Allergic Drug Reactions

1. Allergic Drug Reactions

2. Epidemiology* • It is believed that approximately 2-6% of all hospitalizations are due to adverse drug reactions. • 15-30% of hospitalized patients experience adverse drug reaction. • Drug-attributed deaths occur in 0.01% of surgical inpatients and in 0.14% to 0.17% of medical inpatients. • Risk of allergic reaction is about 1-3% in the general public. * Most adverse drug reactions are not reported Where to report ? http://www.fda.gov/medwatch

3. Incidence of Drug Reactions • Most adverse drug reactions are idiosyncratic and occur as a result of many factors (genetic, slow acetylators, co-morbid conditions, concomitant medication, etc.), but … • 6 - 10% of adverse drug reactions are allergic, and ... • 10% of drug-related anaphylaxis results in death

4. Classification of Drug Reactions • Type A - common & predictable • 80-90% of adverse drug reactions • Often dose dependent • Produced by known pharmacologic drug actions • Drug overdose or toxicity - an exaggerated, but characteristic pharmacologic effect produced at supratherapeutic doses • Side effects - excessive expressions of known pharmacologic effects that occur at recommended doses • Drug interactions - unusual effects due to the combined pharmacologic activity of two or more drugs.

5. Classification of Drug Reactions • Type B - uncommon & unpredictable • Drug intolerance - undesirable pharmacologic effect at a subtherapeutic dosage. • Idiosyncratic reactions - uncharacteristic reaction unrelated to the pharmacologic action of the drug. • Difficult to distinguish from allergic reactions. • Allergic reactions are immunologically (IgE) mediated reactions that share the following characteristics: • occurs in small numbers of patients • requires prior exposure to the same or chemically related drug • develops rapidly after re-exposure • Pseudoallergic reactions - indistinguishable from the above allergic reactions, but are not IgE-mediated. *

6. Classification of Drug Reactions • Other Reactions - • Superinfection: Antibiotics against one organism alters endogenous flora. Example: pseudomembranous colitis • Disease-associated: Reactions to drugs which occur only when the drug is administered in the setting of a specific disease. Examples: Jarisch-Herxheimer reaction (PCN/syphilis), ampicillin rash w/ EBV/CMV • Coincidental: Drug blamed when in fact the primary disease process is responsible. Example: Viral exanthem • Psychogenic: Anxiety, hyperventilation, vasovagal rxns associated w/ drug administration. Example: injections *

7. Approach to The Patient With a Previous Adverse Drug Reaction Type of Adverse Reaction Type B Type A Intolerance or Idiosyncratic Modify Dose or Choose Other Drugs Not Associated With Same Untoward Events Avoid Drug Immunologic or Pseudoallergic Structurally Unrelated Drug Available – Use It. Structurally Unrelated Drug Not Available Previously Blistering, Serum Sickness, or Drug Fever Test For Drug Allergy Available Test For Drug Allergy Not Available Test results Negative Test results Positive Desensitize if Use is Essential Cautiously Administer Drug if Use is Essential

8. Typical Features of Allergic Drug Reactions • No problems with previous treatment • If no previous exposure, reactions generally occur several days into therapy • The reaction occurs only in a small number of patients with doses far below the therapeutic range • Some if not most reactions are due to the metabolites of the parent drug (e.g. PCN and major and minor determinants, sulfa and hydroxylamines) • Specific antibodies or T-cells can be identified with some drugs

9. Types of Allergic Drug Reactions • Multisystem • Anaphylaxis • Antimicrobials, proteins • Anaphylactoid • RCM, NSAIDs, opiates, tubocurarine, dextrans • Serum sickness • Proteins, abx (cefaclor), allopurinol, thiazides, PTU • Drug fever • Sulfonamides, β-lactams, methyldopa, quinidine • Drug-induced SLE • Procainamide, hydralazine

10. Types of Allergic Drug Reactions • Cutaneous • Urticaria/angioedema • Antimicrobials, proteins, opiates, ACE-I • Maculopapular exanthemous eruption • Sulfonamides, β-lactams, barbiturates, anticonvulsants • Stevens-Johnson/TENS • Sulfonamides, β-lactams, phenytoin, carbamazepine • Fixed drug eruptions • Sulfonamides, β-lactams, barbiturates, tetracycline • Photoallergic reactions • Phenothiazines, sulfonamides, griseofulvin • Phototoxic reactions (not IgE-mediated) • Tetracycline, sulfanilamide, chlorpromazine, psoralens • Allergic contact dermatitis • Local anesthetics, neomycin, parabens, antihistamines *

