Drug Hypersensitivity Reactions. Morning Report April 18, 2005

Transcription

1 Drug Hypersensitivity Reactions Morning Report April 18, 2005

2 Drug Reactions: two categories Predictable ~80% of all drug reactions Secondary to the pharmacologic actions of the drug and are generally dose-dependent Overdosage, side effects, secondary effects, drug-drug interactions Unpredictable Not related to pharmacologic actions of the drug Drug intolerance, idiosyncratic reactions, immunemediated reactions Account for the majority of life-threatening reactions

3 Immune-Mediated Reactions Gell and Coombs Classification Type I: immediate hypersensitivity Type II: cytotoxic Type III: immune complex Type IV: cell-mediated *Mixed Immunologic reactions are common Drugs most commonly associated w/ immune reactions: Antimicrobials (pcn, sulfa), anticonvulsants, chemotherapeutic agents, heparin, insulin

4 Clinical Evaluation: history Complete drug history including OTC/health supplements Starting/stopping dates, dose changes Prior drug reaction history Temporal relationship b/w administration of drug and reaction Identify any other causes for signs/sx Host risk factors (atopy, autoimmune dz)

5 Clinical Evaluation: physical exam SKIN!: most common organ involved maculopapular or morbilliform most common Symmetric pattern (often spares face) Pruritis may be present Urticarial rash is not uncommon (esp. w/ type I or serum sickness-like illness) Other: mucous membranes (SJS), fever, vital signs (anaphylaxis), lymph nodes, lungs, liver, spleen and joints

6 Diagnostic Procedures History & physical are most important! Other laboratory tests used: Skin tests (type I IgE-specific reactions)- limited to penicillin RAST (type I) Coombs test (type II) Tryptase- mast cell mediator released 1-2 hrs after anaphylactoid rxn (type I) C3/C4, immune complex assays (Type III) Patch testing, delayed intradermal testing (Type IV)

7 Drug Hypersensitivity Reactions Type I-IV Hypersensitivity Rxns Morbilliform reactions Erythema multiforme EM major/ Steven- Johnson/TENs Anaphylactoid Hypersensitivity syndrome or DRESS Fixed drug eruptions Erythroderma/ exfoliative dermatitis Phototoxic eruptions Pemphigus Acute generalized exanthematous pustulosis Drug-induced lichen planus

8 Immediate-type Hypersensitivity Reactions (type I) IgE mediated rxn occurring usually minutes after exposure Nearly every drug has been implicated Penicillin accounts for 75% of fatal anaphylactic rxns in the U.S. each year Primary effector cell mast cell Mediators released (histamine, leukotrienes, tryptase, etc ) have systemic effects: Smooth muscle spasm, bronchospasm, capillary leak, edema, inflammation Clinical manifestations include: urticaria, angioedema, dyspnea, wheezing, hypotension, shock, N/V, abdominal pain, flushing Incidence and severity are increased w/ IV route

9 Urticaria (type I/IgE mediated) UpToDate; drug eruptions

10 Immediate-type Hypersensitivity Reactions (type I) Diagnosis is usually straightforward during acute episode Lab: tryptase peaks 90 minutes after reaction; remain elevated for 4hrs Post-exposure testing: Prick-testing or intradermal injection B-lactams, latex, local anesthetics, cipro, bactrim, cisplatin, NM blocking agents, some anticonvulsants Has been associated with death Standardized skin testing only established for penicillin RAST in vitro testing of allergen specific IgE Ab Only developed for major determinants of penicillin

11 Immediate-type Hypersensitivity Reactions (type I) Management: ABCs/ IVFs Epinephrine (1:1000) SC or IM 0.01mg/kg (max 0.5ml) in children Diphenhydramine- H1 blocker (1-2mg/kg) Ranitidine- H2 blocker (1mg/kg) +/- corticosteroids Observation 2hrs w/ mild episodes; 24hrs after severe anaphylaxis Repeat drug exposure is contraindicated Drug desensitization is available if drug is needed

12 Cytotoxic Reactions (Type II) Cytotoxic reactions involve IgG, IgM and IgA antibodies to RBCs, WBCs, platelets Hemolytic anemia, leukopenia and thrombocytopenia may result Many drugs have been implicated: PCN, cephalosporins, quinidine, sulfonamides, PTU, anticonvulsants Lab studies: CBC, Coombs test Treatment is drug withdrawal

13 Immune Complex Reactions: (Type III) serum sickness First description made in the early 1900s in patients treated w/ horse serum containing diptheria antitoxin classic serum sickness is caused by exposure to a non-human species Seen today w/ anti-toxin used for snake bites, murine or equine chimeric monoclonal antibodies (infliximab, rituximab, ATG) Serum sickness-like disease is more common Cefaclor, penicillin, bactrim, amoxicillin Also known as hypersensitivity vasculitis

14 Serum Sickness: Pathogenesis Ag + Ab (IgM 7-14 days; IgG 3-7 days if previously exposed) Ag-Ab immune complex Spleen/liver Clearance of Immune complexes (Once phagocytic system is saturated) Complement Activation (release of mediators; C3- mast cell degradation, Inflammatory cell migration) Tissue Deposition (parenchymal tissue, small vessels) Symptoms resolve when antigen is cleared from serum

15 Serum Sickness: Clinical Manifestations (begins 7-10 days after exposure) Rash: earliest and most common feature Urticarial and/or morbilliform; palpable purpura (if vasculitis is present) Pruritis common Anterior lower trunk back, upper trunk extremities Starts in area of injection or IV (if applicable) Characteristic finding is a linear, serpiginous macular rash at the lateral aspect of the hands and feet Urticaria is more long-lasting than typical hives Histologically- may demonstrate a vasculitis (neutrophilic leukocytoclastic vasculitis; IgG/C3 immune complexes via immunoflorescence) Resolves after few days to two weeks

