Objectives 8/30/2012. How Do I Deal with a Person s Multiple (and Single) Drug Allergies? Adverse Drug Reactions

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1 How Do I Deal with a Person s Multiple (and Single) Drug Allergies? Faoud Ishmael, MD, PhD Assistant Professor of Medicine Section of Allergy and Immunology Penn State College of Medicine I have no conflicts of interest. Objectives Recognize the difference between immune mediated drug reactions and other adverse drug reactions. Understand the pathogenesis of drug hypersensitivity reactions. Become familiar with diagnostic options for drug allergy. Recognize when re administration or avoidance of an allergenic drug is warranted. Decide when referral to an allergist is warranted. Adverse Drug Reactions Any noxious, unintended, and undesirable effect of a drug. Type A reactions - Predictable - Dose dependent - Related to the pharmacology of drug % of adverse drug reactions - example: drug with anti cholinergic effects causing urinary retention Type B reactions Unpredictable, unrelated to known pharmacologic action 1. Intolerance: pt develops a known side effect at a lower dose of med than expected. 2. Idiosyncratic: pharmacogenomic effect: pt has a reaction based on the way their body processes a drug secondary to they genetics (i.e. aspirin). 3. Immunologic/Hypersensitivity. 1

2 Why is it Important to Characterize Adverse Drug Reactions and Drug Allergy? Use of alternative agents may be more expensive, less efficacious, and/or have more side effects. Having a history of antibiotic allergy is associated with unexpected adverse outcomes. 1 Longer hospital stays Increased mortality Increased drug resistant infections Most patients carrying a label of drug allergy do not have true hypersensitivity; may be needlessly avoiding drug. Management of patients with multiple drug allergies can be difficult. Reddy, V, Baman, N, Ishmael, F. Manuscript in preparation. Gell Coombs classification of Immune Hypersensitivity Reactions Gell-Coombs classification I II Mechanism Examples of adverse penicillin reactions Anaphylactic (IgE-mediated Acute anaphylaxis injury) Urticaria Complement-dependent Hemolytic anemias cytolysis (IgG/IgM) Thrombocytopenia III Immune complex damage Serum sickness Drug fever Some cutaneous eruptions and vasculitis IV (also types IV a-d) Delayed or cellular hypersensitivity Contact dermatitis Morbilliform eruptions Interstitial nephritis SJS/TEN Hepatitis Distinguishing between Hypersensitivity and Non immune Reactions Immune Rash (macular, hives, angioedema) Fever Bronchospasm Hypotension and tachycardia Mucosal lesions CBC abn: eosinophilia LFTs abn. Non immune Isolated GI symptoms nausea/vomiting/diarrhea (without any other sx) Headache Non specific symptoms Reactions consistent with Type A reactions depending on drug 2

3 Drugs as Allergens Direct hapten allergens: drug (hapten) by itself too small to be immunogenic. Binds covalently to circulating proteins (carrier) and forms a neoantigen. examples: beta lactam antibiotics, quinidine, cis platin Metabolite hapten allergens: drug is metabolized to a reactive form that can act as a hapten: sulfonamide antibiotics, phenytoin, procainamide Complete allergens: Are immunogenic in their native form: proteins/polypeptides (antibodies, insulin), multivalent chemicals (succinylcholine), vaccines IgE Mediated Drug Allergy (Type I Hypersensitivity) Neo antigen drug serum protein recognized as foreign, IgE antibody generated repeat drug exposure Mediator release, Allergic symptoms IgE binds to receptors on surface of mast cells and basophils What Makes a Drug an Allergen? Risk Factors Drug Factors Chemical Properties of Drug Frequency, Dose of Drug Route of Adm. (IV > PO) Patient Factors Age, sex Allergic history Genetic Predisposition Disease Factors Alt. of Metabolic Pathway Immune system turned on or Immunodysfunction Size, immunogenicity Adapted from VanArsdel PP, Jr. Immunol Allergy Clin North Am.1991:

