Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

RationaleDrug hypersensitivity to beta-lactam was often skin tested using benzyl-penicillin, major (PPL) and minor (MDM) penicillin determinants, amoxicillin, ampicillin and any other culprit beta-lactam. However, PPL and MDM were removed from the market. The aim of the study was to assess the influence of benzylpenicillin before and after the withdrawal.MethodsUsing our Drug Allergy and Hypersensitivity Database (3354 patients recorded from Montpellier and Rome), we conducted a historico-prospective cohort study. All patients who consulted, since 1996, for a suspected beta-lactam hypersensitivity reaction and who had at least positive skin test to benzylpenicillin were included. Diagnosis and skin tests followed the ENDA recommendations. Benzylpenicillin, PPL, MDM, Ampicillin, Amoxicillin were always skin tested.Results133 patients (48 – 36.1% men), 15 (11.3%) asthmatics and 41 (30.8%) atopics were included. 13 (9.8%) were only positive to benzylpenicillin, 32 (26.5%) were also positive for PPL and 66 (55.5%) for MDM. Without skin testing for PPL and MDM, the number of positive to benzylpenicillin increased to 20 (15.0%). No difference was observed for asthma and atopic between subjects only positive to benzylpencillin and those also positive for another penicillin (p = 0.84 and p = 0.34 respectively). Anaphylaxis and anaphylactic shock were more common in subjects positive to several penicillins (76 – 67.3% vs 7 – 35%, p = 0.001). Conversely, only 26 (23.0%) vs 8 (40.0%) presented an urticaria/angiodema.ConclusionsSince the withdrawal of PPL and MDM, benzylpenicillin skin test appeared to be mandatory, 15% of the patients being only positive to this drug. This should significantly reduce oral challenges. RationaleDrug hypersensitivity to beta-lactam was often skin tested using benzyl-penicillin, major (PPL) and minor (MDM) penicillin determinants, amoxicillin, ampicillin and any other culprit beta-lactam. However, PPL and MDM were removed from the market. The aim of the study was to assess the influence of benzylpenicillin before and after the withdrawal. Drug hypersensitivity to beta-lactam was often skin tested using benzyl-penicillin, major (PPL) and minor (MDM) penicillin determinants, amoxicillin, ampicillin and any other culprit beta-lactam. However, PPL and MDM were removed from the market. The aim of the study was to assess the influence of benzylpenicillin before and after the withdrawal. MethodsUsing our Drug Allergy and Hypersensitivity Database (3354 patients recorded from Montpellier and Rome), we conducted a historico-prospective cohort study. All patients who consulted, since 1996, for a suspected beta-lactam hypersensitivity reaction and who had at least positive skin test to benzylpenicillin were included. Diagnosis and skin tests followed the ENDA recommendations. Benzylpenicillin, PPL, MDM, Ampicillin, Amoxicillin were always skin tested. Using our Drug Allergy and Hypersensitivity Database (3354 patients recorded from Montpellier and Rome), we conducted a historico-prospective cohort study. All patients who consulted, since 1996, for a suspected beta-lactam hypersensitivity reaction and who had at least positive skin test to benzylpenicillin were included. Diagnosis and skin tests followed the ENDA recommendations. Benzylpenicillin, PPL, MDM, Ampicillin, Amoxicillin were always skin tested. Results133 patients (48 – 36.1% men), 15 (11.3%) asthmatics and 41 (30.8%) atopics were included. 13 (9.8%) were only positive to benzylpenicillin, 32 (26.5%) were also positive for PPL and 66 (55.5%) for MDM. Without skin testing for PPL and MDM, the number of positive to benzylpenicillin increased to 20 (15.0%). No difference was observed for asthma and atopic between subjects only positive to benzylpencillin and those also positive for another penicillin (p = 0.84 and p = 0.34 respectively). Anaphylaxis and anaphylactic shock were more common in subjects positive to several penicillins (76 – 67.3% vs 7 – 35%, p = 0.001). Conversely, only 26 (23.0%) vs 8 (40.0%) presented an urticaria/angiodema. 133 patients (48 – 36.1% men), 15 (11.3%) asthmatics and 41 (30.8%) atopics were included. 13 (9.8%) were only positive to benzylpenicillin, 32 (26.5%) were also positive for PPL and 66 (55.5%) for MDM. Without skin testing for PPL and MDM, the number of positive to benzylpenicillin increased to 20 (15.0%). No difference was observed for asthma and atopic between subjects only positive to benzylpencillin and those also positive for another penicillin (p = 0.84 and p = 0.34 respectively). Anaphylaxis and anaphylactic shock were more common in subjects positive to several penicillins (76 – 67.3% vs 7 – 35%, p = 0.001). Conversely, only 26 (23.0%) vs 8 (40.0%) presented an urticaria/angiodema. ConclusionsSince the withdrawal of PPL and MDM, benzylpenicillin skin test appeared to be mandatory, 15% of the patients being only positive to this drug. This should significantly reduce oral challenges. Since the withdrawal of PPL and MDM, benzylpenicillin skin test appeared to be mandatory, 15% of the patients being only positive to this drug. This should significantly reduce oral challenges.

