pharmacovigilance of drug allergy and hypersensitivity ... allergy and hypersensitivity.pdf ·...

Position Paper

Pharmacovigilance of drug allergy and hypersensitivity using the

ENDA–DAHD database and the GA2LEN platform. The

Galenda project

Nonallergic hypersensitivity and allergic reactions are part of the many differenttypes of adverse drug reactions (ADRs). Databases exist for the collection ofADRs. Spontaneous reporting makes up the core data-generating system ofpharmacovigilance, but there is a large under-estimation of allergy/hypersensi-tivity drug reactions. A specific database is therefore required for drug allergyand hypersensitivity using standard operating procedures (SOPs), as the diag-nosis of drug allergy/hypersensitivity is difficult and current pharmacovigilancealgorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for DrugAllergy (ENDA) under the aegis of the European Academy of Allergology andClinical Immunology and SOPs have been published. Based on ENDA andGlobal Allergy and Asthma European Network (GA2LEN, EU FrameworkProgramme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD�)has been established under FileMaker� Pro 9. It is already available online inmany different languages and can be accessed using a personal login. GA2LEN isa European network of 27 partners (16 countries) and 59 collaborating centres(26 countries), which can coordinate and implement the DAHD across Europe.The GA2LEN–ENDA–DAHD platform interacting with a pharmacovigilancenetwork appears to be of great interest for the reporting of allergy/hypersensi-tivity ADRs in conjunction with other pharmacovigilance instruments.

P.-J. Bousquet1,2*,†, P. Demoly1*,†,A. Romano3,4*,†, W. Aberer5,A. Bircher6, M. Blanca7, K. Brockow8,W. Pichler9, M. J. Torres7,I. Terreehorst10, B. Arnoux2,M. Atanaskovic-Markovic11,A. Barbaud12, A. Bijl13, P.Bonadonna14, P. G. Burney15,S. Caimmi2*, G. W. Canonica16,J. Cernadas17, B. Dahlen18*,J.-P. Daures1, J. Fernandez19,E. Gomes20, J.-L. Gueant21,M. L. Kowalski22, V. Kvedariene23,P.-M. Mertes24, P. Martins25,E. Nizankowska-Mogilnicka26,N. Papadopoulos27, C. Ponvert28,M. Pirmohamed29, J. Ring8,M. Salapatas30*, M. L. Sanz31,A. Szczeklik26, E. Van Ganse32,A. L. De Weck31, T. Zuberbier33,H. F. Merk34, B. Sachs34, A. Sidoroff35,Global Allergy, Asthma EuropeanNetwork (GA2LEN) and Drug Allergyand Hypersensitivity Database(DAHD) and the European Networkfor Drug Allergy (ENDA)1D�partement de Biostatistique Epid�miologie Clinique,Sant� Publique et Information M�dicale, GHUCar�meau, CHU N�mes, N�mes cedex 9, France;2Exploration des Allergies, H�pital Arnaud deVilleneuve, CHU Montpellier, Montpelliercedex 5,France; 3Department of Internal Medicine andGeriatrics, UCSC-Allergy Unit, Complesso IntegratoColumbus, Rome, Italy; 4IRCCS Oasi Maria S.S., Troina,Italy; 5Medizinische Universit�t Graz, Graz, Austria;6Allergy Unit, University Hospital Basel, Basel,Switzerland; 7Research Unit for Allergic Diseases,Allergy Service, Carlos Haya Hospital, Malaga, Spain;8Department of Dermatology and Allergy Biederstein,Helmholtz Zentrum/Tum Technische UniversitaetMuenchen, Munich, Germany; 9Division of Allergology,Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspitel, Berne, Switzerland;10Amsterdam University, the Netherlands; 11UniversityChildren�s Hospital, Belgrade, Serbia; 12DermatologyDepartment, Fournier Hospital, Nancy, France;13Nederlands Bijwerkingen Centrum Lareb, MH�s-Hertogenbosch, the Netherlands; 14Allergy Service,

Allergy 2009: 64: 194–203 � 2009 The AuthorsJournal compilation � 2009 Blackwell Munksgaard

DOI: 10.1111/j.1398-9995.2008.01944.x

194

Verona General Hospital, Verona, Italy; 15RespiratoryEpidemiology & Public Health, Imperial College,London, UK; 16Allergy & Respiratory Diseases Clinic,University of Genova, Genova, Italy; 17Allergy andClinical Immunology Division, Hospital S¼o Jo¼o EPE,Porto, Portugal; 18Karolinska Institute, Stockholm,Sweden; 19Allergy Section, Department of Medicine,Elche Hospital, Elche, Spain; 20Department of Allergyand Clinical Immunology, Centro Hospitalar do Porto –Maria Pia Unit, Porto, Portugal; 21Inserm U-724,Laboratoire de Pathologie Cellulaire et Mol�culaire enNutrition and Department of Clinical Biochemistry,University Hospital Centre, Nancy, France; 22MedicalUniversity of Lodz, Lodz, Poland; 23Vilnius University,Medical Faculty and Center of Pulmonology andAllergology, Vilnius University Hospital Santariskiuklinikos, Vilnius, Lithuania; 24Service d�Anesth�sie-R�animation, H�pital Central, Centre HospitalierUniversitaire, Nancy, France; 25University of Lisbon,Portugal; 26Jagiellonian University School of Medicine,Krakow, Poland; 27Allergy Research Center, Universityof Athens, Athens, Greece; 28H�pital Necker, Paris,France; 29Department of Pharmacology, University ofLiverpool, Liverpool, UK; 30EFA, European Federation ofAllergy and Airway Diseases Patients Association;31Department of Allergology and Clinical Immunology,University Clinic, University of Navarra, Pamplona,Spain; 32Pharmacoepidemiology Unit, CentreHospitalier Universitaire, Lyon, France; 33Department ofDermatology and Allergy, Allergie-Centrum-Charit�,Charit�, Berlin, Germany; 34Department of Dermatology& Allergology, University Hospital of RWTH-Aachen,Germany; 35Department of Dermatology andVenereology, Medical University of Innsbruck,Innsbruck, Austria

Key words: drug allergy; database; DAHD; GA2LEN;ENDA.

