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Adverse drug reactions (ADRs) have been reported to account for 3 to 6% of all hospital admissions and occur in 10 to 15% of hospitalized patients. It is a response to a drug that is noxious and unintended and occurs at doses normally used in man. Drug reactions can be considered as being either predictable or unpredictable. A predictable reaction is the result of the pharmacologic action of the medication, and does not require further workup. An unpredictable reaction might be drug intolerance, idiosyncratic, or might have or imply an immunologic basis, and thus be called drug hypersensitivity. It is potentially dangerous and may lead to fatalities, such as in drug anaphylaxis or in Toxic Epidermal Necrolysis. To come to the correct diagnosis and identify the culprit drug is of great importance. The diagnosis is often hampered by the complexity if this condition: although drug hypersensitivity is altogether frequent, it is rare for each drug. In addition it has very heterogeneous clinical symptoms and may occur as anaphylaxis in immediate (occurring mostly within 1 hour) as well as in various forms of exanthema in non-immediate drug hypersensitivity (occurring mostly after days).
The Interest Group on Drug Hypersensitivity is based on the European Network on Drug Hypersensitivity (ENDA), which has been founded about 20 years ago and is dedicated to develop practical diagnostic and therapeutic methods in drug hypersensitivity and to promote research in this area. In the last years many position papers and guidelines have been developed. The group remains active and we invite all EAACI members to join the activities of the group. Every year in autumn there is an annual meeting. This year, the chairperson (Knut Brockow) and the secretary (Ingrid Terreehorst) together with the local organizers (Jean Louis Gueant, Annick Barbaud, Gisele Kanny, Michel Mertes) are inviting to this meeting in Nancy from 4th to 5th November.

Projects

- the ENDA has three ongoing multicentre studies: Allergic reactions to radio contrast media (project leader: Knut Brockow), the oxaliplatin and chemotherapeutic desensitization protocol (project leader: M Pagani), and a new multicentre study on skin test standardization (location, positivity criteria, amount to inject etc) (project leader: Annick Barbaud).

Task forces

- Task Force on Desensitization in Drug Hypersensitivity: In patients with a drug hypersensitivity reaction, most of the time an alternative is sought. For sensitized patients who have a clinical meaningful benefit from a particular drug, however, continuation with the agent is sometimes desirable. One of the options includes desensitization to the eliciting drug. Acute or rapid desensitization protocols have been developed and used in patients with allergic reactions to antibiotics (mainly penicillin) insulin, sulphonamides, aspirin and other NSAIDs, chemotherapeutics agents and many other drugs. It is a high risk procedure as it requires the introduction of medication to which the patient has reacted, done by repetitive increasing sub-therapeutic doses of the medication involved, until the total cumulative therapeutic dose is achieved. Once desensitization is complete this state can only be maintained by continuous administration of the medication. The task force’s goals are to provide standardized protocols for rapid desensitization for antibiotics, aspirin and other NSAIDS, chemotherapeutics, monoclonal agents and other biological agents. In addition, the group now is developing guidelines for desensitization in non-immediate (delayed) drug hypersensitivity. In some situations, e.g. use of trimethoprim/sulfamethoxazole in HIV patients or antibiotics in cystic fibrosis patients, a non-cross-reactive optimal treatment is not available and desensitization is the only mean to achieve a desired effect, even in patients with prior exanthemas to drugs.

- Task Force Non-steroidal anti-inflammatory drug (NSAID) hypersensitivity: Hypersensitivity to NSAIDs is one of the most common drug hypersensitivity met in general practice and may manifest with different symptoms and syndromes. Several subtypes of hypersensitivity to NSAIDs have been distinguished depending on the symptomatology (respiratory, cutaneous, anaphylaxis), timing (acute, delayed), underlying chronic disease (otherwise healthy subjects, asthmatics, chronic urticaria patients) or putative mechanism of the reaction (allergic versus non-immunologically mediated, single reactors, multiple reactors). The aims of the task force are the collection and analysis of available data on the diagnosis and management of various types of hypersensitivity to NSAIDs including test procedures, the assessment of specificity and sensitivity of available diagnostics tools, establishing of a network of ENDA centers for validation and prospective  collection of  data on concentrations of drugs for skin testing and in vitro testing, to prepare recommendations for alternative drugs selection and tolerance testing and to develop algorithm(s) for diagnosis of various types of specific NSAIDs

- Task Force on Drug hypersensitivity and Mast Cell Disease: In systemic mastocytosis several stimuli, including IgE-mediated reactions, can massively activate mast cells and provoke severe systemic symptoms, including anaphylaxis. This is well known for hymenoptera venom allergy. Similar to what happens with hymenoptera venom allergy, it can be hypothesized that this could also occur in case of systemic reactions due to other causes, for example drugs. Goal of the task force is to collect data regarding the prevalence of mastocytosis in patients with a drug induced anaphylaxis, to assess the level of tryptase in these patients and a possible relation with the severity of the reaction, to assess the incidence of clonal mast cell disorders and to provide risk criteria for anaphylactic reactions to drugs in these patients. Furthermore, the group wants to establish criteria as to when invasive procedures such as bone marrow biopsy are warranted in patients with drug related anaphylaxis and to establish the class of drugs associated with severe systemic reactions in patients with systemic mastocytosis. A review and/or position paper will be written in the course of the task force activities.