Background: Allergic reactions to β ‐lactams are the most frequent cause of adverse drug reactions mediated by specific immunologic mechanisms. They can be explored by in vivo and/or in vitro tests. The measurement of serum‐specific immunoglobulin E (IgE) presents several advantages: safety, simplicity, and availability to nonallergologist physicians. Objectives: To establish the diagnostic value of specific IgE determination in the diagnosis procedure of immediate β ‐lactam allergy. Methods: The in vitro determination of β ‐lactam‐specific IgE antibodies was compared in three well‐defined groups of patients ( n = 45): one with negative skin tests and a positive drug provocation test, another with positive skin tests, and a third control exposed population with good tolerance. Two techniques were used: the CAP‐FEIA system (Phadia ® ) commercially available and a homemade radioallergosorbent test (RAST). Results: The specificity of CAP‐FEIA ranged from 83.3% to 100% and sensitivity from 0% to 25% depending on initial clinical manifestations. The specificity of RAST was between 66.7% and 83.3% and sensitivity 42.9% and 75%. In the subgroup of patients with an anaphylactic shock and negative skin tests, the sensitivity and specificity of RAST were 75%. Positive and negative predictive values were 45.5% and 77.1% with CAP‐FEIA and 38.5% and 81.5% with RAST, respectively. Conclusion: These results indicate that, although the specificity of β ‐lactam‐specific IgE measurement is good, sensitivity is low. Immunoglobulin E measurement should be limited to patients with a clinical history of anaphylactic shock and negative skin tests in order to avoid a drug provocation test. More sensitive assays should be developed.

Background: β‐lactam hypersensitivity reactions are classified as immediate or nonimmediate. Diagnosis is usually based upon skin tests and provocation challenges.Objective: The time course of the reactions in proven β‐lactam hypersensitivities was studied and then correlated with the symptoms to determine the relationship between the clinical presentations and the time course.Method: All of the patients who consulted between 1996 and 2004 for a suspected β‐lactam hypersensitivity reaction were studied. Two hundred and ten patients with a proven hypersensitivity reaction diagnosed according to the European Network on Drug Allergy were included in the present study.Results: Of the patients, 36.7% had urticaria as a single symptom, 19.1% anaphylaxis without shock, 17.6% anaphylactic shock and 19.1% maculopapular exanthema. Anaphylactic shock and anaphylaxis mostly occurred within 1 h after drug administration. Exanthema mainly occurred after 24 h. Urticaria as a single symptom occurred at any time. A firm diagnosis was determined using immediate‐reading skin prick (10.0%) and intradermal tests (38.1%), late‐reading skin tests (19.1%) or provocation tests (32.9%).Conclusion and clinical implication: Depending on the time course of the reaction, three clinical groups were identified: anaphylaxis and anaphylactic shock (immediate reaction); maculopapular exanthema (late reaction) as well as urticaria (immediate and late reaction).

RATIONALE: Biological tests, like basophil activation test (CD63 expression), would be extremely useful in order to establish the nature of the culprit agent in the diagnosis of severe drug hypersensitivity patients. METHODS: 44 patients with a proven diagnosis of drug hypersensitivity were tested with Skin test (18 Prick and 26 IDR positive patients). Beta-lactam were involved in 38 patients (in which, amoxicillin and penicillin were detected in 17 and 14 patients respectively), 6 sensitized to other drugs. 37 subjects without any reaction were analyzed as control group. Basophil CD63 measurement was performed at time delay, at least one month after drug induced reaction, after FMLP or specific drug challenge. Results are expressed in median +/- 25, 75% percentiles. RESULTS: Under FMLP stimulation, basophil CD63 expression was similar in each group, 32.8 % (21,4 to 41.5) in total population. The CD63 expression after specific drug basophil stimulation was significantly highest in Prick positive group (7,4%; 1.7 to 36.3) compared to IDR positive patient (2.1%; 1.4 to 4.0). CD63 expression in the control group after stimulation with the same drug used previously (3.0%; 1.8 to 4.2). CONCLUSIONS: A positive basophil CD63 expression after specific drug challenge gives powerful information for the detection of the drug inducing severe hypersensitivity in patients with positive prick test.

RATIONALE: The severity of Allergic and hypersensitivity reactions to drugs is usually considered to be graded from local reactions such as urticaria or exanthema to fatal reactions. However, this consideration has never been reported in detail for a large population of patients. We report the severity of drug allergy/hypersensitivity symptoms in 123 allergic patients who had previously several reaction histories. METHODS: Between January 1997 and April 2005, we prospectively studied all patients who consulted for a suspected hypersensitivity reaction to any drug. Patients underwent a standardized diagnosis (ENDA questionnaire, skin tests and provocation tests). We selected positive patients who had several reaction histories before testing. RESULTS: 1838 patients were tested and 123 had a positive skin test or oral challenge and had two or more previous reactions before testing. The most common drugs involved were beta-lactams and then Non-Steroidal Anti-Inflammatory drugs. 76.2% of patients had 2 reaction histories, and the number of reactions ranges from 2 to 6. 52.8% had a first history of urticaria as a single symptom, 14.6% anaphylaxis, 7.3 anaphylactic shock, 15.4% exanthema, 2.4% respiratory symptoms, 4.1% other skin reactions and 3.4% other symptoms. 65.9% of patients always express the type of reaction. The more severe reaction was the last reaction in 94.3% of patients. CONCLUSIONS: The severity of Allergic and hypersensitivity reactions to drugs grads from local reactions to fatal reactions.

