The Combined Use of Chronological and Morphological Criteria in the Evaluation of Immediate Penicillin Reactions: Evidence From a Large Study.

BACKGROUND: Immediate hypersensitivity reactions to penicillins are often labeled on the basis of a similar set of symptoms, but a key feature of these reactions that can be reproduced in diagnostic testing may be the timing of a reaction in relation to the dose administration. OBJECTIVE: To determine whether the timing of a reaction in response to the last dose of a penicillin would predict the results of diagnostic testing. METHODS: We evaluated 1074 patients by performing skin tests, serum specific IgE assays (ImmunoCAP), and challenges. Patients who were evaluated by us more than 6 months after their reactions and found negative were reevaluated within 2 to 4 weeks. RESULTS: Patients who had reacted within 1 hour after the first dose, within 1 hour after subsequent doses, more than 1 hour to within 6 hours after the first dose, or more than 1 hour to within 6 hours after subsequent doses were classified as group A (758 individuals), B (92), C (67), or D (157), respectively. Penicillin hypersensitivity was diagnosed in 707 patients (65.8%) by skin tests (407 patients, 57.6%), ImmunoCAP (47, 6.6%), both tests (232, 32.8%), or challenges (21, 3%). A conversion to allergy-test positivity occurred in 7 of 10 patients with anaphylactic reactions and in 1 of 28 patients with other reactions who were reevaluated after negative challenges. The rate of penicillin-allergic patients in groups A, B, C, and D was 85%, 35.9%, 35.8%, and 3.8%, respectively. Only 1 of 107 patients reporting cutaneous reactions lasting more than 1 day had positive results to allergy tests. CONCLUSIONS: IgE-mediated hypersensitivity can be diagnosed by skin tests in about 70% of subjects who react within 1 hour (eg, patients from groups A and B). This hypersensitivity can be lost over time, as demonstrated by the negativization of allergy tests in follow-up studies. In subjects with anaphylactic reactions, however, it is advisable to not consider this phenomenon definitive. In fact, a conversion to allergy test positivity can be observed in up to 20% of such subjects retested after negative challenges.

Evaluating Immediate Reactions to Cephalosporins: Time Is of the Essence.

BACKGROUND: Few studies have assessed the diagnostic value of cephalosporin skin tests in patients with immediate reactions to these ß-lactams. OBJECTIVE: To evaluate the usefulness of skin tests and challenges in assessing such subjects. METHODS: We conducted a prospective study of 236 consecutive subjects who had suffered 249 immediate reactions (mostly anaphylaxis) to cephalosporins. Skin tests were performed with penicillin reagents and suspected cephalosporins. Serum specific IgE assays (ImmunoCAP) were also carried out for penicillins and cefaclor. Subjects with negative results underwent challenges with the suspected cephalosporins; patients with negative results who had been assessed more than 6 months after their reactions were reevaluated. RESULTS: In the first allergy workup, an IgE-mediated hypersensitivity to cephalosporins was diagnosed in 164 (69.5%) of the 236 patients on the basis of skin test (162 patients) or cefaclor ImmunoCAP positivity (2 patients). Of the 72 patients with negative results, 55 underwent cephalosporin challenges; 3 reacted. Twenty subjects were reevaluated after cephalosporin negative challenges, with a conversion to cephalosporin skin test positivity occurring in 5 of the 6 subjects who had had anaphylactic reactions and in none of the remaining 14 subjects with other reactions. Overall, an immediate hypersensitivity to cephalosporins was diagnosed in 172 patients (of whom it was diagnosed in 5 after retesting). CONCLUSIONS: Most immediate reactions to cephalosporins are IgE-mediated. Cephalosporin skin testing is a useful tool for evaluating these reactions. IgE-mediated cephalosporin hypersensitivity may be a transient condition; therefore, allergy examinations should be repeated in patients with negative results who experienced anaphylaxis more than 6 months before the allergy workup, including challenges.

Tolerability of Cefazolin and Ceftibuten in Patients with IgE-Mediated Aminopenicillin Allergy.

