DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Although allergic reactions to antibiotics account for only a small proportion of reported adverse drug reactions, they are associated with substantial morbidity and mortality and increased health care costs. Estimates of the prevalence of antibiotic allergy vary widely. Any organ may be affected, but the skin is most commonly involved. Recognizind and understanding these peculiar, man-made iatrogenic diseases may be the first step to reduce the side of this problems and possibly prevent. 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 Although rare, hypersensitivity reactions do occur in children under 6 months of age. Urticaria (hives) is one of the most common childhood dermatoses, affecting up to 15–20% of children prior to adolescence, but is relatively uncommon under the age of 6 months. 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 T cells play a predominant role in delayed hypersensitivity reactions, including antibiotic-induced maculopapular eruptions, whereas drug-specific IgE antibodies cause urticarial reactions. 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 Numerous generalized pruritic erythematous macules an papules. 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 Acute generalized exanthematous pustulosis (AGEP) is a rare adverse drug reaction characterized by fever and generalized erythema followed by the sudden appearance of widespread pustules. It typically has a rapid onset after ingestion of a medication, but its course is self-limited.  The onset of AGEP is abrupt, with high fever (39_C) accompanying or preceding the rash, which usually begins in the skin creases, sometimes on the face, and spreads within 24 hours. It manifests first as an edematous burning or pruritic confluent erythema of skin, which is quickly covered by numerous small pustules less than 5 mm in diameter. McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

Leukocytoclastic vasculitis Cutaneous vasculitis is the most commonly encountered vasculitic manifestation in clinical practice. Palpable purpura is the most frequent presentation of small-vessel vasculitis. Lesions are usually round and 1 to 3 mm in diameter. They may coalesce to form plaques, and they may ulcerate. Palpable purpura is most frequently observed on the legs . In more than 70% of cases, cutaneous vasculitis occurs in the setting of an underlying process, such as a medication exposure, infection, malignancy, or connective tissue disease, or as a manifestation of a primary systemic vasculitis. Antibiotics are the most common drugs that can cause cutaneous vasculitis, particularly beta-lactams. McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

Toxic epidermal necrolysis The disorder is characterized by widespread erythematous or purpuric macules and targetoid lesions. Widespread, full-thickness epidermal necrosis with involvement of more than 30% of the body surface area occurs. Commonly, the mucous membranes are also involved. Drugs are implicated in approximately 65% of cases, and the mortality rate can approach 40% [47]. Penicillins and sulfonamide antibiotics are the drugs most commonly identified as etiologic agents. 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 The most common sensitizers in this population are neomycin and chloramphenicol. An example of a patient with chronic, fissured, fingertip dermatitis which was self-treated with topical antibiotics and later found to be allergic to those 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. 1) type A reactions that are common (approximately 80%) owing to the pharmacologic or toxic property of the causative drug and thus predictable that may occur in any individual. (2) type B reactions that are uncommon (approximately 10% to 15%), not predictable, and occur only in susceptible individuals. (3) type C reactions that are associated with long-term therapy (eg, benzodiazepine dependence). (4) type D reactions that are carcinogenic and teratogenic effects. 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 10

Allergic reactions are, by definition, immunologically mediated. 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. 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. For instance, a major antigenic determinant and several minor determinants have been identified for penicillin. T cells play a predominant role in delayed hypersensitivity reactions, including antibiotic-induced maculopapular eruptions, whereas drug-specific IgE antibodies cause urticarial reactions. 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 pharmacologic effect. A drug allergy is always associated with an immune mechanism for which evidence can be shown of drug-specific antibodies or activated T lymphocytes. This mechanism holds true for reactions to myorelaxants and proteins such as insulin or b-lactams. Schematically, several criteria characterize an allergic 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 pharmacologic effect. A period of sensitization precedes the reaction. A drug allergy is always associated with an immune mechanism for which evidence can be shown of drug-specific antibodies or activated T lymphocytes. This mechanism holds true for reactions to myorelaxants and proteins such as insulin or b-lactams. Schematically, several criteria characterize an allergic reaction:   Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356. 13