Philippe-Jean BousquetD�partement de Biostatistique Epid�miologieCliniqueSant� Publique et Information M�dicaleGHU Car�meauCHU N�mes30 029 N�mes cedex 9France

*Member of GA2LEN (Global Allergy and AsthmaEuropean Network), supported by the Sixth EUFramework programme for research, contract no.FOOD-CT-2004-506378.

�The first three authors have participated equallyto the paper.

Accepted for publication 30 September 2008

Abbreviations: ADR, adverse drug reaction; CDISC, Clinical Data Interchange Standards Consortium; CM, contrast media; DAHD, DrugAllergy and Hypersensitivity Database; DIHS, drug-induced hypersensitivity syndrome; DPT, drug provocation test; DRESS, drug reactionwith eosinophilia and systemic symptoms; EAACI, European Academy of Allergology and Clinical Immunology; EFA, European Federationof Allergy and Airways Disease Patients; EMEA, European Medicines Agency; ENDA, European Network for Drug Allergy; FP, EUFramework Programme; GA2LEN, Global Allergy and Asthma European Network; ICD, International Classification of Diseases; INN,International Nonproprietary Names; MedDRA, Medical Dictionary for Regulatory Activities; NCA, national competent medicinesauthorities; SCAR, severe cutaneous adverse reaction; SOP, standard operating procedure.

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� 2009 The AuthorsJournal compilation � 2009 Blackwell Munksgaard Allergy 2009: 64: 194–203 195

Adverse drug reactions (ADRs) encompass all adverseevents related to drug administration, regardless ofaetiology and pathogenic mechanism. An ADR is definedby the World Heath Organization as a noxious andunintended response to a drug occurring at a dosenormally used in man (1). The traditional pharmaco-logical classification of ADRs separates them into twomajor subtypes: type A reactions, which are dose-depen-dent and predictable and type B reactions, which are notdose-dependent and which are unpredictable. A majorityof ADRs are of type A (2). Type B reactions compriseapproximately 10–15% of all ADRs and include hyper-sensitivity drug reactions. According to the Nomencla-ture Review Committee of the World AllergyOrganization, the term �hypersensitivity� should be usedto describe objectively reproducible symptoms or signsinitiated by exposure to a defined stimulus at a dosetolerated by normal persons. This Committee alsodistinguishes allergic hypersensitivity reactions fromnonallergic ones. Drug allergy refers to a hypersensitivityreaction where a definite immunological mechanism,either IgE or T-cell mediated, is demonstrated, whilenonallergic hypersensitivity refers to reactions, such asthose to acetylsalicylic acid, in which other pathogenicmechanisms play a role (3). Therefore, the terms �drugallergy� and �drug hypersensitivity� should not be usedinterchangeably. �Drug allergy� should be used only for anADR in which an immunological mechanism has beendemonstrated (4). In contrast, drug hypersensitivity is amuch broader term with extremely diverse presentation,including IgE-mediated allergic reactions in the form ofimmediate anaphylactic shock or generalized urticariaand/or angioedema and/or bronchospasm (4) as well asnonimmunological reactions and nonimmediate reac-tions, which typically occur several days after the elicitingdrug administration (5–7). These late reactions areextremely polymorphic and occur in the form of urticaria,maculopapular eruptions, fixed drug eruptions, acutegeneralized exanthematic pustulosis, vasculitis, toxic epi-dermal necrolysis, Stevens-Johnson syndrome or drugreaction with eosinophilia and systemic symptoms(DRESS)/drug-induced hypersensitivity syndrome(DIHS). A classification has been recently proposed forbiological agents (8).Adverse drug reactions affect 10–20% of hospitalized

patients and more than 7% of the general population.They represent more than 15% of all ADRs (9). Theymay be potentially life-threatening, prolong hospitaliza-tion, affect the drug prescribing patterns of physiciansand result in socioeconomic costs. Moreover, they areone of the main causes for drug withdrawal from themarket and thus of great financial importance for thepharmaceutical industry. Apart from the ongoing Reg-iscar project, which focuses on severe cutaneousreactions (10–12) only, as well as a few nationalcontinuous surveys such as the French Groupe d�etudedes reactions anaphylactoides peranesthesiques survey

on anaphylaxis during general anaesthesia (13), well-designed epidemiological studies on drug hypersensitiv-ity reactions are lacking as most studies have focusedon ADRs in general. A connection between clinicalmanifestations and drug intake is rarely proven andboth under-diagnosis and over-diagnosis must be takeninto account. Severe reactions including anaphylaxis,drug hypersensitivity syndromes, DRESS/DIHS,Stevens-Johnson syndrome/toxic epidermal necrolysis,vasculitis and hepatitis are also associated with signi-ficant morbidity and mortality.

Databases exist for the collection of ADRs. Sponta-neous reporting forms the core data-generating systemof pharmacovigilance, relying on healthcare profession-als (and in some places consumers) to identify andreport any suspected ADR (14). One of this system�smajor weaknesses is under-reporting (15), though thefigures vary greatly between countries and in relation tominor and serious ADRs. Another problem is thatmedical personnel do not always consider reporting asa priority if the symptoms are not serious and ADRsmay not be recognized as the effect of a particular drug(16). Moreover, allergic ADRs are not easily deter-mined and need a specific diagnosis work-up as shownby the inaccuracy of pharmacovigilance algorithms (17).