RATIONALE: Allergic and hypersensitivity reactions to drugs are usually classified as immediate or non-immediate depending on their mechanisms and clinical presentation. However, the time course of common manifestations of allergic/hypersensitivity drug reactions has never been reported in detail for a large population of patients. We report the time course of drug allergy/hypersensitivity symptoms in 1537 patients. METHODS: Between January 1997 and April 2005, we prospectively studied all patients who consulted for a suspected hypersensitivity reaction to any drug except aspirin and non steroidal anti-inflammatory agents since these drugs commonly induce respiratory symptoms which have a specific mechanism. Patients underwent a standardized diagnosis (ENDA questionnaire, skin tests and provocation tests). RESULTS: 1537 patients were tested and 366 had a positive skin test or oral challenge. The most common drugs involved were beta-lactams and then other antibiotics. 47.6% had a history of urticaria as a single symptom, 19.4% anaphylaxis, 18.6% exanthema, 3.2% respiratory symptoms, 6.8% other skin reactions and 4.5% other symptoms. The time between drug intake and symptoms was available in 87.4% allergic patients. Among them, 38.0% of the reactions occurred before 1hrs and 26.0% after 24hrs. 73.7% of anaphylaxis occurred before 1h and 63.0% of exanthema after 24hrs. However, urticaria occurred within 1hrs (29.5%), between 1hrs and 24hrs (30.8%) and after 24hrs (26.0%). CONCLUSIONS: Patients report anaphylaxis as an early symptom and exanthema as a late occurring symptom. Urticaria ranged from early to late symptoms.

BACKGROUND:Immunoglobulin E (IgE)-mediated hypersensitivity reactions to neuromuscular blocking agents (NMBA) are common and life threatening. Basophil activation based upon the expression of CD63 in the presence of specific allergens was found to be of importance for the diagnosis of IgE-mediated hypersensibility.METHODS:The Basotest was evaluated for the diagnosis of NMBA in 47 patients with proven NMBA anaphylaxis, 40 atopic subjects nonallergic to NMBA and five healthy volunteers. Diagnosis of NMBA was made according to international standards on clinical history, skin tests and provocation tests when needed.RESULTS:In the NMBA allergic patients, sensitivity of Basotest was 36.1%, but it increased to 85.7% for reactions which occurred within the last 3 years. The specificity was 93.3%.CONCLUSION:Basotest may be useful for the diagnosis of NMBA allergy in patients with a suspicion of recent IgE-mediated hypersensitivity reaction to NMBA.

RATIONALE: After specific allergenic stimulation basophils become activated which is associated to the expression of CD63. CD63 is not expressed in non-stimulated cells. Others cell surface markers, like CD203c, could be modulated according to cell activation. The purpose of this study was to relate the CD203c expression to the stage of basophil activation METHODS: Patients: Allergic patients (n=13) with positive prick tests and control subjects (n=5) without history of allergy or with negative prick tests volunteered for this study. Heparinized and/or EDTA blood samples (2*5ml) were analyzed immediately after puncture. Basophil CD203c expression was analyzed before activation, and after non-specific, specific allergenic or anti IgE in vitro stimulation. Basophils were selected as CRTH2-FITC+/CD203c-PE+/CD3-PC7- (Beckman-Coulter INC) cells by flow cytometry (FAScalibur, BD). RESULTS: In the absence of stimulation, the level of CD203c expression was 5 times higher in allergic compared to non-allergic patients. Similar increased expression of CD203c was observed in the two populations after anti-IgE or non-specific allergenic stimulation. Specific allergenic stimulation induced an important CD203c expression. Similar results were observed with the 2 types of sampling. CONCLUSIONS: The CD203c expression analysis is a good cell surface marker to detect specific cellular activation process. According to this preliminary data, it seems to be a potent marker for detecting in vivo cellular basophil activation, in allergic patient compared to non-allergic.