11. Types of Allergic Drug Reactions • Hematologic • Eosinophilia • Allopurinol, digitalis, ASA, Amp., TC antidepressants • Hemolytic anemias • Hapten-type (PCN, cisplatin) • Innocent bystander (sulfonamide, chlorpromazine, quinine, para-aminosalicylic acid) • Autoimmune (methyldopa, penicillin, aldomet) • Thrombocytopenia • Quinidine, sulfonamides, heparin • Granulocytopenia • Sulfasalazine, procainamide, penicillin, phenothiazines *

12. Types of Allergic Drug Reactions • Hepatic • Cholestasis • Macrolides, nitrofurantoin, imipramine, phenothiazines • Hepatocellular dysfunction (inc. transaminases) • Valproic acid, halothane, isoniazid, sulfonylurea, methyldopa • Granulomatous hepatitis • Quinidine, allopurinol, methyldopa, sulfonamides

13. Types of Allergic Drug Reactions • Renal • Interstitial nephritis • β-lactams (methicillin), rifampin, NSAIDs, sulfonamide • Nephrosis (membranous glomerulonephritis) • Captopril, NSAIDs, anticonvulsants, probenecid

14. Types of Allergic Drug Reactions • Respiratory • Asthma • β-lactams, sulfites, NSAIDs, β- blockers • Pulmonary infiltrates with Eosinophilia (PIE) • Nitrofurantoin, MTX, NSAID, sulfonamides, tetracycline, isoniazid • Rhinitis • Reserpine, hydralazine, α-blockers, iodides, levodopa

15. Classification of Drug Reactions Gell and Coombs: • Type I: Immediate Hypersensitivity (IgE) • Type II: Cytotoxic Antibody (IgM or IgG) • Type III: Immune Complex (IgM or IgG) • Type IV: Delayed-type Hypersensitivity (T-cell) Unfortunately, the mechanism for drug reactions are often unknown, so clinical classification is more useful.

16. T Y P E I

17. Type I Drug Reactions • Anaphylaxis • Implies IgE-mediated • “Anaphylactoid” = another mechanism • Angioedema • Urticaria • Morbilliform = most common

18. TYPE II

19. Type II Reactions • IgG or IgM recognizes drug adherent to cells • Activate complement • Cells cleared by splenic macrophages • Hemolytic anemia • Autoimmune thrombocytopenia

20. Hemolytic Anemia • Evidence of anemia and hemolysis: • NCNC or high MCV • Direct Combs +, high LDH & retic, low haptoglobin • Drug is hapten, RBC antigen is carrier • Penicillin • Antibodies to drug cross-react w/ RBC • Aldomet, L-dopa, mefenamic acid • Plasma protein & drug cause immune response • RBC innocent bystander • Sulfonamides, phenothiazines, quinine

21. Immune Thrombocytopenia • Diagnosis: low platelets o/w normal CBC smear • Drug adsorbs to platelet surface, forms neo-Ag • Quinidine complexes w/ gp IIb/IIIa and gp Ib/IX • Heparin complexes with circ PF4 • IgG Fab binds neoantigen • In HIT attached IgG Fc binds platelet FcγRII • Triggers activation and consumption • Low platelets and thrombosis • Other drugs: sulfa, β-lactam, indinavir, Lipitor, Ticlid, gold, acetazolamide and Trental

22. Type III

23. Type III Reactions • Soluble immune complexes of drug & IgG/M • Complexes deposit in vessel walls • Activate complement • Serum sickness • 1-3 weeks • Fever, urticaria, serpiginous rash, LAD, arthralgias • Other rashes are morbilliform or target lesions • Drug fever • Vasculitis

28. TYPE IV

29. Type IV Reactions • Protype is allergic contact dermatitis • Patch testing with the medication is sometimes performed.

30. Drug Hypersensitivity Reactions • Reactions that can not be easily classified into the Gel and Coombs Classification.