There is therefore a need for a specific database on drugallergy and hypersensitivity using standard operatingprocedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult (18) and current pharmaco-surveillance algorithms are insufficient (17).

History suggestive of drug allergyto §-lactam

Skin prick test

Intradermalskin test

Positive Negative

Positive Negative

Oral challenge

Positive Negative

Drug allergy

Figure 1. Diagnostic work up of immediate drug allergy toß-lactams.

Bousquet et al.

� 2009 The Authors196 Journal compilation � 2009 Blackwell Munksgaard Allergy 2009: 64: 194–203

ENDA and GA2LEN SOPs for the diagnosis of drug allergyand hypersensitivity

The patient�s history is fundamental in the diagnosis ofdrug allergy/hypersensitivity and the allergological exam-ination includes in vivo and in vitro tests selected on thebasis of clinical features (18). Prick, intradermal and patchtests are the most readily available forms of allergy testingbut, for many drugs, have not been standardized. Thedetermination of specific IgE levels is still the most widelyaccessible in vitro method for diagnosing immediatereactions. However, as most drugs cannot be tested, thismethod is available only for a fewdrugs and its sensitivity is

often insufficient. The basophil activation test and thelymphocyte proliferation assays test may increase thesensitivity of diagnostic work-ups, but more data arerequired to allow their use in routine. There is an urgentneed to obtain appropriate reagents for the diagnosisof drug allergy/hypersensitivity (19). In many patients,provocation tests are needed to confirm the diagnosis.

Although difficult, the allergy diagnosis of reactions tomany drugs has been standardized by the EuropeanNetwork for Drug Allergy (ENDA) of the EuropeanAcademy of Allergology and Clinical Immunology(EAACI, http://www.eaaci.net) and SOPs have been pub-lished (Fig. 1). ENDA was initiated as a EU Framework

Figure 2. ENDA questionnaire.

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Programme 3 (FP3 EU) project and has been self-sustainable following EU funding. This network is uniquein the world and is linked with the EAACI Drug AllergyInterest Group focusing on improvement in diagnosingpatients with drug allergy/hypersensitivity. Moreover, ithelps in the organization of drug allergy teaching withinEAACI and undertakes collaborative research. Itinvolves several groups from all over Europe.For an accurate diagnosis, the method shown in Fig. 1

was proposed. A detailed history is of paramountimportance as to whether a certain disease reflects drughypersensitivity and regarding the question of which drugis causing the reaction. To facilitate the recording of anappropriate history and to harmonize this procedure inEurope, the members of ENDA have developed aquestionnaire, which provides a standardized guide inthis difficult area of clinical medicine (20). It takes onlyabout 5–6 min to complete this standardized protocolwhich has been translated into many languages (Fig. 2)and which is available online (http://www.eaaci.net). Thequestionnaire is a practical compromise, as it combinesquestions and investigations which are important for theacute as well as remission stages. It emphasizes theclinical status (skin and internal involvement) andincludes some laboratory markers available in all clinicallaboratories that are of potential interest in drug hyper-sensitivity reactions (blood differential, liver and kidneyparameters). These aspects of the history and the exam-inations represent a common denominator within thedifferent European centres using this protocol.Skin tests represent an essential tool for the diagnosis

of drug allergy, although many drugs cannot be tested(21–23). The standardized procedure for immediate skintests to ß-lactams, the most common class of drug-induced allergic reactions, has been published by ENDA(22, 24, 36). Particular caution should be taken duringtesting, starting with the appropriate dilutions of thestock reagents, as some systemic reactions have beenobserved during skin tests (25).In vitro tests can be used in drug allergy/hypersensitiv-

ity, but they are usually less sensitive and/or specific thanthose used for inhalant allergy (26). There has been someprogress for detecting specific IgE to chlorhexidine orrocuronium, but these commercially-available methodsfor IgE detection are still quite limited and their relevanceis unclear (27). Although promising, some cellular tests,such as histamine release, basophil activation (28, 29),cysteinyl-leukotriene release or T-cell based assays(proliferation, activation) (30, 31), are interesting researchtools. Their sensitivity and specificity vary across centresand still require further validation.The standardized methodology for drug provocation

tests (DPTs), the controlled administration of a drug todiagnose drug allergy/hypersensitivity reactions, has beenpublished by ENDA (32). An accurate identification ofthe agent inducing a patient�s hypersensitivity reaction isimportant, as the consequences of the diagnosis can be

severe. Confirmation of a presumptive diagnosis by aDPT is often the only reliable way to establish adiagnosis. This procedure should only be undertakenwith great caution and a compelling need, as DPTs canalso cause life-threatening reactions. As a consequence,they are not suitable for many situations. The testperformance should follow established criteria andrespect the many limitations, potentially leading tofalse-positive or false-negative test results. Finally, fordelayed reactions, protocols are still not standardized.

Causality and imputation must follow defined rules.The �WHO Drug Monitoring Program� suggests thefollowing terms: certain, probable/likely, possible,unlikely, conditional/unclassified and unassessible/unclassifiable (33). However, even a negative DPT isnot an absolute guarantee for tolerance. Altogether, drugallergy diagnosis does not have a 100% predictive valueand must be relied on combination of history, in vivo andin vitro tests. Moreover, they may not necessarily predictabsolute life-long tolerance upon future exposure(as proven in food allergy testing).