Several criteria characterize an allergic reaction The reaction is not an expected pharmacologic effect. A period of sensitization precedes the reaction. The reaction may occur at a dose much lower than that required for a pharmacologic effect. A drug allergy is always associated with an immune mechanism for which evidence can be shown of drug-specific antibodies or activated T lymphocytes. This mechanism holds true for reactions to myorelaxants and proteins such as insulin or b-lactams. Schematically, several criteria characterize an allergic reaction:   Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356. 14

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. 15

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. 16

Classification of allergic reactions to drugs 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: 1115-25) 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; 1968. p. 575–96.) Allergic (ie, hypersensitivity) drug reactions are distinguished from other unpredictable reactions in that they are mediated by a specific immune mechanism. No single classification scheme is able to account for all allergic drug reactions. The widely used Gell and Coombs classification scheme of type 1 to type 4 hypersensitivity reactions may be applied to some drug-induced allergic reactions. Certain reactions cannot be categorized into any classification scheme despite our insight into their underlying mechanism. In other instances, reactions cannot be classified because the mechanism of their elicitation is not understood. 17

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 Most medications, because of their small size, are unable to elicit an immune response independenthy. Drugs must first covalently bind to large carrier molecules such as tissue or serum proteins to act as complete multivalent antigens (This process is called haptenation) and the drug act as hapten. Middleton’s. allergy: Principles and Practices. Seventh edition. 2009

A schematic comparison of the p-i concept with the hapten model According to the p-i concept, the non-covalent, reversible binding of a drug to a matching TCR together with co-stimulatory signalling by MHC molecules would suffice to drive the activation and expansion of cross-reactive, peptide-specific memory T cells. In this way, the induction of a primary immune response can be ‘circumvented’, which would explain the strong allergic reactions observed in some patients without previous exposure to certain drugs. In contrast, the hapten-specific immune response relies on ‘normal’ priming of naı¨ve T cells with the involvement and activation of APCs, such as dendritic cells.   Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity. Current Opinion in Immunology 2004, 16:732–737

referring to the onset of the symptoms, 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 La unión de un alergeno polivalente a la porción variable de dos o más IgE produce la liberación demediadores preformados o recien sintetizados responsables de los síntomas alergicos, la reacción inducida provoca la la secreción de una serie de citocinas que aumentan en las cel inflamatorisas y en los linfocitos B la expresión de CD 23 (que se expresa en linfocitos T, B, monocitos , macrofagos eosinofilos y plaquetas ) e interviene en la presentación de IgE farmacodependiente a celulas T y en la adhesion de cel B asi como la migración de estas células a los centros germinales de los folículos secundarios de GL y bazo lo que aumeta los nivees de IgE farmaco especifico circulante . Efecto denominado respuesta secundaria al fármaco. En el caso de los medicamentos una molecula trasportadora puede unir varios haptenos cada uno de los cuales formaria un epitopo capaz de lograr el entrecruzamiento de las moleculas de IgE. 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 Representación esqeumatica de funciones inmunes concomitantes. La sintomatología clínica de enfermedades a menudo complejas y pueden ser desencadenadas por diversas funciónes inmunológicas que pueden ocurrir juntos o secuencialmente. Las de tipo c estan en el centro ya que pueden combinarse con las demas para formar un patron clínico de presentación 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 T Cell Th17 Th2 T Reg Drugs can elicit all types of immune reactions. Actually, all reactions are T-cell regulated, but the effector function relies mainly on antibody-mediated effector functions (type I – III) or more T-cell/cytokine–dependent functions (type IVa to IVd). Type IVa reactions correspond to Th1 reactions with high IFN-g/TNF-a secretion and involve monocyte/macrophage activation. Often, one can see a CD8 cell recruitment (type IVc reaction). Type IVb reactions correspond to eosinophilic inflammation and a Th2 response with high IL-4/IL-5/IL-13 secretion. They are often associated with an IgE-mediated type I reaction. Type IVc cytotoxic reactions (by CD4 and CD8 cells) rely on cytotoxic T cells themselves as effector cells. They seem to occur in all drug-related delayed hypersensitivity reactions. Type IVd corresponds to a T-cell – dependent, sterile neutrophilic inflammatory reaction. It is clearly distinct from the rapid influx of neutrophils in bacterial infections and seems to be related to high CXCL-8/GM-CSF production by T cells (and tissue cells). Th9 Th1 Th 9 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