4 Allergic Profile of Antibiotics HIGH Beta lactams Amino-penicillins Other penicillins 1 st gen cephalosporins Carbapenems 2 nd & 3 rd gen cepahlo. Monobactams, etc. Cefaclor Sulfonamides Antimicrobials MODERATE Anti-tuberculous drugs Vancomycin Aminoglycosides LOW Macrolides Erythromycin Clarithromycin Azythromycin Quinolones Moxifloxacin Levofloxacin Ciprofloxacin Tetracyclines Metronidazole Clindamycin Slide courtesy of N. Franklin Adkinson Prevalence of Specific Antibiotic Allergy at HMC Drug Class Total # % Beta Lactams Sulfa Macrolide Quinolone Tetracyclines Vancomycin Clindamycin Metronidazole Aminoglycoside Anti mycobacterial Linezolid Other Daptomycin Total # Antibiotic Allergies Jhaveri, P and Ishmael, F Manuscript in preparation Hypersenstivity to other Classes of Drugs Likely to cause hypersensitivity Latex NSAIDs Aromatic anticonvulsants Anesthetics/muscle relaxants Opioids Radiocontrast agents Unlikely to cause hypersensitivity (but often implicated) Local anesthetics (lidocaine) Antihypertensives B blockers diuretics ACE Inhibitors (angioedema is a rare, but real side effect) Glucocorticoids 4

5 Penicillin Allergy Most frequently reported drug allergy (rate 3 10%). About 90% of patients labeled as penicillin allergic are not truly allergic. Prevalence of true allergy is about 1 3%. Personal history of atopy (allergic rhinitis, eczema, food allergy) increases risk. Even in patients with true allergy, about 80% will lose their allergy within 10 years. Clinical Features Classic history prior use of penicillins without difficulty. Subsequent course results in symptoms after first dose. Dose and route of administration may increase risk and severity (high dose, IV, repeated administration more likely to induce). Skin findings: hives, angioedema (in contrast to non IgE mediated reactions tend to be macular). Systemic symptoms: bronchospasm, GI sx, cardiovascular collapse. Penicillin Allergenic Determinant Associated with urticarial reactions (85 95%) (5 15%) Associated with anaphylaxis Adapted from Middleton s Allergy Text 7 th ed. 5

6 Skin Testing for Penicillin Allergy Consists of two components: major determinant: a conjugated penicillin to a polylysine group (mimics hapten carrier) and native penicillin G (minor determinant). The major determinant is the only conjugated reagent for antibiotic testing. Now available again for testing. Administered as a skin prick and intradermal test. If IgE is present on skin mast cells, mediator release causes formation of a wheal and flare response. Penicillin skin testing Sensitivity using the combination of conjugated penicillin and penicillin G is around 95 97%. If skin prick testing and intradermal testing are both negative, an oral challenge is performed using penicillin or amoxicillin ( mg). A combination of negative skin test and challenge effectively rules out IgE mediated allergy. A positive skin test or challenge confirms IgE mediated allergy and penicillins should be avoided. High level of cross reactivity within penicillin family. Drug Allergy Practice Parameters, Ann Allergy Asthma Immunol; 2010;105: Is Skin Testing Useful for Other Drugs? Sensitivity to other small molecules drugs is low: no agents other than PCN that mimic haptencarrier. may be useful if test is positive. High sensitivity skin testing can be performed for: complete antigens (do not need to form haptens): recombinant proteins, vaccines, insulin. functionally multivalent compounds: succinylcholine and quaternary amines. 6

7 Other Diagnostic Tests In vitro testing none that are standardized or useful clinically. Gold standard is provocation testing (drug challenge). Administer implicated drug at increasing doses (1:100, 1:10, 1:1). Objective reaction confirms hypersensitivity. Only done if pre test probability of true allergy is LOW. Drugs can activate T cells via a variety of mechanisms haptens covalent linkage to proteins (penicillins/cephalosporins) prohaptens drug metabolized, electrophilic metabolite binds to proteins T cell activation organ dysfunction (liver, kidney) direct interaction with TCR, MHC (p i model) Pichler et al. Allergol. Int. 2006, 55:17 T cell Mediated Drug Reactions Severity Mild Moderate Severe Macular rash Stevens Johnson can safely use again Macular rash+ fever/other combination of symptoms/rash More extensive Avoid drug,?? use again if clinical need exists DRESS (Drug Rash With Eos & Systemic Sx) Toxic epidermal necrolysis Never use drug again, or same class 7