The methodology for provocation tests with aspirinand nonsteroidal anti-inflammatory agents follows theGA2LEN–EAACI guidelines (34).

Nonimmediate manifestations (i.e. occurring morethan 1 h after drug administration), particularly maculo-papular and urticarial eruptions, are common, especiallyduring ß-lactam treatment (35). The mechanisms involvedin most nonimmediate reactions seem to be heteroge-neous and are not yet all completely understood (36).However, clinical and immunohistological studies, as wellas the analysis of drug-specific T-cell clones obtainedfrom the circulating blood and the skin, suggest that atype-IV (cell-mediated) pathogenic mechanism may beinvolved in many nonimmediate reactions such as macu-lopapular or bullous eruptions and acute generalizedexanthematous pustulosis (5, 6). In the ENDA diagnosticalgorithm for evaluating nonimmediate reactions toß-lactams (36), both patch tests and delayed-readingintradermal tests are proposed. In the case of negativeresults in such tests, consideration should be given toprovocation tests and to the careful administration of thesuspect agents. With regard to in vitro tests, the lympho-cyte transformation test may contribute to the identifica-tion of the responsible drug, but is not widely available.

All iodinated contrast media (CM) are known to causeboth immediate ( £ 1 h) and nonimmediate (>1 h) hyper-sensitivity reactions (37). Although allergic hypersensitivitycannot be demonstrated for most immediate reactions,recent studies indicate that the severe immediate reactionsmay be IgE-mediated, while most of the nonimmediateexanthematous skin reactions appear to be T-cell mediated.Patients who experience such hypersensitivity reactions aretherefore advised to undergo allergological evaluation.Several investigators have found skin testing to be useful inconfirming a CM allergy, especially in patients withnonimmediate skin eruptions (38). ENDA has also

Bousquet et al.


provided information on the diagnosis and preventionof hypersensitivity reactions to iodinated CM (37).Severe and sometimes fatal reactions to general anaes-

thetics may occur. The diagnosis of these reactionsfollows the guidelines of the Societe Francaise d�Anes-thesiologie et de Reanimation published in collaborationwith ENDA (39).

The DAHD� based on ENDA

The Drug Allergy and Hypersensitivity Database(DAHD�) is a historical prospective, mixed cohort,which was developed in the Allergy Department of theMontpellier University Hospital in collaboration withINSERM. As an epidemiological and pharmacovigilancetool, DAHD was designed to store information onpatients having undergone a standardized procedure ofdrug allergy/hypersensitivity diagnosis following theENDA recommendations (20, 22, 32, 36, 37). After adetailed clinical history, patients with a compatiblehistory of drug allergy/hypersensitivity are tested in theabsence of any contraindication. Depending on the drugs,patients undergo skin tests (prick tests, intradermal tests),in vitro tests and then allergen challenges. For cutaneousdrugs, patch tests are also performed. Those with a severecutaneous reaction (toxic epidermal necrolysis or Stevens-Johnson syndromes), vasculitis, multi-organs failureincluding DRESS are not challenged because of possibleserious, systemic and uncontrollable events (40–42). Thework up in these reactions should be standardized,starting with in vitro tests and limited to patch tests atthe lowest reagent concentrations (only when an alterna-tive is not available). At the end of the procedure, patientsare identified as �sensitive� or �not sensitive� to the testeddrugs (suspected and alternative ones). There is also theProject on Severe Cutaneaous Adverse Drug Reactions(RegisCAR) (http://regiscar.uni-freiburg.de). This is aEuropean Registry of severe cutaneous adverse reaction(SCAR) for the continuous surveillance of new drugswith adequate pharmacoepidemiological methods, whichcollects samples to study the phenotype of patients (43).

DAHD

The database was developed under FileMaker� Pro 9(http://www.filemaker.com), allowing an easy onlineaccess (using the Internet network). The database has beentranslated into several languages including Dutch, French,English and Portuguese and can be translated into anyother language as required. The choice of the platform wasmade to comply with the most recent standardized proce-dures: the Clinical Data Interchange Standards Consor-tium (CDISC, http://www.cdisc.org) standard, even ifDAHD is not a clinical trial database. TheCDISChas beendeveloped to support global, platform-independent datastandards that enable information system interoperability

to improve medical research and related areas of healthcare. It integrates Food and Drug Administration andEuropean Medicines Agency (EMEA) recommendationson databases. As with all databases, it promotes consistentdata entry and retrieval, and reduces the existence ofduplicate data among the database tables.

Security and privacy of the patient

Drug Allergy and Hypersensitivity Database is availableonline using a personal login and a centre affiliation. Thisaccess can be restricted to a read-only. To ensure confi-dentiality of the information and a higher security level,only the DAHD administrator can access the entiredatabase. However, a country coordinator can access datafrom a single country after acceptance from the othercountry centres. Additionally, it is not possible to exportdata (i.e. in a comma separated value or text file) using anon-line access. This function is restricted to the DAHDadministrator, guarantying an optimal level of security.DAHD is an anonymous database registered by theComiteNational Informatique et Liberte (http://www.cnil.fr), theFrench regulatory institution for databases and electronicfiles. It is therefore impossible to access information using aname, address, patient hospital electronic folder number ornational insurance number. To allow an inter-operabilitywith the pharmacovigilance systems, each medical centreusing DAHD keeps a local file linking the anonymitynumber to the patient�s identity.

