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Drug allergy
T-cell 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
Antibody mediated hypersensitivity reactions (I-III) and delayed type hypersensitivity reactions (IV a-d)
Type I Immune reactant Type II Type III Type IV a IFN, TNF (TH1 cells) Antigen presented by cells or direct T cell stimulation Macrophage activation Type IV b IL-5, IL-4/IL-13 (TH2 cells) Antigen presented by cells or direct T cell stimulation Type IV c Perforin/ GranzymeB (CTL) Cell-associated antigen or direct T cell stimulation Type IV d CXCL-8. GM-CSF, IL-17 (?) (T-cells) Antigen presented by cells or direct T cell stimulation IgE IgG IgG
Antigen
Soluble antigen
Soluble antigen
Eosinophils
T cells
Neutrophils
platelets Ag
IFN-
CTL
Pichler W.J. Delayed drug hypersensitivity reactions, Ann Int Med 2003
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
12 9
13 1
13 3
13 5
Delayed type: Sensitization and symptoms often at 8th 10th day of therapy (exanthema)
45 40 35 30 25 20 15 10 5 0
() ()
1 2 3
4 5 6
7 8
9 10 11 12 13 14 15 16 17
13 7
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
Drug provocation tests can be positive in allergic and non allergic reactions
haptencarrier
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)
Exanthems
T-cells recognize the drug and exert, depending on their function, a specific pathology
Bullous Exanthem
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
10 30 % 10 %
5% ?
5.
6. 7.
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 )
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.
Specific Sensitive Simple to perform Rapid (result in 15-20 min) Educational for patient
Illustration of a Widely Used Assay (ImmunoCAP System) for Allergen Specific IgE Quantification
Patient IgE
Fluorogenic substrate
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.
Courtesy: Pichler WJ
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.
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,..)
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
cefadroxil
amoxicillin
Same side chains: IgE cross-reactivity possible* T-cell cross-reactivity extremely rare
Padovan
* Blanca M, et al: Allergy 2001 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/Samters triad) Aspirin induced urticaria/angioedema (AIU) Underlying chronic idiopathic urticaria (CIU) NSAID induced urticaria/angioedema/anaphylaxis No underlying risk factors NSAID single reactors
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
Antibiotic
10 20 %
Radiocontrast Media
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
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 methylcellulose 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
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