Transcript Antibiotic Allergy: General review
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
Urticarial plaques associated with cephalexin
Carder K.R. Hypersensitivity reactions in neonates and infants. Dermatologic Therapy, Vol. 18, 2005, 160–175
Urticaria associated with ampicillin allergy
Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9. Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom.
Maculopapular rash associated with flucloxacillin allergy
Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9. Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom.
Exanthematous drug eruption caused by amoxicillin
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
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Leukocytoclastic vasculitis
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
Toxic epidermal necrolysis
McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions.
Immunol Allergy Clin N Am 24 (2004) 399– 423
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.
ADRs have been classified by Rawlins and Thompson in four types:
Type A reactions
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; 1991. p. 18–45.
Schnyder B. Approach to the Patient with Drug Allergy. Immunol Allergy Clin N Am 29 (2009) 405–418
Pathogenic Features
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;11:969-88.
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;100:136-41.
Several criteria characterize an allergic reaction
The reaction is not an expected effect.
pharmacologic
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize an allergic reaction
The reaction is not an expected effect.
pharmacologic
A period of sensitization precedes the reaction.
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize an allergic reaction
The reaction is not an expected effect.
pharmacologic
A period of sensitization precedes the reaction.
The reaction may occur at a dose much lower that required for a pharmacologic effect.
than
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize an allergic reaction
The clinical symptoms are characteristic of an allergic reaction
Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Several criteria characterize an allergic reaction
The clinical symptoms are characteristic of an allergic reaction
Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent
Chemical cross-reactivity may occur
Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions.
Immunology Allergy Clin N Am. 24(2004) 345-356.
Classification of allergic reactions to drugs
Gell and Coombs classification (1960): The physiological mechanisms Levine classification (1966): The time taken for symptoms to appear
Immediately: Fast: Delayed: Less than an hour 6-48 hours later. After 48 hours.
(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; 1968. p. 575–96.) (Immunologic mechanisms of penicillin allergy. A haptenic model system for the study of allergic diseasess of man. NEJM 1966; 275: 1115-25)
Is a fishing net adequate for our purposes ?
http://www.monografias.com/trabajos59/fabula-lanzador-redes/Image23883.gif
My personal opinion is that, like our fisherman here Our fishing net is not big enough to catch all drug allergies
My personal opinion is that, like our fisherman here AND Our fishing net allows too many of them to escape
OR MAYBE...
We need to discover new knowledge or create a new system that captures everything.
Multivalency theory of haptenic drug allergy
Middleton’s. allergy: Principles and Practices. Seventh edition. 2009
A schematic comparison of the p-i concept with the hapten model
Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity. Current Opinion in Immunology 2004, 16:732–737
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 2003. J Allergy Clin Immunol 2004; 113:832-836.
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)
Schematic representation of overlapping immune functions
Werner J. Pichler, MD Immune mechanism of drug hypersensitivity Immunol Allergy Clin N Am 24 (2004) 373–397
Revised Gell and Coombs classification of drug reactions
Th2 Th1
T Cell
Th17 T Reg Th17
Pichler, W.J. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004) 373– 397 Scheme adapted from Janeway CA, Travers P, Walport M, Shlochik M. Immunobiology. New York: Garland Publishing; 2001
Th1 Th2 T Treg Cell T Th17 Th9
type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T Th1 Treg Cell T Th2 Th17 Th9
type IVb eosinophils type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T Th1 Treg Cell T IL 5, IL4/IL13 cell B IgE Th2 type I Th9 Th17
type II IgG cell B IgG type III type IVa macrophage C, O 2 IL 5, IL4/IL13 cell B IgE Th2 type I type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T Th1 Treg Cell T Th9 Th17 type IVb eosinophils
type II IgG cell B IgG type III type IVa macrophage C, O 2 IL 5, IL4/IL13 cell B IgE Th2 type I type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T Th1 Treg Cell T Th9 Th17 IL 17 type IVd neutrophils type IVb eosinophils
type II IgG cell B IgG type III type IVa macrophage C, O 2 IL 5, IL4/IL13 cell B IgE Th2 type I type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T IL 10, TGF β Th1 Treg Pre Th Cell T Th9 Th17 IL 17 type IVd neutrophils type IVb eosinophils Th1 IL 12 β Th2
type II IgG cell B IgG type III type IVa macrophage type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T IL 10, TGF β Th1 Treg Pre Th C, O 2 type IVb eosinophils Cell T IL 5, IL4/IL13 cell B IgE Th2 ?