Information

This multi-table database registers demographic charac-teristics, atopy or asthma as well as medical historiesinvolving a suspicion of drug allergy/hypersensitivity andall the tests performed. For each medical suspicion, thefollowing data are collected: date, symptoms, delaybetween drug intake and clinical symptoms, drug names.A specific algorithm allows an automatic conversion fromclinical symptoms to a symptom group such as anaphy-laxis or anaphylactic shock. Finally, the date of testing,the molecule and the reactions are collected for each test.This database structure allows specific research onsymptoms, symptom classes or positive tests.

Symptom terms

Drug Allergy and Hypersensitivity Database codes theENDA questionnaire in medical terms. However, it iscurrently being checked as to whether these terms can becoded according to Medical Dictionary for RegulatoryActivities (MedDRA) (44, 45), a clinically validatedinternational medical terminology used by regulatoryauthorities in many countries. In addition, MedDRA isthe adverse event classification dictionary endorsed by theInternational Conference on Harmonization of TechnicalRequirements for Registration of Pharmaceuticals for

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Human Use (45). It incorporates the most importantterminology dictionary, which includes the World HealthOrganization Adverse Reaction Terminology, regulatory-related terminology from the International Classificationof Diseases (ICD), regulatory-related terminology fromthe ICD with clinical modification and the codingsymbols for a thesaurus of adverse reaction terms.EudraVigilance�, the European Union pharmacovigi-lance system, uses the MedDRA terms.

Drug code

Drugs included in the database are coded using either theircommercial name or their International NonproprietaryName (INN), i.e. the scientific (active molecule) name.Additionally, each commercial name is linked to itsrespective INN (one or more, depending on the number ofactive molecules included in the drug). Finally, an internallink enables a grouping according to the drug class, forinstance, nonsteroidal anti-inflammatory drug, ß-lactamor penicillin/cephalosporin. Using these different links, it ispossible to perform specific searches on the commercialname or on the INN drug class (Fig. 3). A search involvingseveral countries can also be performed even if thecommercial names are different between countries.

Current use

Drug Allergy and Hypersensitivity Database is usedprospectively in Montpellier and involves over 3500patients, including around 800 with positive skin testsor challenges. It has also started in Rome, Malaga andLeiden. Using these data, several studies have beenpublished from the Montpellier data (mainly on beta-lactam allergy) (25, 27, 35, 38, 46) or as a part of a multi-centre analysis (radio-CM European survey).Through this network, standardized questionnaires and

methods will be distributed throughout Europe, optimiz-ing diagnosis and pharmacovigilance tools. These toolswill not be based on suspicion only, but also on confirmeddiagnosis. At large, pharmacovigilance can be increased,reporting all cases of proven drug allergy/hypersensitiv-ity. In accordance with European authorities, a sanitarysurvey can be established for newly developed drugs aswell as for the older ones.

Interactions between ENDA–DAHD and GA2LEN

Global Allergy and Asthma European Network(GA2LEN, FP6) is a European network of 27 partners(16 countries) and 59 collaborating centres (26 countries)(47). Interaction is optimal between allergists, respiratoryphysicians, paediatricians, ENT physicians, dermatolo-gists, General Practitioners, epidemiologists, methodolo-gists, basic scientists and patients. All methods needed fora project on allergy as well as asthma and related diseasesare regularly used in the ongoing network and theharmonization of methods within centres has beenestablished (2004–2009). GA2LEN uses SOPs for diag-nosis, sampling procedures and exchange of samples (48,49). A particular effort has been made to standardizemethods within and between centres (49). Severalnetworks have been established in GA2LEN. ENDA isa GA2LEN collaborating centre.

One challenge for asthma and allergy is to match thecomplexity of the diseases which are dependent on manyfactors including gene, environment and age. It is thereforenecessary to have a generic platform with a networkembeddingall areasofEurope andall age groups.GA2LENis presently designing a generic platform for allergy andasthma derived from the current FP6 network of excellencewith key characteristics (efficiency, modularity, flexibility,expansibility, scalability and cost-effectiveness). Usingmodularity and flexibility, this generic platform may beused for different purposes including a network ofDAHD�

(Fig. 4). Flexibility will be met by a federated, multilayerarchitecture in which independent components, datasources, scientific services and links can be configureddynamically and articulated by rules and ethic. TheGA2LEN platform allows this modularity and flexibilityas it uses the same interface between modules and the sameorganization. Moreover, the data management to bedeveloped will provide the system with feedback channelsfrom the differentmodules with closed-loop configurations.

In each country, a GA2LEN centre will be the singleDAHD� centre or coordinator of DAHD� centres.Many of these are already GA2LEN partners or collab-orating centres, and any one may become a new collab-orating centre. The same methodology will be usedthroughout Europe to diagnose and report drug allergy/hypersensitivity using the best available methods. Know-ledge transfer will be needed for some centres andGA2LEN will help in the training of investigators andin the accreditation of centres using the usual proceduresdeveloped and implemented by GA2LEN. This willconsiderably increase the education of the personnelwithin all centres across Europe concerning drug allergy/hypersensitivity and adequate ADR reporting.

European Federation of Allergy and Airways DiseasePatients (EFA) is a GA2LEN partner and will be activelyassociated with the GA2LEN–ENDA–DAHD platform.

This platform will use GA2LEN expertise in thedissemination of results to all stakeholders including

ClamoxylBristamox

ÉAmoxicillin

Ampicillin

ILA

ILC

Beta-lactam

Name

AgramAmoxicillin

sodiumILA

Molecule

Beta-lactam

Beta-lactam

Internal

Links

Code

DAHD

Figure 3. Drug coding.

Bousquet et al.


physicians, patients (EFA), media and politicians toincrease awareness and reporting on drug allergy/hyper-sensitivity, which is often largely underestimated.

