocortisone-17-butyrate, methylprednisolone acetponate and prednicarbate
• Tixocortol-21-pivalate may result in allergy to hydrocortisone (acetate), prednisolone, dludrocortisone, methylprednisolone, hydrocortisone-17-butyrate, methylprednisolone aceponate and prednicarbate
• Hydrocortisone-17-butyrate allergy may result in allergy to methylprednisolone aceponate, prednicarbate, alclomethasone dipropionate, budesonide and hydrocortisone (acetate)
Multiple drug hypersensitivity
• An existing contact dermatitis or previous drug allergy may be a risk factor for an allergic reaction to CM
• About 10% of patients with severe drug hypersensitivty may develop another drug allergy to a structurally not related compound
• Patients suffering from an allergy e.g. to an antibacterial drug and switched to another drug may react to the second compound (with or without detectable sensitization/skin test)
Treatment• Stop the suspected drug/ drugs
• Resuscitation in serious reactions– ABC (airway, breathing, circulation) in anaphylaxis
• Drugs:– Antihistamine: i/v, oral.– i/m epinephrine: anaphylaxis– Systemic corticosteroids: for DiHS, SJS– High dose IVIG 1g/kg/d x 2 days : for early TEN/SJS
overlap, TEN
• Emollients & Skin care
• Hydration and prevention of skin superinfection (TEN)
Treatment• Inpatient: observation, i/v, skin care, allergist referral
– Angioedema (oropharyngeal/laryngeal), anaphylaxis– Severe skin: bullous drug eruption, EM/SJS/TEN– Systemic symptoms: fever, lymphadenopathy, organomegaly– possibly > 1 implicated drug
• Outpatient– Urticaria/ maculopapular rash– Fixed drug eruption– Drug allergy without systemic symptoms
• When to refer to allergist– Uncertain whether the reaction was drug allergy– Uncertain which drug: need for re-evaluation and specific
testing– Desensitization
Desensitization
• Making a patient tolerant to a drug he/she is allergic to• When there are no reasonable alternatives• Contraindicated: SJS/TEN• Not contraindicated: anaphylaxis• Patient still considered allergic to the drug• Rapid desensitization
– immediate hypersensitivity: penicillin G, insulin• Slow desensitization
– delayed hypersensitivity: allopurinol, sulphasalazine, TB drugs, SMX
Desensitization
• Possible mechanisms (IgE-mediated reactions)– Consumption of IgE in immune complexes– Hapten inhibition– Mediator depletion from mast cells and basophils– Antigen specific mast cell desensitization
• Recent research models– Cross-linking of inhibitory receptors on mast cells– In-vitro desensitization of human mast cells depletes
syk, an upstream signal transducing molecule necessary for IgE signalling
• Mechanism in delayed reactions unknown
Prevention
• Patient Education– Potentially cross-reacting drugs– Medic Alert cards/bracelets
• Pharmacovigilance– Notify local drug regulatory
agencies• Electronic Medical Records
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