AllergyVolume 60, Issue 1 p. 131-132 Correlation between former and new assays of latex IgE-specific determination using the K82 and K82 recombinant allergens from the Pharmacia Diagnostics® laboratory M.-L. Hemery, M.-L. Hemery Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorB. Arnoux, B. Arnoux Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorM. Rongier, M. Rongier Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorE. Barbotte, E. Barbotte Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorJ. Bousquet, J. Bousquet Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorP. Demoly, P. Demoly Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this author M.-L. Hemery, M.-L. Hemery Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorB. Arnoux, B. Arnoux Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorM. Rongier, M. Rongier Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorE. Barbotte, E. Barbotte Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorJ. Bousquet, J. Bousquet Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this authorP. Demoly, P. Demoly Exploration des Allergies Maladies Respiratoires INSERM U454 – IFR3 Hôpital Arnaud de Villeneuve CHU Montpellier 34295 Montpellier Cedex 5 France E-mail: [email protected]Search for more papers by this author First published: 03 December 2004 https://doi.org/10.1111/j.1398-9995.2005.00649.xCitations: 10 The new Hev b5-enriched latex-specific IgE K82+ is superior in the detection of latex sensitization. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Chapman MD, Smith AM, Vailes LD, Arruda LK, Dhanaraj V, Pomes A. Recombinant allergens for diagnosis and therapy of allergic disease. J Allergy Clin Immunol 2000; 106: 409–418. 10.1067/mai.2000.109832 CASPubMedGoogle Scholar 2 Akasawa A, Hsieh LS, Martin BM, Liu T, Lin Y. A novel acidic allergen, Hev b5, in latex. Purification, cloning and characterization . J Biol Chem 1996; 271: 25389–25393. 10.1074/jbc.271.41.25389 CASPubMedWeb of Science®Google Scholar 3 Slater JE, Vedvick T, Arthur-Smith A, Trybul DE, Kekwick RG. Identification, cloning, and sequence of a major allergen (Hev b5) from natural rubber latex (Hevea brasiliensis). J Biol Chem 1996; 271: 25394–25399. 10.1074/jbc.271.41.25394 CASPubMedWeb of Science®Google Scholar 4 Kurup VP, Fink JN. The spectrum of immunologic sensitization in latex allergy. Allergy 2001; 56: 2. 10.1034/j.1398-9995.2001.00130.x CASPubMedWeb of Science®Google Scholar 5 Sutherland MF, Drew A, Rolland JM, Slater JE, O'Hehir RE. 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To the Editor:β-Lactams are the most common class of antibiotics inducing drug allergic reactions.1Gruchalla R.S. Clinical assessment of drug-induced disease.Lancet. 2000; 356: 1505-1511Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar β-Lactams are low-molecular-weight molecules that function as haptens. These are capable of inducing immediate IgE-mediated and nonimmediate, mostly T cell–mediated allergic reactions. These reactions can be induced by all β-lactams, ranging from penicillin G (benzyl penicillin) to those newly introduced.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar Thus not only the major penicillin determinant benzylpenicilloyl and some minor determinants are currently involved but also a few other conjugates.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google ScholarSkin tests represent the first step for the confirmation of an immediate allergic reaction to β-lactams. Guidelines for performing skin tests have been published by the European Network on Drug Allergy (ENDA), and they are used in most European centers dealing with drug allergy.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar, 3Brockow K. Romano A. Blanca M. Ring J. Pichler W. Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity.Allergy. 2002; 57: 45-51PubMed Google Scholar It was proposed to use commercially available haptens to major and minor determinants (benzylpenicilloyl poly-l-lysine [PPL] and a mixture of minor determinants [MDM]), penicillin G, injectable amoxicillin, and ampicillin and cephalosporins if they are incriminated by the patients.4Green G.R. Rosenblum A.H. Sweet L.C. Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. A comparative prospective study of the penicillin study group of the American Academy of Allergy.J Allergy Clin Immunol. 1977; 60: 339-345Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 5Gadde J. Spence M. Wheeler B. Adkinson Jr., N.F. Clinical experience with penicillin skin testing in a large inner-city STD clinic.JAMA. 1993; 27: 2456-2463Crossref Scopus (275) Google Scholar, 6Torres M.J. Romano A. Mayorga C. Moya M.C. Guzman A.E. Reche M. et al.Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing.Allergy. 2001; 56: 850-856Crossref PubMed Scopus (221) Google Scholar However, both PPL and MDM commercialization has been stopped in most countries. In previous studies PPL and MDM skin tests were reported,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar but there is no assessment of their importance using the ENDA recommendations.In this retrospective analysis of the clinical case series of one drug allergy department, we evaluated the effect of such a withdrawal from the market for the diagnosis of β-lactam allergy.Between September 1996 and August 2004, we included all the patients who had consulted at our allergy clinic (University Hospital of Montpellier, France) with a clinical history suggestive of a β-lactam allergy. We did not include patients with noncompatible clinical symptoms and signs, with symptoms disappearing without cessation of the suspected causal drug, and with reactions occurring several days after the cessation of treatment. We also did not include patients who had experienced severe life-threatening skin reactions or drug-induced autoimmune disease, as we previously published.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google ScholarInformation was collected with the standardized ENDA questionnaire.8Demoly P. Kropf R. Bircher A. Pichler W.J. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity.Allergy. 1999; 54: 999-1003Crossref PubMed Scopus (273) Google Scholar Skin tests were performed as previously described,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar with the major and minor determinants of penicillin PPL and MDM (Allergopharma, Merck, Darmstadt, Germany), penicillin G, amoxicillin, ampicillin, and any other β-lactam suspected from the patient's history if the injectable form was available. After 15 to 20 minutes for skin prick tests, a wheal larger than 3 mm accompanied by erythema with a negative response to the control saline was considered a positive response. For intradermal tests, reactions were considered positive when a change in the size of the initial wheal of 3 mm or greater in diameter was observed 20 minutes after testing and was associated with a flare. A late reading in those patients with an unknown chronology or a suspicion of nonimmediate reactions was made after 24 to 48 hours. Drug provocation tests with the suspected β-lactams were carried out only when skin test results were negative, including the one used for the provocation test, and under strict hospital surveillance.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google ScholarBecause no alternative test for drug allergy exists and because patients need to take the drugs in question, neither our institutional policy nor the ethical committee at our institution require the drug provocation test to receive authorization from an ethics committee. However, we obtained the patient's written informed consent in every case.We calculated the median and interquartile ranges for age and described qualitative data using numbers and frequencies. Because the number of positive skin test responses to PPL alone, MDM alone, or both was low, we decided to group these data for comparison. The Mann-Whitney U test and χ2 test were used for statistical comparisons between patients with positive results only to PPL, MDM, or both and other patients. All data were collected in a drug allergy and hypersensitivity database with FileMaker Pro 7 software (Filemaker Inc, Santa Clara, Calif). Analysis was performed with SAS version 8 software (SAS Institute Inc, Cary, NC).Eight hundred twenty-four patients with a suspicion of β-lactam allergy underwent the full diagnostic procedure. There were 254 men and 570 women, and the mean age was 37 ± 19 years. A positive skin test response was found in 136 (16.5%) patients (Fig 1). Among them, 6 patients (4.4% of those with positive skin test responses) had positive skin test responses to PPL only, 9 (6.6%) to MDM only, and 5 (3.7%) to PPL and MDM without any positivity to other β-lactams (Table I). One hundred sixteen (85.3%) patients had positive skin test responses to other β-lactams; among them, 32% to 27.6% of those with positive skin test responses also had positive responses to PPL, MDM, or both.Table ICharacteristics of the patients with positive skin test responsesPPLMDMPPL + MDMAny positive skin test responses∗Excluding patients with positive PPL skin test responses alone, positive MDM skin test responses alone, or both.P value†P value: grouping PPL, MDM, and PPL plus MDM.N695116Sex ratio (M/F)0.51.2500.47NSAtopy69538<.001Asthma24230NSAge (y)36 (33-40)30 (16-32)33 (23-54)42 (27-53).04Clinical reactionsND Urticaria and angioedema55366 Anaphylaxis12221 Exanthema00022 Anaphylactic shock0104 Not defined0103Drug involved‡Cephalosporin, first generation: cefalexine, cefapirine, cefatrizine, cefadroxil, cefazoline; cephalosporin third generation, ceftriaxone, cefotaxime.ND Penicillin A (aminopenicillin)34265 Penicillin M (methicillin)0001 Penicillin V (phenoxymethylpenicillin)1001 Cephalosporin 102221 Cephalosporin 20000 Cephalosporin 30007 Undefined23121Immediate reaction (<1 h)03254NSDelay between clinical reaction and tests (y)4.8 (4.6-7.1)0.4 (0.3-8.0)3.6 (1.1-26.0)0.9 (0.3-7.3)NSResults are given in numbers or medians and (25th-75th) percentiles. NS, Not significant; ND, not done (patient populations are too small).∗ Excluding patients with positive PPL skin test responses alone, positive MDM skin test responses alone, or both.† P value: grouping PPL, MDM, and PPL plus MDM.‡ Cephalosporin, first generation: cefalexine, cefapirine, cefatrizine, cefadroxil, cefazoline; cephalosporin third generation, ceftriaxone, cefotaxime. Open table in a new tab Most of the patients with positive responses only to PPL, MDM, or both had a history of cutaneous reactions (urticaria, angioedema, and exanthema). Two of them had anaphylaxis, and none of them had a history of anaphylactic shock. The exact name of the β-lactam involved was known for 109 patients. For the others, the patients were not able to accurately recall the β-lactam. The most common drug suspected was penicillin A (aminopenicillin), which concerned 3, 4, 2, and 65 patients, respectively, with positive skin test responses to PPL, MDM, PPL plus MDM, and other β-lactams. The second suspected drug was a first-generation cephalosporin. All the patients with skin test responses positive only to PPL, MDM, or both were atopic, which was significantly more frequent than in the other patient group (P < .001). These patients were younger than the others (P < .04). There were no differences concerning asthma status, sex, delays between drug intake and clinical reaction, and delays between the clinical reaction and tests. Among the 688 patients with negative skin test responses who underwent a drug provocation test, only 53 (7.7%) had a positive test response (Table II).Table IICharacteristics of patients with positive oral challenge resultsNo.N53Clinical reactions Urticaria and angioedema16 Anaphylaxis11 Exanthema7 Anaphylactic shock11 Not defined8Drug tested∗Cephalosporin, first generation: cefazoline, cefaclor, cefapirine, cefatizine; cephalosporin, second generation: cefuroxime; cephalosporin, third