type I Th9 type IVb eosinophils Th17 IL 17 type IVd neutrophils Th1 IL 12 β Th2
type II IgG cell B IgG type III type IVa macrophage type IVa macrophage INF γ, TNFα (Th1 cells) type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) type IVc CD4 and CD8 Cytotoxic T cell CXCL 8, GM-SCF (T cell) Perforin/Granzyme B (CTL) T IL 10, TGF β Th1 Treg Pre Th C, O 2 type IVb eosinophils Cell T IL 5, IL4/IL13 cell B IgE Th2 ?
type I Th9 type IVb eosinophils Th17 IL 17 type IVd neutrophils Th1 IL 12 β Th2
Areas of Uncertainty
The mechanisms underlying antibiotic allergy have not been clearly elucidated .
..Some people believe that everything they see is true; like “the world is flat”...
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;29:503-516
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;29:503-516
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;29:503-516
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;29:503-516
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;29:503-516
Clinical assessment
Medical history taking is critical in the evaluation of antibiotic allergy and in distinguishing allergic reactions from other adverse reactions
Ancient Greek painting in a vase, showing a physician (iatros) bleeding a patient Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.
Diagnosis tests
Skin Testing: Skin testing is the basic diagnostic tool , although in patients with a history of severe reactions,
in vitro
tests may be the recommended choice.
Skin testing is highly accurate for the identification of penicillin allergy.
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193
Diagnosis tests
Other Testing: 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
The basophil activation test as a funtional
in vitro
test in immediate-type drug allergy.
Hausmann O.V et al. The basophil activation test in immediate-type drug allergy. Immunol Allergy Clin N Am 29 (2009) 555 –566
Diagnosis tests
Other Testing: Drug-specific T cells, which are involved in some hypersensitivity reactions, may be detected with the use of in vitro lymphocyte transformation tests
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193 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
Diagnosis tests
Other Testing: 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.
Romano A, Blanca M, Torres MJ, Bircher A, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;59:1153-1160
.
Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193
Clinical History of reaction Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Any Positive Both negative Late with intradermal or epicutaneous with drug envolved Positive Negative Allergy PEC(**) Allergy PEC(**) Positive Allergy Any positive Negative Reaction over two Years ago No Yes Skin test + PEC (**)(^^) Both Negative No Allergy Positive Allergy Negative Complete curse of the treatment Tolerance Reaction No Allergy Allergy Allergy No Allergy
Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.
Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)
Clinical History of reaction Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Any Positive Both negative Late with intradermal or epicutaneous with drug envolved Positive Negative Allergy PEC(**) Allergy PEC(**) Positive Allergy Any positive Negative Reaction over two Years ago No Yes Skin test + PEC (**)(^^) Both Negative No Allergy Positive Allergy Negative Complete curse of the treatment Tolerance Reaction No Allergy Allergy Allergy No Allergy
Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento.
Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)
Identification and future management of the most common drug reactions
Volcheck G.W. Clinical evaluation and manegement of drug hypersensitivity.Immunol Allergy Clin N Am 24(2004) 357-371
Drug Provocation Test: Contraindications
Autoimmune diseases:
Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus
Severe exfoliative skin reactions:
AGEP, DRESS/Drug-induced hypersensitivity syndrome, Exfoliative dermatitis, SJS, Toxic epidermal necrolysis
Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity.
Immunol Allergy Clin N Am 29 (2009) 567–584
Drug Provocation Test: Contraindications
Severe vasculitis syndrome Specific organ manifestations:
Blood cytopenia, hepatitis, nephritis, pneumonitis
Aberer W. And Kranke B. ProvocationTests in Drug Hypersensitivity.
Immunol Allergy Clin N Am 29 (2009) 567–584
Genetic susceptibility to drug hypersensitivity
Culprit drug Disease Carbamazepine SJS/TEN HLA Ethnicity HLA-B 1502 Han-Chinese Allopurinol SJS/TEN/HSS HLA-B 5801 Han-Chinese Abacavir HSS HLA-B 5701 Caucasians
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
Summary
“Drug allergy and hypersensitivity have been recognized for decades, 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