Interactions of the GA2LEN–ENDA–DHAD platform withpharmacovigilance networks

Pharmacovigilance is the continual monitoring of adverseeffects and other safety-related aspects of marketedmedications, biological products, herbal drug and tradi-tional medicines with a view to identifying new informa-tion regarding hazards associated with medicines andpreventing harm to patients. It is essential to have athorough postmarketing surveillance system of marketedproducts to ensure a positive benefit: risk balance ofmedicines. In the past, pharmacovigilance tended to be aprocess focusing on spontaneous reporting, which wasoften insufficient to allow meaningful assessment becauseof under reporting and poor data quality (50).Pharmacovigilance in Europe is coordinated by the

EMEAandconductedby thenational competentmedicinesauthorities (NCA).One of the responsibilities of theEMEAis to maintain and develop the pharmacovigilance databaseconsisting of all suspected serious adverse reactions tomedicines observed in the European Union. The system,called EudraVigilance�, is a data-processing network andmanagement system for reporting and evaluating suspectedADR during the development and following the marketingauthorization of medicinal products (http://eudravigi-lance.emea.europa.eu). The EudraVigilance Post-Authori-sation Module is designed for postauthorization ICSRs,Regulation (EC) No 726/2004, Directive 2001/83/EC.Reporting is one of the limitations of pharmacovigi-

lance, and this is particularly true for drug allergy andhypersensitivity reactions (51–57). Moreover, for drugallergy, reports are often limited to severe reactions suchas anaphylaxis and anaphylactic shock or SCAR. Otherreactions, like urticaria or maculopapular exanthema,which are the most common, are barely reported inpharmacovigilance databases.Another limitation, more specific to drug allergy, is the

inadequacy of pharmacovigilance algorithms (17). This

limitation is linked to several problems. First of all, clinicaldata can be insufficient, making the use of the algorithmsimpossible (lack of criteria). Additionally, it is sometimesdifficult to define the culprit drug whenmore than one drugwas taken at the time of the reaction. Moreover, drugallergy/hypersensitivity reactions can occur at any timefrom the onset of the treatment, even after years of use.Finally, inmany cases, the clinical reaction can be either theconsequence of the disease or of the drug (e.g. a maculo-papular reaction during a viral infection and a concomitantuse of analgesic drugs or antibiotics).

Therefore, there is a need for a complementary system tocollect accurately diagnosed drug allergy/hypersensitivityreactions. This will be an important shift to a moreproactive approach, requiring a broadening evidence baseand a widening of expertise, resources and methodologies.

The GA2LEN–ENDA–DAHD platform interactingwith a pharmacovigilance network appears to be of greatinterest for the reporting of drug allergy/hypersensitivityADRs in conjunction with other pharmacovigilanceinstruments. The aim is to expedite the generation ofmore and more reliable pharmacoepidemiological datafor proactive pharmacovigilance and risk management ofmedicines throughout their life-cycle.

European Medicines Agency is developing the Euro-pean Network for Centers for Pharmacoepidemiologyand Pharmacovigilance (http://www.emea.europa.eu)and the GA2LEN–ENDA–DHAD platform may be ofinterest within this network.

A change of focus is expected in pharmacovigilance,which will require the inclusion of disciplines such asadvanced epidemiology, biostatistics, drug utilization,pharmacoepidemiology and the use of large automatedpopulation-based exposure-outcome databases. There isthus a pressing need to expand the knowledge ofpharmacovigilance professionals to support proactivepharmacovigilance and risk management of medicinesthroughout their life-cycle. An understanding of phar-macovigilance is also needed for journalists and patientorganizations to improve their communication ofhazards associated with medicines. All these needs arealready used by GA2LEN through its disseminationprogrammes.

- Questionnaire for drug allergy- Immediate skin tests- Non-immediate skin tests- Provocation challenges- Radio-contrast media work-up- Anesthetics work-up

- Aspirin-NSAID challenges Dissemination of information (with EFA)

ENDA

GA2LEN-HANNA

Drug Allergy and Hypersensitivity

Database (DAHD)

GA2LEN centre in each EU country

Training of personnel

Certification of centres

Link with pharmacovigilance

Figure 4. Interactions between ENDA–DAHD and GA2LEN correct �centre� and �personnel�.

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Need for a network using a common database

• Although ENDA protocols are used by most majorgroups in Europe for the diagnosis of drug allergy/hypersensitivity reactions, a network will increase thestandardization of the procedure and will alsoincrease the number of centres using ENDAdiagnosis protocols.

• There are regional/national differences regardingdrug prescription.

• All drugs may induce hypersensitivity reactions, butthere is a need for a network to increase the numberof cases tested identically.

• A network will rapidly detect new reaction patterns(e.g. signal identification/detection).

• An exhaustive database will reinforce the epidemio-logical findings and risk factors.

Acknowledgments

The authors would like to thank Ms Anna Bedbrook for therevision of the paper.

References

1. WHO. International drug monitoring:the role of national centres. Tech RepSer 1972;498:1–25.

2. Rawlins MD, Thompson JW. Patho-genesis of adverse drug reactions. In:Davies DM, editor. Textbook of adversedrug reactions. Oxford: OxfordUniversity Press, 1977:10–45.

3. Johansson SG, Bieber T, Dahl R,Friedmann PS, Lanier BQ, Lockey RFet al. Revised nomenclature for allergyfor global use: Report of the Nomen-clature Review Committee of the WorldAllergy Organization, October 2003.J Allergy Clin Immunol 2004;113:832–836.

4. Sanchez E, Torres MJ, Mayorga C,Reche M, Padial A, Romano A et al.Adverse drug reactions with an immu-nological basis: from clinical practice tobasic research. Allergy 2002;57(Suppl.72):41–44.