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

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

Perforin/Granzyme B (CTL) type IVb eosinophils type IVa macrophage type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVc CD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) type II IgG cell B type IVa macrophage IgG type III IL 5, IL4/IL13 cell B C, O2 type I type IVb eosinophils

Perforin/Granzyme B (CTL) type IVb eosinophils type IVa macrophage type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVc CD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) type II IgG cell B type IVa macrophage IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2 type I type IVb eosinophils

Perforin/Granzyme B (CTL) type IVb eosinophils type IVa macrophage type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVc CD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 type II IL 10, TGF β IgG IL 12 β cell B type IVa macrophage Pre Th Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2 type I type IVb eosinophils

Perforin/Granzyme B (CTL) type IVb eosinophils type IVa macrophage type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVc CD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 type II IL 10, TGF β IgG IL 12 β cell B type IVa macrophage Pre Th Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2 type I type IVb eosinophils type IVb eosinophils

Perforin/Granzyme B (CTL) type IVb eosinophils type IVa macrophage type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVc CD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 type II IL 10, TGF β IgG IL 12 β cell B type IVa macrophage Pre Th Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2 type I type IVb eosinophils type IVb eosinophils

The mechanisms underlying have not been clearly elucidated. 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 Main clinical manifestations are urticaria or angioedema and anaphylaxis, often due to drug-specific IgE. These ADRs are the principal indications for skin prick tests (SPTs) and intradermal tests (IDTs) in drug allergy work-up. 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. Later readings of IDTs are used for delayed, non–IgE-mediated allergies. A list of ADRs that represent no indications or even contraindications for IDTs with immediate readings or where IDT may cause exacerbations of an allergy   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 Later readings of IDTs are used for delayed, non–IgE-mediated allergies. A list of ADRs that represent no indications or even contraindications for IDTs with immediate readings or where IDT may cause exacerbations of an allergy   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 40

SPT and IDT with the major and minor determinates of penicillin Most studies performed in recent decades, mainly in the United States, have shown that PPL incombination with MDM is adequate (sensitivity up to 70% and high specificity reaching 97% to 100%) to evaluate patients by SPT and IDT with immediate-type allergies to b-lactams. For instance, a major antigenic determinant and several minor determinants have been identified for penicillin. Penicillin is the must prevalent medication allergy, with approximately 10% of patients reporting being penicillin-allergic. 95% of penicillin degrades to the penicilloyl moiety. Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516 41

Clinical assessment Medical history taking is critical in the evaluation of antibiotic allergy and in distinguishing allergic reactions from other adverse reactions Medical history taking is critical in the evaluation of antibiotic allergy and in distinguishing allergic reactions from other adverse reactions. This information is important, since overdiagnosis of allergic reactions can lead to unnecessary use of more costly antimicrobial agents and may promote the development of resistant microorganisms. 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 may be used to detect allergen-specific IgE antibodies. However, with the exception of penicillin, the relevant immunogens (which may be derived from an unidentified drug metabolite or degradation product) are not known for most drugs. Thus, there are no valid in vivo or in vitro diagnostic reagents available for identifying most antibiotic-specific IgE antibodies. Although the parent antibiotic compound may be used in testing by allergy specialists, a negative response on a skin test cannot be interpreted to mean that IgE antibodies are absent 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 43

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 In conclusion, the measurement of the IL-5 as a very specific marker in combination with either IFN-gamma, IL-13 or IL-2 as a more sensitive marker might be a useful tool for the in vitro detection of T-cell sensitization to drugs. For b-lactam sensitization, INF- alfa migth be suitable as well. 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 44