generation.: ceftriaxone, cefotaxime. Penicillin A (aminopenicillin)27 Penicillin M (methicillin)0 Penicillin V (phenoxymethylpenicillin)0 Cephalosporin 116 Cephalosporin 21 Cephalosporin 32 Undefined7Immediate reaction (<1 h)17∗ Cephalosporin, first generation: cefazoline, cefaclor, cefapirine, cefatizine; cephalosporin, second generation: cefuroxime; cephalosporin, third generation.: ceftriaxone, cefotaxime. Open table in a new tab The ENDA guidelines are used in most European centers dealing with drug allergy. In β-lactam allergy skin tests represent the first-line method. It is therefore important to assess the effect of the lack of PPL and MDM reagents. This study identified 20 patients with positive responses only to PPL, MDM, or both and 116 with positive responses to other β-lactams. According to recent guidelines,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar these 20 patients would have needed a drug provocation test in the absence of PPL and MDM reagents. Although controversial, drug provocation tests on suspected individuals performed in carefully controlled settings can confirm (or deny) the presence of drug hypersensitivity.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google Scholar This is crucial for important drugs, such as β-lactams. Indeed, only 7.7% of patients with negative skin test responses had positive provocation in this study. No particular clinical parameters could identify these 20 patients, and the withdrawal from the market of the 2 reagents would be a problem. Thus this study shows that MDM and PPL are useful reagents, making it possible to reduce the need for drug provocation tests. To the Editor: β-Lactams are the most common class of antibiotics inducing drug allergic reactions.1Gruchalla R.S. Clinical assessment of drug-induced disease.Lancet. 2000; 356: 1505-1511Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar β-Lactams are low-molecular-weight molecules that function as haptens. These are capable of inducing immediate IgE-mediated and nonimmediate, mostly T cell–mediated allergic reactions. These reactions can be induced by all β-lactams, ranging from penicillin G (benzyl penicillin) to those newly introduced.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar Thus not only the major penicillin determinant benzylpenicilloyl and some minor determinants are currently involved but also a few other conjugates.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar Skin tests represent the first step for the confirmation of an immediate allergic reaction to β-lactams. Guidelines for performing skin tests have been published by the European Network on Drug Allergy (ENDA), and they are used in most European centers dealing with drug allergy.2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar, 3Brockow K. Romano A. Blanca M. Ring J. Pichler W. Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity.Allergy. 2002; 57: 45-51PubMed Google Scholar It was proposed to use commercially available haptens to major and minor determinants (benzylpenicilloyl poly-l-lysine [PPL] and a mixture of minor determinants [MDM]), penicillin G, injectable amoxicillin, and ampicillin and cephalosporins if they are incriminated by the patients.4Green G.R. Rosenblum A.H. Sweet L.C. Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. A comparative prospective study of the penicillin study group of the American Academy of Allergy.J Allergy Clin Immunol. 1977; 60: 339-345Abstract Full Text PDF PubMed Scopus (188) Google Scholar, 5Gadde J. Spence M. Wheeler B. Adkinson Jr., N.F. Clinical experience with penicillin skin testing in a large inner-city STD clinic.JAMA. 1993; 27: 2456-2463Crossref Scopus (275) Google Scholar, 6Torres M.J. Romano A. Mayorga C. Moya M.C. Guzman A.E. Reche M. et al.Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing.Allergy. 2001; 56: 850-856Crossref PubMed Scopus (221) Google Scholar However, both PPL and MDM commercialization has been stopped in most countries. In previous studies PPL and MDM skin tests were reported,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar but there is no assessment of their importance using the ENDA recommendations. In this retrospective analysis of the clinical case series of one drug allergy department, we evaluated the effect of such a withdrawal from the market for the diagnosis of β-lactam allergy. Between September 1996 and August 2004, we included all the patients who had consulted at our allergy clinic (University Hospital of Montpellier, France) with a clinical history suggestive of a β-lactam allergy. We did not include patients with noncompatible clinical symptoms and signs, with symptoms disappearing without cessation of the suspected causal drug, and with reactions occurring several days after the cessation of treatment. We also did not include patients who had experienced severe life-threatening skin reactions or drug-induced autoimmune disease, as we previously published.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google Scholar Information was collected with the standardized ENDA questionnaire.8Demoly P. Kropf R. Bircher A. Pichler W.J. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity.Allergy. 1999; 54: 999-1003Crossref PubMed Scopus (273) Google Scholar Skin tests were performed as previously described,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar with the major and minor determinants of penicillin PPL and MDM (Allergopharma, Merck, Darmstadt, Germany), penicillin G, amoxicillin, ampicillin, and any other β-lactam suspected from the patient's history if the injectable form was available. After 15 to 20 minutes for skin prick tests, a wheal larger than 3 mm accompanied by erythema with a negative response to the control saline was considered a positive response. For intradermal tests, reactions were considered positive when a change in the size of the initial wheal of 3 mm or greater in diameter was observed 20 minutes after testing and was associated with a flare. A late reading in those patients with an unknown chronology or a suspicion of nonimmediate reactions was made after 24 to 48 hours. Drug provocation tests with the suspected β-lactams were carried out only when skin test results were negative, including the one used for the provocation test, and under strict hospital surveillance.