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DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria.

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Presentation on theme: "DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria."— Presentation transcript:

1 DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria - Clínica León XIII Medical School Universidad de Antioquia

2 Carder K.R. Hypersensitivity reactions in neonates and infants. Dermatologic Therapy, Vol. 18, 2005, 160–175 Urticarial plaques associated with cephalexin

3 Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom. Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354: Urticaria associated with ampicillin allergy

4 Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom. Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354: Maculopapular rash associated with flucloxacillin allergy

5 McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423 Exanthematous drug eruption caused by amoxicillin

6 McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423 Acute generalized exanthematous pustulosis from amoxicillin

7 McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423 Leukocytoclastic vasculitis

8 McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423 Toxic epidermal necrolysis

9 Allergic contact dermatitis to topical antibiotics Kathryn A. Gehrig k.A. and Warshaw E.M. Allergic contact dermatitis to topical antibiotics: Epidemiology, responsible allergens, and management. J Am Acad Dermatol 2008;58:1-21.

10  Type A reactions Type B reactions that are uncommon  Type B reactions that are uncommon (approximately 10% to 15%), not predictable, and occur only in susceptible individuals  Others: type C and type D reactions. Rawlins M, Thompson W. Mechanisms of adverse drug reactions. In: Davies D, editor. Textbook of adverse drug reactions. New York: Oxford Press; p. 18–45. Schnyder B. Approach to the Patient with Drug Allergy. Immunol Allergy Clin N Am 29 (2009) 405–418 ADRs have been classified by Rawlins and Thompson in four types:

11 immunologically mediated. Allergic reactions are, by definition, immunologically mediated. A single drug may initiate multiple immune responses, and multiple antigenic determinants may be formed from a single drug. Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol 1998;11: Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHCdependent presentation of the drug sulfamethoxazole to human alpha/beta T cell clones. J Clin Invest 1997;100: Pathogenic Features

12 is not an expected  The reaction is not an expected pharmacologic effect. Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) Several criteria characterize an allergic reaction

13 is not an expected  The reaction is not an expected pharmacologic effect. sensitization precedes  A period of sensitization precedes the reaction. Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) Several criteria characterize an allergic reaction

14 is not an expected  The reaction is not an expected pharmacologic effect. sensitization precedes  A period of sensitization precedes the reaction. dose much lower  The reaction may occur at a dose much lower than that required for a pharmacologic effect. Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) Several criteria characterize an allergic reaction

15 Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) are characteristic of an  The clinical symptoms are characteristic of an allergic reaction allergic reaction Several criteria characterize an allergic reaction within an expected interval,  Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent

16 Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) are characteristic of an  The clinical symptoms are characteristic of an allergic reaction allergic reaction Several criteria characterize an allergic reaction within an expected interval,  Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent may occur  Chemical cross-reactivity may occur

17 Classification of allergic reactions to drugs Gell and Coombs classification (1960): The physiological mechanisms (Gell P. and Coombs R. Clinical aspects of immunology Blalckwell Scient Publ Oxford; 1964). (Coombs PRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell RRA, editor. Clinical aspects of immunology. Oxford: Oxford University Press; p. 575–96.) Levine classification (1966): The time taken for symptoms to appear Immediately: Less than an hour Fast: 6-48 hours later. Delayed: After 48 hours. (Immunologic mechanisms of penicillin allergy. A haptenic model system for the study of allergic diseasess of man. NEJM 1966; 275: )

18 Is a fishing net adequate for our purposes ?

19 My personal opinion is that, like our fisherman here Our fishing net is not big enough to catch all drug allergies

20 My personal opinion is that, like our fisherman here AND Our fishing net allows too many of them to escape

21 We need to discover new knowledge or create a new system that captures everything. OR MAYBE...

22 Middleton’s. allergy: Principles and Practices. Seventh edition Multivalency theory of haptenic drug allergy

23 Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity. Current Opinion in Immunology 2004, 16:732–737 A schematic comparison of the p-i concept with the hapten model