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. European Network for Drug Allergy (Romano et al Allergy 2004; 59:1153-1160) 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 46

Clinical History of reaction Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Late with intradermal or epicutaneous with drug envolved Any Positive Both negative Positive Negative Allergy PEC(**) Allergy PEC(**) Positive Negative Positive Negative Reaction over two Years ago Allergy Complete curse of the treatment Allergy Yes No Tolerance Reaction Skin test + PEC (**)(^^) Any positive Both Negative No Allergy 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) 47

Reacción de más de dos años Clinical History of reaction Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Delayed (> 1 hour) (Urticaria, AE, rash) Skin test(*) Specific IgE (CAP) Late with intradermal or epicutaneous with drug envolved Any Positive Both negative Positive Negative Allergy PEC(**) Allergy PEC(**) Positive Negative Positive Negative Reaction over two Years ago Allergy Complete curse of the treatment Allergy * Las pruebas cutáneas deben incluir al menos el PPL, el MDM, y el fármaco implicado en la reacción. ** Prueba de exposición controlada. ^^ Se debe repetir un mes después del estudio inicial con el fin de identificar la adquisición de re-sensibilización durante el protocolo de estudio, la cual puede ser de hasta el 16%. Reacción de más de dos años Yes No Tolerance Reaction Skin test + PEC (**)(^^) Any positive Both Negative No Allergy 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 A myriad of drug sensitivities affect all organ systems. Using the guidelines outlined previously, the remainder of this article focuses on the most commonly seen immune-mediated drug reactions, with an emphasis on their clinical evaluation and management. These reactions include the Gell and Coombs types 1 to 4 immune reactions, morbilliform reactions, erythema multiforme, Stevens-Johnson syndrome, TEN, anaphylactoid reactions, and HSS/DRESS syndrome. Patients may undergo drug desensitization if that drug is required for treatment. Various protocols are available for different drugs. These protocols consist of the administration of incremental doses of a drug over a period of hours or days to convert the patient from being drug sensitive to drug tolerant. The patient needs to be observed closely during this procedure. The patient will remain in the desensitized state for as long as he or she receives the drug. After discontinuation of the drug, a repeat desensitization would have to be performed before the drug could be given at maintenance dosage 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 A DPT should never be performed in patients who have experienced severe reactions. A DPT is frequently performed when skin and in vitro diagnostic methods have been ineffective (eg, hypersensitivity reactions to NSAIDs), in vitro tests are not available or skin tests are not admissible because of local irritation (eg, quinolones), the sensitivity of the tests is limited (eg, for heparins and glucocorticosteroids), or other allergy tests with a high negative predictive value yield negative test results (eg, immediate or nonimmediate hypersensitivity reactions after b-lactams).2 In most cases, however, it is difficult to justify a DPT with drugs that are largely obsolete today, such as sulfonamides (except in HIV-positive persons), or substances of doubtful value, such as herbal products or ‘‘lifestyle drugs.’’ 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 51

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 52

Genetic susceptibility to drug hypersensitivity Culprit drug Disease HLA Ethnicity Carbamazepine SJS/TEN HLA-B 1502 Han-Chinese Allopurinol SJS/TEN/HSS HLA-B 5801 Abacavir HSS HLA-B 5701 Caucasians For example, Stevens–Johnson syndrome to carbamazepine in Han-Chinese shows a strong association with HLA-B∗1502, but HLA-B∗1502 is not increased in Han-Chinese patients with milder, maculopapular drug eruptions.[67] European Caucasians do not show this association of HLA-B∗1502 and Stevens–Johnson syndrome. Se podría postular que solo ciertos alelos del HLA son capaces de aumentar la estimulación del TCR por carbamazepina monomerica de acuerdo con el concepto p-i, o uno podría explicar la restricción del HLA por el rol del MHC en presentar un hapteno y su transportador al TCR. 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

Thanks !!