- Task Force on Skin Test Concentrations in Drug Hypersensitivity: Skin prick, patch, and intradermal tests are the most readily available tools for the evaluation of hypersensitivity drug reactions. A skin test reaction to a drug tested in a concentration that does not cause a reaction in a sufficient number of controls is indicative of a drug allergy and a potentially harmful drug provocation test can be avoided. However, for many drugs, the diagnostic value of skin tests still has not been fully established because optimal skin test concentrations are not readily known. The most important information for allergists is the skin test concentrations, which may be used in drug allergy and this is only well-known for betalactam drugs. Reliable skin test concentrations for other drugs have to be defined, and these test concentrations will have to be validated for later multicenter studies as it is now done in the field of contrast media. For some drugs multiple data on skin test concentrations can be found in the literature, especially for muscle relaxants, insulins, platinum salts, streptokinase, and chymopapain, but for a multitude of other drugs these consist of case reports and case series. As an aid to the practicing allergist in the community, but also as a prerequisite to be able to perform multicenter studies, optimal skin test concentrations should be published. The aim of this task force is to review the literature and own data on optimal test concentrations for all available drugs, evaluate the grade of evidence to support the proposed concentrations and publish the results. A draft of the document will be prepared and discussed during the autumn meeting in Nancy this year.

Upcoming meetings

- 3 – 5 November 2010 Autumn meeting in Nancy
- IG meeting during EAACI Istanbul in 2011
- Drug Hypersensitivity Meeting V in Munich in 2012

Recent papers

- K. Brockow, A. Romano, W. Aberer, A.J. Bircher, A. Barbaud, P. Bonadonna, E. Faria, G. Kanny, M. Lerch, W.J. Pichler, J. Ring, J. Rodrigues Cernadas, E. Tomaz, P. Demoly, C. Christiansen. Skin testing in patients with hypersensitivity reactions to iodinated contrast media – a European multicenter study. Allergy. 2009; 64:234-41.
- Bousquet PJ, Demoly P, Romano A, Aberer W, Bircher A, Blanca M, Brockow K, Pichler W, Torres MJ, Terreehorst I, Arnoux B, Atanaskovic-Markovic M, Barbaud A, Bijl A, Bonadonna P, Burney PG, Caimmi S, Canonica GW, Cernadas J, Dahlen B, Daures JP, Fernandez J, Gomes E, Gueant JL, Kowalski ML, Kvedariene V, Mertes PM, Martins P, Nizankowska-Mogilnicka E, Papadopulos N, Ponvert C, Pirmohamed M, Ring J, Salapatas M, Sanz ML, Szczeklik A, Van Ganse E, De Weck AL, Zuberbier T, Merk HF, Sachs B, Sidoroff A. Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project. Allergy 2009; 64:194-203
- Blanca M, Romano A, Torres MJ, Fernandez J, Mayorga C, Rodriguez J, Demoly P, Bosquet PJ, Merk HF, Sanz ML, Ott H, Atanaskovic-Markovic M, and ENDA members. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009; 64:183-193.
J.R. Cernadas, A. Romano, K. Brockow, W. Aberer, M.J. Torres, A. Bircher P. Campi, M.L. Sanz, M. Castells, P. Demoly, W.J. Pichler. General considerations on     rapid desensitization for drug hypersensitivity – a consensus statement. Allergy (in press)
M. L. Kowalski, J. S. Makowska,  M. Blanca , S.Bavbek, G. Bochenek,  J. Bousquet, P. Bousquet, G.Celik, P. Demoly, E. Rebelo Gomes, E. Nizankowska-Mogilnicka, A.Romano, M. Sanchez-Borges, M.J. Torres, A. De Weck,  A. Szczeklik, K. Brockow Hypersensitivity to Non- Steroidal Anti-Inflammatory Drugs (NSAIDs) – classification, diagnosis and management. Review of the EAACI/ENDA and GA2LEN/HANNA guidelines. Allergy (in press)
K. Scherer, et al.
Desensitization in delayed drug hypersensitivity reactions (Manuscripts in preparation)

Further recommended articles from the Drug Hypersensitivity Interest Group:

Reducing the risk of anaphylaxis during anaesthesia: guideline for clinical practice. PM Mertes for ENDA. J Investig Allergol Clin Immunol 2005; 15(2):91-101

Management of hypersensitivity reactions to iodinated contrast media. Brockow K for ENDA. Allergy. 2005 Feb;60(2):150-8

The Drug Ambassador Project. E. Gomes for ENDA. Allergy Clin Immunol Int - J Worl Allergy Org 2005,17:1

Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Romano A for ENDA. Allergy. 2004 Nov;59(11):1153-60

Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. W Aberer for ENDA. Allergy 2003, 58:854-8

Diagnosis of immediate allergic reactions to beta-lactam antibiotics. MJ.Torres for ENDA. Allergy 2003, 58,10:961-1082

General Considerations for Skin Tests Procedures in the Diagnosis of Drug Hypersensitivity. K Brockow for ENDA. Allergy 2002, 57:45-51

Drug Hypersensitivity: Questionnaire. P Demoly for ENDA. ALLERGY 1999, 54:999-1003