24 immediatedelayed The World Allergy Organization has recommended the use of the adjectives immediate and delayed referring to the onset of the symptoms, as helpful in distinguishing whether the probable immunologic mechanism is antibody mediated or T-lymphocyte-mediated. Johansson S.G., Bieber T., Dahl R., et al: Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization October J Allergy Clin Immunol 2004; 113:

25 Gell and Coombs classification Ricardo Cardona V. y Carlos Serrano,Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 1, Aspectos Básicos de la Alergia y Reacciones de Hipersensibilidad. Ed. Panamericana (en prensa)

26 Werner J. Pichler, MD Immune mechanism of drug hypersensitivity Immunol Allergy Clin N Am 24 (2004) 373–397 Schematic representation of overlapping immune functions

27 Pichler, W.J. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004) 373– 397 Revised Gell and Coombs classification of drug reactions Scheme adapted from Janeway CA, Travers P, Walport M, Shlochik M. Immunobiology. New York: Garland Publishing; 2001 Th17 Th 9 T Cell T Reg Th2 Th1 Th17 Th9

28 Cell T T Treg Th17 Th9 Th2 Th1

29 type IVa macrophage type IVd neutrophils type IVb eosinophils INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell Cell T T Treg Th17 Th9 Th2 Th1

30 type IVa macrophage type IVd neutrophils type IVb eosinophils type Itype IVb eosinophils cell B INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell IgE

31 type IVa macrophage type IVd neutrophils type IVb eosinophils type IVa macrophage type II type III cell B type Itype IVb eosinophils cell B C, O 2 IgG INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell

32 IgE IL 17 type IVa macrophage type IVd neutrophils type IVb eosinophils type IVa macrophage type II type III cell B type Itype IVb eosinophils type IVd neutrophils cell B C, O 2 IgG INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell

33 IL 17 IgE type IVa macrophage type IVd neutrophils type IVb eosinophils type IVa macrophage type II type III cell B type Itype IVb eosinophils type IVd neutrophils Pre Th cell B C, O 2 IgG Th1 Th2 INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 10, TGF β IL 12 β IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell

34 IgE ? IL 17 type IVa macrophage type IVd neutrophils type IVb eosinophils type IVa macrophage type II type III cell B type Itype IVb eosinophils type IVd neutrophils Pre Th cell B C, O 2 IgG Th1 Th2 INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 10, TGF β IL 12 β IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell

35 IgE ? IL 17 type IVa macrophage type IVd neutrophils type IVb eosinophils type IVa macrophage type II type III cell B type Itype IVb eosinophils type IVd neutrophils Pre Th cell B C, O 2 IgG Th1 Th2 INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) IL 10, TGF β IL 12 β IL 5, IL4/IL13 (Th2 cells) IL 5, IL4/IL13 type IVc CD4 and CD8 Cytotoxic T cell

36 The mechanisms underlying antibiotic allergy have not been clearly elucidated. have not been clearly elucidated...Some people believe that everything they see is true; like “the world is flat”... Areas of Uncertainty

37 Indications for ‘skin prick test’ and ‘intradermal test’ Erythematous eruption/flushing Bronchospasm/asthma Conjunctivitis Anaphylaxis Angioedema Urticaria Rhinitis Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

38 No indications for ‘skin prick test’ and ‘intradermal test’ Drug-induced autoimmune diseases: Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus. Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

39 No indications for ‘skin prick test’ and ‘intradermal test’ Drug-induced autoimmune diseases: Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus. Severe vasculitis syndromes Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

40 No indications for ‘skin prick test’ and ‘intradermal test’ Severe exfoliative skin reactions: Acute generalized exanthematic pustulosis, drug reaction with eosinophilia and systemic symptoms or drug hypersensitivity syndrome, exfoliative dermatitis, multilocalized bullous fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis. Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

41 SPT and IDT with the major and minor determinates of penicillin Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:

42 evaluation Medical history taking is critical in the evaluation of antibiotic allergy and distinguishing in distinguishing allergic reactions from other adverse reactions Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354: Clinical assessment Ancient Greek painting in a vase, showing a physician (iatros) bleeding a patient

43 Skin Testing: the basic diagnostic tool Skin testing is the basic diagnostic tool, although in patients with a history of severe reactions, in vitro tests may be the recommended choice. Diagnosis tests Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy , Skin testing is highly accurate for the identification of penicillin allergy.

