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GLORIA Module 11: Drug Allergy (Part 2) Clinical Management of Drug Allergy. an educational program of. Updated: June 2011. Global Resources in Allergy (GLORIA™).

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gloria module 11 drug allergy part 2 clinical management of drug allergy

GLORIA Module 11:Drug Allergy (Part 2)Clinical Management of Drug Allergy

an educational program of

Updated: June 2011

slide3

Global Resources in Allergy (GLORIA™)

Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations and local training programs. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.

slide4

US GLORIA Program

In conjunction with the American College of Allergy, Asthma and Immunology (ACAAI), GLORIA is now presented for CME Credit in the US to Regional, State and Local Societies.

The GLORIA educational materials are available for download on WAO’s website www.worldallergy.org/gloria

slide5

World Allergy Organization (WAO)

The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.

slide6

WAO’s Mission

WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

slide7

GLORIA MODULE 11:Drug Allergy (Part 2)Clinical Management of Drug AllergyAuthorsWerner Pichler, SwitzerlandBernard Thong, Singapore

learning objectives
Learning Objectives
  • Understand the clinical features of drug allergy in relation to the underlying pathogenetic mechanisms
  • Understand the principles in the clinical diagnosis of drug allergy
  • Understand the principles of diagnostic and provocation tests
  • Manage drug allergies
clinical features of drug hypersensitivity
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 ...)

Drug allergy

IgE

IgG

&

Compl.

T-cell

slide11

immune complex

blood vessel

TH2

platelets

TH1

IFN-

Ag

IL-4IL-5

eotaxin

CXCL8GM-CSF

PMN

CTL

cytokines, inflammatory mediators

chemokines, cytokines, cytotoxins

cytokines, inflammatory mediators

Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d)

Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003

drug allergy heterogeneous clinical manifestations pathophysiology
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
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
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 allergy

 

Immediate 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)

        () ()

Appearance of symptoms in immediate or delayed type drug allergy
allergic vs non allergic drug hypersensitivity
Allergic

Immune reactions (T-cells, IgE,

IgG against a drug/metabolite

with 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 the

drug detectable, symptoms can

occur 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

Allergic vs non-allergic drug hypersensitivity

Drug provocation tests can be positive in allergic and non allergic reactions

allergic or non allergic drug hypersensitivity

MC

hapten-

carrier

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, TNFa,

Tryptase,....

* Both IgE and non-immune mediated mechanisms

possible

slide18

Clinical Symptoms and Signs

  • 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
slide20

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)
slide21
Exanthems

T-cells recognize the drug and exert, depending on their function, a specific pathology

Maculopapular exanthem

(MPE)

Acute generalized

exanthematous

pustulosis (AGEP)

Bullous

Exanthem

slide22

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
a cute g eneralized heterogeneous exanthematous p ustulosis agep patch tests
Acute Generalized Heterogeneous Exanthematous Pustulosis (AGEP) - Patch Tests
  • Patch tests are frequently positive
  • The patch test reaction at48 hrs

imitates the early phase of the

disease withT-cell infiltration

  • After 96 hrs, pustule formation

can be observed

delayed reactions danger symptoms and signs
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
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
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
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
Diagnosis of drug allergy
  • Can it be a drug hypersensitivity ? If so, allergic or non-allergic?
  • 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
  • Identifying the responsible drug
identifying the responsible drug
Identifying the responsible drug
  • History
  • Experience with the drug: books indicating specific side effects of drugs
  • Definition of presumed pathomechanism (IgE, T-cell, IgG)
  • Skin tests with non toxic preparations of the drug
    • Skin prick test (SPT); Intradermal test (IDT)
    • Late reading IDT and patch tests
  • 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
  • Lymphocyte transformation/activation test
  • 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 tests for 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 )

Laboratory testsfor serious reactions

In late reactions certain laboratory tests are recommended to assess severity

immediate reactions serum tryptase
Immediate reactionsSerum tryptase

Plasma histamine

Serum tryptase

24-hr Urinary histamine metabolite

0 30 60 90 120 150 180 210 240 270 300 330

An elevated level supports a diagnosis of anaphylaxis.

Normal levels do not exclude anaphylaxis.

immediate reactions skin prick and intradermal tests
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
Skin Prick Test (SPT)
  • Specific
  • Sensitive
  • Simple to perform
  • Rapid (result in 15-20 min)
  • Educational for patient
intradermal skin test idt
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 reactions drug specific ige tests
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)
slide36

Illustration of a Widely Used Assay (ImmunoCAP® System) for Allergen Specific IgE Quantification

Patient IgE

Allergen coupled to

ImmunoCAP

Conjugate;

Enzyme Anti-IgE

PatientIgE ab bound to

ImmunoCAP allergen

Fluorogenic substrate

Conjugate bound to

patient IgE

Conjugate enzyme reacts with

substrate forming a fluorescent product

immediate reactions flow cast
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 reactions cast
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 reactions lymphocyte transformation test ltt
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

slide41
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 reactions patch tests
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, 321–328

Barbaud A. Toxicology 2005; 209:209–216

a cute g eneralized exanthematous p ustulosis agep patch tests
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
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 dpt45
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
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
Anti-convulsants

Carbamazepine, lamotrigine, phenobarbital

  • Anticonvulsants can cause mild tovery severemainfestations 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
Anti-infectious agents

b-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 b lactam group
Cross-reactivity within b-lactam group

Same core

structure

T-cells§ + IgE

amoxicillin

cefadroxil

* Blanca M, et al: Allergy 2001

§Padovan E. et al. Eur J Immunol 1996

Mauri-Hellweg D et al J.I. 1996

Same side chains: IgE cross-reactivity possible*

T-cell cross-reactivity extremely rare

anti infectious agents50
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
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 sensitivity52
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
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 like

suxamthonium, 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%

Causes of perioperative anaphylaxis
skin tests in peri operative anaphylaxis
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
radiocontrast media
Radiocontrast media

Iodixanol,

non ionic dimer

Iohexol

a non ionic monomer

Iobitridol

a non ionic monomer

Iomeprol,

a non ionic monomer

Differentiate between the older ionic and the newer, and better tolerated

non-ionic CM, and between monomers (e.g. iohexol) and dimers (iodihexanol)

radiocontrast media58
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
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
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
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
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
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)
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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
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
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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
Prevention
  • Patient Education
    • Potentially cross-reacting drugs
    • Medic Alert cards/bracelets
  • Pharmacovigilance
    • Notify local drug regulatory agencies
  • Electronic Medical Records
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World Allergy Organization (WAO)

For more information on the World Allergy Organization (WAO), please visit www.worldallery.org or contact the:

WAO Secretariat

555 East Wells Street, Suite 1100

Milwaukee, WI 53202

United States

Tel: +1 414 276 1791

Fax: +1 414 276 3349

Email: info@worldallergy.org