5. Pichler WJ. Delayed drug hypersensi-tivity reactions. Ann Intern Med 2003;139:683–693.

6. Posadas SJ, Pichler WJ. Delayed drughypersensitivity reactions – new con-cepts. Clin Exp Allergy 2007;37:989–999.

7. Roujeau JC. Immune mechanisms indrug allergy. Allergol Int 2006;55:27–33.

8. Pichler WJ. Adverse side-effects tobiological agents. Allergy 2006;61:912–920.

9. Guglielmi L, Guglielmi P, Demoly P.Drug hypersensitivity: epidemiologyand risk factors. Curr Pharm Des2006;12:3309–3312.

10. Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C,Roujeau JC. Nevirapine and the riskof Stevens-Johnson syndrome or toxicepidermal necrolysis. AIDS2001;15:1843–1848.

11. Mockenhaupt M, Viboud C, Dunant A,Naldi L, Halevy S, Bouwes Bavinck JNet al. Stevens-Johnson syndrome andtoxic epidermal necrolysis: assessment ofmedication risks with emphasis onrecently marketed drugs. The Euro-SCARstudy. J Invest Dermatol 2008;128:35–44.

12. Schneck J, Fagot JP, Sekula P, SassolasB, Roujeau JC, Mockenhaupt M.Effects of treatments on the mortalityof Stevens-Johnson syndrome and toxicepidermal necrolysis: a retrospectivestudy on patients included in the pro-spective EuroSCAR Study. J Am AcadDermatol 2008;58:33–40.

13. Laxenaire MC, Mertes PM. Anaphy-laxis during anaesthesia. Results of atwo-year survey in France. Br J Anaesth2001;87:549–558.

14. Lindquist M. The need for definitions inpharmacovigilance. Drug Saf 2007;30:825–830.

15. Edwards IR. The management ofadverse drug reactions: from diagnosisto signal. Therapie 2001;56:727–733.

16. Lindquist M. Data quality managementin pharmacovigilance. Drug Saf2004;27:857–870.

17. Benahmed S, Picot MC, Dumas F,Demoly P. Accuracy of a pharmaco-vigilance algorithm in diagnosing drughypersensitivity reactions. Arch InternMed 2005;165:1500–1505.

18. Romano A, Demoly P. Recent advancesin the diagnosis of drug allergy. CurrOpin Allergy Clin Immunol 2007;7:299–303.

19. Blanca M, Romano A, Torres MJ,Demoly P, DeWeck A. Continued needof appropriate betalactam-derived skintest reagents for the management ofallergy to betalactams. Clin Exp Allergy2007;37:166–173.

20. Demoly P, Kropf R, Bircher A, PichlerWJ.Drughypersensitivity:questionnaire.EAACI interest group on drug hypersen-sitivity. Allergy 1999;54:999–1003.

21. Brockow K, Romano A, Blanca M,Ring J, Pichler W, Demoly P. Generalconsiderations for skin test proceduresin the diagnosis of drug hypersensitivity.Allergy 2002;57:45–51.

22. Torres MJ, Blanca M, Fernandez J,Romano A, Weck A, Aberer W et al.Diagnosis of immediate allergic reac-tions to beta-lactam antibiotics. Allergy2003;58:961–972.

23. Torres MJ, Romano A, Mayorga C,Moya MC, Guzman AE, Reche M et al.Diagnostic evaluation of a large groupof patients with immediate allergy topenicillins: the role of skin testing.Allergy 2001;56:850–856.

24. Torres MJ, Blanca M. Importance ofskin testing with major and minordeterminants of benzylpenicillin in thediagnosis of allergy to betalactams.Statement from the European Networkfor Drug Allergy concerning AllergoPenwithdrawal. Allergy 2006;61:910–911.

25. Co Minh HB, Bousquet PJ, Fontaine C,Kvedariene V, Demoly P. Systemicreactions during skin tests with beta-lactams: a risk factor analysis. J AllergyClin Immunol 2006;117:466–468.

26. BlancaM,MayorgaC, TorresMJ,RecheM, Moya MC, Rodriguez JL et al. Clin-ical evaluation of Pharmacia CAP Sys-tem RAST FEIA amoxicilloyl andbenzylpenicilloyl in patients with peni-cillin allergy. Allergy 2001;56:862–870.

27. Fontaine C, Mayorga C, Bousquet PJ,Arnoux B, Torres MJ, Blanca M et al.Relevance of the determination ofserum-specific IgE antibodies in thediagnosis of immediate beta-lactamallergy. Allergy 2007;62:47–52.

Bousquet et al.


28. Kvedariene V, Kamey S, Ryckwaert Y,Rongier M, Bousquet J, Demoly Pet al. Diagnosis of neuromuscularblocking agent hypersensitivity reac-tions using cytofluorimetric analysisof basophils. Allergy 2006;61:311–315.

29. de Weck AL, Sanz ML, Gamboa PM,Aberer W, Bienvenu J, Blanca M et al.Diagnostic tests based on humanbasophils: more potentials and per-spectives than pitfalls. Int Arch AllergyImmunol 2008;146:177–189.

30. Beeler A, Zaccaria L, Kawabata T,Gerber BO, Pichler WJ. CD69 upregu-lation on T cells as an in vitro markerfor delayed-type drug hypersensitivity.Allergy 2008;63:181–188.

31. Pichler WJ, Tilch J. The lymphocytetransformation test in the diagnosisof drug hypersensitivity. Allergy2004;59:809–820.