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google Scholar Because no alternative test for drug allergy exists and because patients need to take the drugs in question, neither our institutional policy nor the ethical committee at our institution require the drug provocation test to receive authorization from an ethics committee. However, we obtained the patient's written informed consent in every case. We calculated the median and interquartile ranges for age and described qualitative data using numbers and frequencies. Because the number of positive skin test responses to PPL alone, MDM alone, or both was low, we decided to group these data for comparison. The Mann-Whitney U test and χ2 test were used for statistical comparisons between patients with positive results only to PPL, MDM, or both and other patients. All data were collected in a drug allergy and hypersensitivity database with FileMaker Pro 7 software (Filemaker Inc, Santa Clara, Calif). Analysis was performed with SAS version 8 software (SAS Institute Inc, Cary, NC). Eight hundred twenty-four patients with a suspicion of β-lactam allergy underwent the full diagnostic procedure. There were 254 men and 570 women, and the mean age was 37 ± 19 years. A positive skin test response was found in 136 (16.5%) patients (Fig 1). Among them, 6 patients (4.4% of those with positive skin test responses) had positive skin test responses to PPL only, 9 (6.6%) to MDM only, and 5 (3.7%) to PPL and MDM without any positivity to other β-lactams (Table I). One hundred sixteen (85.3%) patients had positive skin test responses to other β-lactams; among them, 32% to 27.6% of those with positive skin test responses also had positive responses to PPL, MDM, or both. Results are given in numbers or medians and (25th-75th) percentiles. NS, Not significant; ND, not done (patient populations are too small). Most of the patients with positive responses only to PPL, MDM, or both had a history of cutaneous reactions (urticaria, angioedema, and exanthema). Two of them had anaphylaxis, and none of them had a history of anaphylactic shock. The exact name of the β-lactam involved was known for 109 patients. For the others, the patients were not able to accurately recall the β-lactam. The most common drug suspected was penicillin A (aminopenicillin), which concerned 3, 4, 2, and 65 patients, respectively, with positive skin test responses to PPL, MDM, PPL plus MDM, and other β-lactams. The second suspected drug was a first-generation cephalosporin. All the patients with skin test responses positive only to PPL, MDM, or both were atopic, which was significantly more frequent than in the other patient group (P < .001). These patients were younger than the others (P < .04). There were no differences concerning asthma status, sex, delays between drug intake and clinical reaction, and delays between the clinical reaction and tests. Among the 688 patients with negative skin test responses who underwent a drug provocation test, only 53 (7.7%) had a positive test response (Table II). The ENDA guidelines are used in most European centers dealing with drug allergy. In β-lactam allergy skin tests represent the first-line method. It is therefore important to assess the effect of the lack of PPL and MDM reagents. This study identified 20 patients with positive responses only to PPL, MDM, or both and 116 with positive responses to other β-lactams. According to recent guidelines,2Torres M.J. Blanca M. Fernandez J. Romano A. Weck A. Aberer W. et al.Diagnosis of immediate allergic reactions to beta-lactam antibiotics.Allergy. 2003; 58: 961-972Crossref PubMed Scopus (504) Google Scholar these 20 patients would have needed a drug provocation test in the absence of PPL and MDM reagents. Although controversial, drug provocation tests on suspected individuals performed in carefully controlled settings can confirm (or deny) the presence of drug hypersensitivity.7Messaad D. Sahla H. Benahmed S. Godard P. Bousquet J. Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction.Ann Intern Med. 2004; 140: 1001-1006Crossref PubMed Scopus (266) Google Scholar This is crucial for important drugs, such as β-lactams. Indeed, only 7.7% of patients with negative skin test responses had positive provocation in this study. No particular clinical parameters could identify these 20 patients, and the withdrawal from the market of the 2 reagents would be a problem. Thus this study shows that MDM and PPL are useful reagents, making it possible to reduce the need for drug provocation tests.

Background: The flow cytometry CD63-based basophil activation test (Basotest(R)) has already been validated for the diagnosis of immediate-type allergy such as venom, house dust mite or cypress pollen allergies. The aim of this study was to evaluate the performance ( specificity and sensitivity) of Basotest in the diagnosis of natural rubber latex allergy. Methods: We included 46 latex allergic patients ( clinical symptoms of latex allergy, positive latex skin prick tests and/or latex specific IgE) and 33 control subjects and performed Basotest on all subjects. Results: The sensitivity and specificity of Basotest were 84.8 and 87.9%, respectively, when we considered the theoretic cut-off at 15% of CD63-positive cells. Using ROC curves, the optimal cut-off was evaluated at 22%, for which sensitivity and specificity were 79.3 and 96.7%, respectively. Conclusion: The Basotest is a reliable test in addition to clinical history and tests already validated ( such as skin prick tests and specific IgE) to confirm the diagnosis of natural rubber latex allergy. Copyright (C) 2005 S. Karger AG, Basel.

