Importance of mixture of minor determinants and benzylpenicilloyl poly-l-lysine skin testing in the diagnosis of β-lactam allergy
2005; Elsevier BV; Volume: 115; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2005.02.026
ISSN1097-6825
AutoresPhilippe‐Jean Bousquet, H.‐B. Co‐Minh, B. Arnoux, J.-P. Daurès, Pascal Demoly,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoTo 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.
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