16 Serum Sickness: Clinical Manifestations (begins 7-10 days after exposure) Arthralgias MCP, knees, wrists, ankles, shoulders Swelling and erythema uncommon Begins after rash has started and resovles before rash is gone Fever High fevers w/ true serum sickness Low grade w/ serum sickness-like dz Other features: H/A, blurred vision, LAD, splenomegaly, edema, abdominal pain, diarrhea, mild proteinuria, peripheral neuropathy

17 Serum Sickness: laboratory studies Labs generally not indicated clinical diagnosis CBC: neutropenia, reactive lymphocytes, mild thrombocytopenia UA: mild proteinuria; mild hematuria (w/out casts) BMP: +/- elevated Cr (renal function normal w/in a few days) Complement: C3/C4 low (only during severe episodes) ESR/CRP: may be elevated during active dz

18 Serum Sickness: Treatment Withdraw offending agent/ disease is self-limited Antihistamines for pruritis, rash NSAIDs for arthralgias Corticosteroids may be used for extensive disease Symptoms resolve within 48hrs of treatment Avoidance of drug in the future is recommended Some recommend avoidance of all B-lactams (if a B-lactam was the causative agent)

19 Cell-Mediated Reactions (type IV) Allergic contact dermatitis is the most common medication-induced DTH Topical penicillins, local anesthetics, antihistamines, preservatives Skin lesions range from mild erythema to edematous papules, weeping vesicles Pruritis is a hallmark of the dz Onset occurs 7-20 days after initial sensitization; hours w/ subsequent exposures Diagnosis confirmed w/ patch testing Treatment is with topical steroids

20 Morbilliform Reactions Morbilliform (or maculopapular) eruptions are the most common immune-mediated reactions to medications Pathogenesis unclear; likely T-cell mediated given the delay in presentation Skin lesions are typically symmetric beginning in dependent areas and then generalize Face, palms and soles are typically spared Occur 4-10 days after beginning therapy Can occur up to 2 weeks after drug is stopped Rash lasts 1-2 weeks May be associated with pruritis; +/- low grade fever Not a strong contraindication to future use of the drug

21 Morbilliform reaction

22 Erythema Multiforme Associated w/ medications and infectious agents Sulfonamides, PCNs, NSAIDs/ HSV, mycoplasma Likely cell-mediated mechanism Target lesions develop symmetrically from distal extremities (+palms/soles) and spread proximally Skin findings occur 1-2 weeks after exposure and last ~4 weeks Difficult to predict who will progress to SJS/TEN Future use is contraindicated

23 Erythema multiforme emedicine.com; erythema multiforme

24 EM Major/Stevens-Johnson/TEN EM major involves skin and mucous membranes SJS features confluent pupuric lesions w/ severe mucosal erosions (> 1 site) + constitutional symptoms <10% skin detachment TEN is associated w/ bullous lesions, mucosal involvement and skin detachment >30% skin detachment Treatment is supportive Corticosteroids controversial in SJS; contraindicated in TENs

25 Steven-Johnson/TENs

26 Anaphylactoid Drug Reactions Caused by direct release of mast cell mediators (not IgE-mediated) Signs/symptoms resemble anaphylaxis (but negative skin test) Opiates, ASA and radiocontrast material are the most common causative agents red man syndrome after rapid vancomycin infusion also is due to direct mast cell activation Management is the same as for anaphylaxis

27 Hypersensitivity Syndrome (HSS)/ Drug Rash Eosinophilia and Systemic Symptoms (DRESS) Distinct drug reaction w/ morbilliform rash and progression to exfoliative dermatitis, fever, LAD, multisystem involvement Bone marrow, liver, kidney, CNS, GI, lungs Symptoms start within 8 weeks after initiation of therapy Aromatic anticonvulsants most common phenytoin, phenobarbital, carbamazepine

28 B-lactam hypersensitivity Penicillin is the most prevalent medication allergy 10% of patients report a pcn allergy 90% of pts when formally tested do not have an allergy! Major and minor penicillin antigenic determinants Major (95%)- penicillioyl; accounts for majority of allergic reactions Minor (5%)- penicilloate and penilloate R group side chain (distinguishes b/w different pcn compounds)- small subset of pts who react to one pcn, but can tolerate another A definitive dx of IgE mediated pcn allergy requires a skin test Reagents for both major and minor determinants exist

29 Major and minor penicillin antigenic determinants

30 Penicillin hypersensitivity Any patient with a possible h/o IgE mediated rxn to pcn is a candidate for skin testing Late-onset rashes w/ amoxiciilin are not considered to be a risk for IgE mediated rxns and do not need skin testing Negative predictive value for pcn skin testing is excellent Graded challenge can be used to alleviate apprehension 80% of patients lose their sensitivty over a period of 10 years h/o Non-IgE mediated pcn reaction (EM, SJS, serum sickness, etc..) should NOT undergo skin testing

31 Cephalosporin hypersensitivity Antigenic determinants not known (therefore, no skin test exists) Immune responses are thought to be directed to the R side chain Why pts w/ allergy to one cephalosporin can tolerate another Pencillin/cephalopsporin cross-reactivity is low (~3%) Graded challenges can be used in pts w/ +pcn skin test in need of cephalosporin tx

32

33 Sulfonamide hypersensitivity Maculopapular eruption following 7-10 days of therapy is the most common rxn May be associated with fever IgE anaphylaxis and other immunologic reactions are rare Graded challenge and desensitization protocols have been effective Should not be done if h/o SJS/TENs