Rationale Hypersensitivity reactions to β-lactam are common and may be severe, these include immediate (IgE-mediated) and non-immediate reactions. The value of biological test like; basophil degranulation test, in a non-selected population of patients suspected of drug allergy has never been fully established. Methods We randomly studied 35 patients who consulted for a suspected immediate hypersensitivity reaction to β-lactams. Clinical history, skin tests or drug provocation test (DPT) and/or serum specific IgE antibodies were performed to establish the diagnosis of allergy to β-lactam. The Basotest, based upon the expression of CD63 in the presence of specific allergens was evaluated as biological test to confirmed the clinical analysis in this unselected population. 35 β-lactam suspected allergic patients (13 urticaria, 9 macula papular eruption, 7 choc, 3 angioedema), 40 atopic subjects non-allergic to β-lactam were studied. History, provocation test and Basotest, to detect a specific sensitization to β-lactam were studied in all subjects. Results No statistical difference in the basal CD63 expression was observed between basophils of β-lactam allergic patients and those from control subject. In the 35 β-lactam allergic patients, Basotest, was positive in 3 subjects, two with a confirmed allergy (amoxicillin or ceftriaxon) and another one with a negative DPT (ceftriaxon), all control were negative. Conclusion This study does not confirm the data of Sanz et al (Clin Exp Allergy 2002) who used a different method of activation of basophils and analysis method. Thus, the Basotest® cannot be used in patients with immediate hypersensitivity reactions to β-lactams.

Rationale The flow cytometry CD63 based basophil activation test (Basotest®) has already been validated for the diagnosis of immediate-type allergy such as venom, house dust mite or cypress pollen allergies. The aim of this study was to evaluate the interest of Basotest® for the diagnosis of natural rubber latex allergy. Methods We included 46 latex allergic patients (who presented clinical symptoms of latex allergy, positive latex skin prick tests and specific IgE) and 33 control subjects and performed Basotest® in all subjects. Results The sensitivity and specificity of Basotest® were 84.8% and 87.9% respectively when we considered the cut-off at 15% of CD63 positive cells. Using ROC curves, the optimal cut-off was evaluated at 22%, for which sensitivity and specificity were 79.3% and 96.7% respectively. Conclusion The Basotest® is a reliable test in complement to clinical history and already validated tests (such as skin prick tests and specific IgE) to confirm the diagnosis of natural rubber latex allergy.

Le diagnostic d'allergie médicamenteuse est difficile et repose encore principalement sur l'histoire clinique, parfois les tests cutanés et, dans certains centres spécialisés, les tests de provocation. La place des explorations biologiques est limitée, permettant parfois d'apprécier la gravité de la réaction dans certaines formes cliniques, souvent d'orienter vers un mécanisme immunopathogénique devant une anaphylaxie peropératoire, voire, plus rarement actuellement, d'identifier le médicament responsable. Les quelques tests proposés dans cet objectif (dosage d'IgE spécifiques, tests d'histaminolibération et de libération de sulfidoleucotriènes notamment) sont peu validés, et leur reproductibilité et valeurs prédictives doivent encore être établies. La cytométrie de flux est dans ce cadre là la technique la plus prometteuse. The diagnosis of drug allergy is difficult and is usually based on clinical history, skin tests (for some drugs) and, in a few specialised allergy centers, provocation tests. Currently available laboratory tests are of limited interest: they sometimes provide information on the severity of certain clinical conditions, they may suggest an immunopathological mechanism in cases of intra-operative anaphylaxis and, more rarely, they can lead to the identification of the responsible drug. The few available tests, in particular, measurement of specific IgE antibody, in vitro leukocyte histamine and leukotrienes release, have not been sufficiently validated, lacking data on reproducibility and predictive values. The use of flow cytometry for that purpose appears to be a promising technique.

The diagnosis of allergic reactions in clinical practice is based on both clinical history and the determination of specific immunoglobulin E (IgE), either in the serum or on skin mast cells. However, for various reasons, identification of the causative factors is not possible in all the cases. Moreover, not all allergies are IgE-dependent. In an attempt to find sensitive, specific and cost-effective methods to investigate hypersensitivity reactions, in vitro tests were developed at a very early stage. Allergen-induced mediator release assays analyze the mediator released from effector cells, mainly peripheral blood cells, when stimulated in vitro with serial dilutions of the putative allergens. Described initially as research tools, they could well become diagnostic tests. However, relatively few high quality reports have been published so far. In this review, we will detail allergen-dependent histamine, tryptase, arachidonic acid metabolite, e.g. cysteinyl leukotrienes and 15-hydroxyeicosatetraenoic mediator release tests.