31. Erythema Multiforme

32. Target Lesions • Three zones: • An erythematous central papule that may blister • an edematous middle ring • an erythematous outer ring • Predilection for extremities, Symmetrical

34. Erythema Multiforme Minor • Cell-mediated hypersensitivity reaction • Associated with infections and drugs (10-20%) • Target lesions are characteristic

35. Erythema Multiforme Minor • Drug should be stopped immediately • Anti-histamines may decrease itching • Steroids (1 mg/kg/day) may be necessary • “Early treatment of erythema multiforme minor may prevent progression to Erythema multiforme major.

36. Stevens Johnson Syndrome

37. Stevens Johnson Syndrome • SJS • mortality <10% • Mucus membrane & conjunctival involvement in 85% • widespread bullae & purpuric macules of the face, trunk, and genital areas. • Constitutional symptoms, <10% epidermal detachment • SJS/TEN overlap 10-30% epidermal-lysis

38. Stevens-Johnson Syndrome • Drugs caused 50% of cases • More than 100 drugs have been implicated as causing EM, SJS and TEN • High relative risk drugs: sulfonamides, Ampicillin, anticonvulsants, NSAIDS & allopurinol cause 2/3 of SJS. (TB drugs in developing countries) • Readministration causes recurrence.

39. EMM and SJS • Stop the drugs • Steroids are “controversial…if it is started, it should be started early in the course of the disease and in very large doses…” • Late in the course, TEN could supervene, in which case steroids are contraindicated

40. Toxic Epidermal Necrolysis

41. Toxic Epidermal Necrolysis • Epidermal detachment of 30% or more • Almost always drug induced (>80%) • Steroids are contraindicated • Patients are managed in burn units • IVIG has been used in some patients • Mortality 30-40%

42. Fixed Drug Eruptions • Fixed drug eruptions (FDEs) characteristically recur in the same site or sites each time a particular drug is taken; with each exposure however, the number of involved sites may increase. • Mechansim: Unknown

44. ANGIOEDEMA

45. Angioedema • Abnormal Bradykinin metabolism • ACE inhibitors • Reports also with ARBs • ASA/NSAID reactions: dual mechanism • COX-1/2 inhibition • IgE-mediated • Unusual in IgE-mediated w/o urticaria

46. Diagnosis • History • The cardinal diagnostic tool. Key points include: • suspicion that an unexplained clinical event may be caused by a drug • complete and accurate documentation of all drugs, including nonprescription ones, taken over the previous month • temporal relationships between drug administration and the onset of symptoms or signs • correlation of the clinical manifestations with known reactions induced by a particular drug • previous tolerance of the drug (sensitization) • prior history of a similar reaction to the same or cross reacting drug.

47. Diagnosis • History • A few points regarding the temporal relationship: • virtually impossible to react allergically on the 1st exposure to a drug • Reactions rarely occur within the first 7 days of treatment; rather, within 2-4 weeks • the classic IgE-mediated drug allergy typically appears after the first dose of a new course. • if a drug has been taken continuously for a year or more, it is unlikely to cause a reaction (tolerance induction?)

48. Testing Finding a reagent is a problem. Most drugs have a low molecular weight & are not immunogenic. The antigenic determinants are unknown. • Skin testing • Immediate hypersensitivity (IgE, Type I) • Prick skin testing, intradermal skin testing • Most accurate in evaluating protein drugs (insulin, vacc) • Somewhat useful for PCN, drugs of general anesthesia • Delayed hypersensitivity (T-cell, Type IV) • Patch testing • Most useful for allergic contact dermatitis

49. Testing • In-vitro testing (RAST, ELISA, etc.) • Measures circulating drug specific IgE antibodies • Less specific and less sensitive than skin testing • Of limited availability & usefulness • Provocative challenge • Oral, SQ, or IV • Has inherent risk!

50. Decision Path:Patient with Drug Allergy History • The ability to detect drug-specific IgE antibodies helps to assess the risk for allergic reactions. • However, the IgE must be clinically relevant (e.g., IgE anti-insulin antibodies are common in diabetics, but allergic reactions are rare). • Conversely, the inability to detect drug-specific IgE antibodies does not R/O the possibility of sensitivity. • Desensitization protocols are indicated in established cases of drug hypersensitivity where there is NO substitute and treatment is essential (e.g. penicillin for neurosyphilis)