8 T Cell Induced Reactions Type IV immune reactions: Most common reaction is a macular drug eruption: characterized by delayed reactions, patient on med for ~1 week when rash begins. usually self limited. may be able to treat through rash if clinically indicated. can use the same agent again (or same class). Taken from immunobiology textbook, Janeway et al. 6 th ed. Severe T cell Reactions More severe reactions characterized by: Fever Mucous membrane involvement Involvement of other organ systems: CBC abnormalities Elevation in LFTs, decreased renal function Target lesions, bullous rash These are signs of a more severe drug reaction: definitely avoid implicated medication, refer to ER A.D.A.M. Atlas ten.html Diagnostic Tests for T cell Reactions Patch testing (similar to contact dermatology testing): low sensitivity and specificity. In vitro testing: no good commercially available tests. We have an experimental test based on measuring gene expression changes in T cells on exposure to allergenic drugs. May be useful to identify allergenic drug and find a safe alternative. 8

9 Multiple Drug Allergies Common to have more than one class of drug listed as an allergy Gender and race biases Usually many of the drugs listed are not true allergies Has significant effects on drug and healthcare utilization Difficult to manage patients Number of patients % of all pts with abx allergy have 2 or more classes of drugs listed as an allergy Number of Antibiotic Class Allergies % Female Number of Abx Allergies Jhaveri, P and Ishmael, F Manuscript in preparation Multiple Drug Allergies (MDA) Case Presentation: 60 y/o female with common variable immunodeficiency and need for recurrent antibiotic therapy presents with hives after receiving the first dose of each of the following antibiotics: amoxicillin clavulante penicillin cefdinir 3 rd generation cephalosporin azithromycin macrolide levofloxicin quinolone doxcycline tetracycline trimethoprim sulfametoxazole sulfonamide Differential Diagnosis for MDA Chronic idiopathic urticaria Non immunologic reactions: type A or intolerances Conditioned responses Co existing infection Hypersensitivity to excipient Multiple drug allergy syndrome 9

10 Workup of patient Are reactions suggestive of immune mediated mechanism? Are drugs known to be allergenic? Other factors that might play a role (i.e. CIU)? What is the likelyhood that this is a true allergic reaction to all the meds? Multiple Drug Allergy Syndrome The likelihood of having an IgE mediated allergy to all of these: 3/100 x 10/100 x 1/100 x 1/100 x 1/100 x 3/100 = 1 in 10 billion. Rather, this is a non specific immune response, possibly triggered by infection (rash induced by ampicillin in pts with mononucleosis may be a similar mechanism). Appears to be a T cell process. Infection activates T cells, there appears to be a nonspecific pre activation of T cells that are weakly reactive to drugs and have a lower threshold for activation. Daubner et al. Allergy 2011 Multiple Drug Allergy Syndrome Reactions are limited to rash/hives only. Tends to occur with the first dose or first few doses. Skin test to penicillin r/o IgE mediated allergy. Challenges may be useful, but patients may have hives. Patients can safely tolerate antibiotics with premedication with antihistamines. An antibiotic class with a low allergy profile (such as quinolones or macrolides) is usually a good choice. Patients are likely to develop hives again with any antibiotic. Offer reassurance. 10

11 Case Presentation 55 y/o male that presented for a drug allergy workup to a number of different medications: Omeprazole: bloating and diarrhea Ranitidine: headache Atorvastatin: numbness in fingers Metoprolol: fatigue Case Presentation 35 y/o female with a history of sensation of throat closure with multiple medications: Multiple NSAIDs Penicillin Azithromycin Thiazide diuretics No rashes, no angioedema or other symptoms. Conditioned Responses Laryngeal edema can be seen with true drug hypersensitivity. However, it can also be a subjective finding. In the absence of objective findings, and with multiple unrelated medications, it suggests absence of true hypersensitivity. Difficult to manage these patients. Placebo controlled graded challenges to drugs and use of laryngoscopy can be helpful to prove that these are not real reactions. 11

12 Summary Detailed history and physical exam Consistent with type A reaction(s) Consistent with hypersensitivity Consider a dose reduction Alternative family member Combined Features or History unclear Mild sx (i.e. mild macular rash) Consider using same medication or class member again More severe rash Avoid medication And class. Consider allergy Referral or ER referral Consistent With IgE reaction Avoid Medication And class. Refer to Allergy Refer to Allergy Skin testing if appropriate Graded challenges Can refer to allergy for PCN skin testing if ambiguous. Take Home Points History is crucial to the characterization of ADRs Important to classify type A reactions and hypersensitivity reactions Use of medication again, family member, or a different agent depends on the history Skin testing to some medications is useful (penicillin, complete antigens). Graded challenges (+/ placebo) can be very helpfup. Please utilize Allergy for referrals/questions about diagnosis and management. 12