32. Aberer W, Bircher A, Romano A,Blanca M, Campi P, Fernandez J et al.Drug provocation testing in the diag-nosis of drug hypersensitivity reactions:general considerations. Allergy 2003;58:854–863.

33. Venulet J, Ciucci AG, Berneker GC.Updating of a method for causalityassessment of adverse drug reactions.Int J Clin Pharmacol Ther Toxicol1986;24:559–568.

34. Nizankowska-Mogilnicka E, BochenekG, Mastalerz L, Swierczynska M,Dahlen B, Dahlen S et al. Aspirinprovocation tests for diagnosis ofaspirin sensitivity. EAACI/GA2LENguideline. Allergy 2007;62:1111–1118.

35. Bousquet PJ, Kvedariene V, Co-MinhHB, Martins P, Rongier M, Arnoux Bet al. Clinical presentation and timecourse in hypersensitivity reactionsto beta-lactams. Allergy 2007;62:872–876.

36. Romano A, Blanca M, Torres MJ,Bircher A, Aberer W, Brockow K et al.Diagnosis of non-immediate reactions tobeta-lactam antibiotics. Allergy 2004;59:1153–1160.

37. Brockow K, Christiansen C, Kanny G,Clement O, Barbaud A, Bircher A et al.Management of hypersensitivityreactions to iodinated contrast media.Allergy 2005;60:150–158.

38. Kvedariene V, Martins P, Rouanet L,Demoly P. Diagnosis of iodinated con-trast media hypersensitivity: results of a6-year period. Clin Exp Allergy 2006;36:1072–1077.

39. Mertes PM, Laxenaire MC, Lienhart A,Aberer W, Ring J, Pichler WJ et al.Reducing the risk of anaphylaxis duringanaesthesia: guidelines for clinical prac-tice. J Investig Allergol Clin Immunol2005;15:91–101.

40. Bachot N, Roujeau JC. Differentialdiagnosis of severe cutaneous drugeruptions. Am J Clin Dermatol 2003;4:561–572.

41. Bocquet H, Bagot M, Roujeau JC.Drug-induced pseudolymphoma anddrug hypersensitivity syndrome (drugrash with eosinophilia and systemicsymptoms: DRESS). Semin Cutan MedSurg 1996;15:250–257.

42. Roujeau JC. Clinical heterogeneity ofdrug hypersensitivity. Toxicology2005;209:123–129.

43. Lonjou C, Borot N, Sekula P, Ledger N,Thomas L, Halevy S et al. A Europeanstudy of HLA-B in Stevens-Johnsonsyndrome and toxic epidermal necrolysisrelated to five high-risk drugs. Pharma-cogenet Genomics 2008;18:99–107.

44. Brown EG. Using MedDRA: implica-tions for risk management. Drug Saf2004;27:591–602.

45. Brown EG, Wood L, Wood S. Themedical dictionary for regulatory activ-ities (MedDRA). Drug Saf 1999;20:109–117.

46. Bousquet PJ, Pipet A, Bousquet-Rouanet L, Demoly P. Oral challengesare needed in the diagnosis of beta-lactam hypersensitivity. Clin ExpAllergy 2008;38:185–190.

47. Van Cauwenberge P, Watelet JB, VanZele T, Bousquet J, Burney P, ZuberbierT. Spreading excellence in allergy andasthma: the GA2LEN (Global Allergyand Asthma European Network)project. Allergy 2005;60:858–864.

48. Heinzerling L, Frew AJ, Bindslev-Jensen C, Bonini S, Bousquet J,Bresciani M et al. Standard skin pricktesting and sensitization to inhalantallergens across Europe – a survey fromthe GALEN network. Allergy 2005;60:1287–1300.

49. Burney P, Potts J, Kowalski M, Joos G,Godnic-Cvar J, Skadhauge L et al. Acase-control study of the relationbetween plasma selenium in Europeanpopulations. A GA2LEN project.Allergy. 2008;63:865–871.

50. Strom B, Klimmel S. Textbook ofpharmacoepidemiology. Sussex: JohnWiley, 2006.

51. Conforti A, Leone R, Moretti U, MozzoF, Velo G. Adverse drug reactionsrelated to the use of NSAIDs with afocus on nimesulide: results of sponta-neous reporting from a northern Italianarea. Drug Saf 2001;24:1081–1090.

52. Leone R, Conforti A, Venegoni M,Motola D, Moretti U, Meneghelli Iet al. Drug-induced anaphylaxis: case/non-case study based on an Italianpharmacovigilance database. Drug Saf2005;28:547–556.

53. Sachs B, Fischer-Barth W, Erdmann S,Merk HF, Seebeck J. Anaphylaxis andtoxic epidermal necrolysis or Stevens-Johnson syndrome after nonmucosaltopical drug application: fact or fiction?Allergy 2007;62:877–883.

54. Sachs B, Riegel S, Seebeck J, Beier R,Schichler D, Barger A et al. Fluoroqui-nolone-associated anaphylaxis in spon-taneous adverse drug reaction reports inGermany: differences in reporting ratesbetween individual fluoroquinolonesand occurrence after first-ever use. DrugSaf 2006;29:1087–1100.

55. Durrieu G, Olivier P, Bagheri H,Montastruc JL. Overview of adversereactions to nefopam: an analysis ofthe French pharmacovigilance database.Fundam Clin Pharmacol 2007;21:555–558.

56. de Boer HJ, Hagemann U, Bate J,Meyboom RH. Allergic reactions tomedicines derived from Pelargoniumspecies. Drug Saf 2007;30:677–680.

57. Holdcroft A. UK drug analysis printsand anaesthetic adverse drug reactions.Pharmacoepidemiol Drug Saf 2007;16:316–328.

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