44 Other Testing: IL-2, IL-5, IL-13 or IFN-gamma The measurement of IL-2, IL-5, IL-13 or IFN-gamma or a combination there of might be a useful in vitro tool for detection of T-cell sensitization to drugs Lochmatter P., Beeler A., Kawabata T.T., Gerber B.O., Pichler W. J. Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity. Allergy 2009: 64: 1269–1278 Diagnosis tests Hausmann O.V et al. The basophil activation test in immediate-type drug allergy. Immunol Allergy Clin N Am 29 (2009) 555–566 a funtional in vitro test The basophil activation test as a funtional in vitro test in immediate-type drug allergy.

45 Other Testing: lymphocyte transformation tests Drug-specific T cells, which are involved in some hypersensitivity reactions, may be detected with the use of in vitro lymphocyte transformation tests Diagnosis tests Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy , Bernstein I.L., James T., Li J.T., Bernstein D.I.,Hamilton R., et al, Allergy Diagnostic Testing: An Updated Practice Parameter. ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY. VOLUME 100, MARCH, 2008: S1-S148

46 Other Testing: Drug provocation test. to confirm Drug provocation test. The ENDA document stated that the DPT was, at that time, the best tool to confirm a causal relationship between drug administration and non-immediate adverse reactions. Diagnosis tests Romano A, Blanca M, Torres MJ, Bircher A, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;59: Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy ,

47 Clinical History of reaction Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Any Positive Both negative Late with intradermal or epicutaneous with drug envolved Negative Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Positive PEC(**)Allergy PEC(**) Allergy Negative Positive Reaction Negative Tolerance Allergy Skin test + PEC (**)(^^) Yes Reaction over two Years ago No No Allergy Allergy No Allergy Allergy Both Negative Any positive Complete curse of the treatment Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press) No Allergy

48 Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Any Positive Both negative Late with intradermal or epicutaneous with drug envolved Negative Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Positive PEC(**)Allergy PEC(**) Allergy Negative Positive Reaction Negative Tolerance Allergy Skin test + PEC (**)(^^) Yes Reaction over two Years ago No No Allergy Allergy No Allergy Allergy Both Negative Any positive Complete curse of the treatment Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press) No Allergy Clinical History of reaction

49 Volcheck G.W. Clinical evaluation and manegement of drug hypersensitivity.Immunol Allergy Clin N Am 24(2004) Identification and future management of the most common the most common drug reactions

50

51 Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity. Immunol Allergy Clin N Am 29 (2009) 567–584 Autoimmune diseases: Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus Drug Provocation Test: Contraindications Severe exfoliative skin reactions: AGEP, DRESS/Drug-induced hypersensitivity syndrome, Exfoliative dermatitis, SJS, Toxic epidermal necrolysis

52 Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity. Immunol Allergy Clin N Am 29 (2009) 567–584 Severe vasculitis syndrome Drug Provocation Test: Contraindications Specific organ manifestations: Blood cytopenia, hepatitis, nephritis, pneumonitis

53 Midlleton´s Allergy Principles and practice 7 edition. Werner J Pichler, Andreas Beeler. Pharmacological Interaction of Drugs with Immune Receptors: The p-I Concept Allergology International Vol 55, No1, 2006 Culprit drug DiseaseHLAEthnicity CarbamazepineSJS/TENHLA-B 1502Han-Chinese AllopurinolSJS/TEN/HSSHLA-B 5801Han-Chinese AbacavirHSSHLA-B 5701Caucasians Genetic susceptibility to drug hypersensitivity drug hypersensitivity

54 “Drug allergy and hypersensitivity have been recognized for decades, large gaps but there are still large gaps in our knowledge” Bousquet P-J., Demoly P. & Romano A. Drug allergy and hypersensitivity: still a hot topic. Allergy 2009: 64: 179–182 Summary

55 Thanks !!


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