BACKGROUND: Side-chain similarities or identities constitute the predominant factor for cross-reactivity between penicillins and cephalosporins, whereas differences in the side-chain structure seem to account for the absence of such cross-reactivity. OBJECTIVE: We sought to assess the cross-reactivity between penicillins and 2 cephalosporins (ie, cefazolin and ceftibuten) that have side chains different from those of penicillins, as well as to evaluate the possibility of using these cephalosporins in penicillin-allergic subjects. METHODS: We conducted a prospective study of 131 consecutive subjects who had suffered 170 immediate reactions (mostly anaphylaxis) to penicillins and had positive skin test results to at least 1 penicillin reagent. All patients underwent skin tests with cefazolin and ceftibuten. Patients with negative results were challenged with them. RESULTS: One participant had positive skin test results to cefazolin and ceftibuten, as well as to all other reagents tested, including aztreonam and carbapenems. All 129 subjects who underwent challenges with cefazolin and ceftibuten tolerated them. One subject refused cephalosporin challenges. CONCLUSIONS: Subjects with an IgE-mediated hypersensitivity to penicillins could be treated with cephalosporins such as cefazolin and ceftibuten, which are among the cephalosporins that have side-chain determinants different from those of penicillins. Nevertheless, in patients with such hypersensitivity who need these alternative ß-lactams, pretreatment skin tests are advisable because of the possibility of coexisting sensitivities or, much less frequently, of a sensitivity to an antigenic determinant of the common ß-lactam ring.

Cross-Reactivity and Tolerability of Cephalosporins in Patients with IgE-Mediated Hypersensitivity to Penicillins.

BACKGROUND: Studies performed since 1990 on samples of at least 30 subjects with a documented IgE-mediated hypersensitivity to penicillins have found a rate of positive responses to allergy tests with cephalosporins ranging from 0% to 27%. OBJECTIVE: We sought to assess the cross-reactivity with cephalosporins and evaluate the possibility of using cephalosporins in penicillin-allergic subjects. METHODS: We conducted a prospective study of 252 consecutive subjects who had suffered 319 immediate reactions (mostly anaphylaxis) to penicillins and had positive skin tests to at least 1 penicillin reagent. All patients underwent serum specific IgE assays for cefaclor, as well as skin tests with 3 aminocephalosporins (cephalexin, cefaclor, and cefadroxil), cefamandole, cefuroxime, ceftazidime, ceftriaxone, cefotaxime, and cefepime. Patients with negative results for the last 5 cephalosporins were challenged with cefuroxime axetil and ceftriaxone; those with negative results for aminocephalosporins were also challenged with cefaclor and cefadroxil. RESULTS: Ninety-nine participants (39.3%) had positive allergy tests for cephalosporins. Specifically, 95 (37.7%) were positive to aminocephalosporins and/or cefamandole, which share similar or identical side chains with penicillins. All 244 subjects who underwent challenges with cefuroxime axetil and ceftriaxone tolerated them. Of the 170 patients who underwent aminocephalosporin challenges, 3 reacted to cefaclor and 4 to cefadroxil. CONCLUSIONS: Cross-reactivity between penicillins and cephalosporins seems to be mainly related to side chain similarity or identity. Subjects with an IgE-mediated hypersensitivity to penicillins could be treated with cephalosporins such as cefuroxime and ceftriaxone that have side-chain determinants different from those of penicillins and are negative in pretreatment skin testing.

Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins.

BACKGROUND: The few studies performed in adults with T cell-mediated hypersensitivity to penicillins have found a rate of cross-reactivity with cephalosporins ranging from 2.8% to 31.2% and an absence of cross-reactivity with aztreonam. OBJECTIVE: We sought to evaluate the possibility of using cephalosporins and aztreonam in subjects with documented delayed hypersensitivity to penicillins who especially require them. METHODS: We conducted a prospective study of 214 consecutive subjects who had 307 nonimmediate reactions to penicillins (almost exclusively aminopenicillins) and had positive patch test and/or delayed-reading skin test responses to at least 1 penicillin reagent. To assess cross-reactivity with cephalosporins and aztreonam and the tolerability of such alternative ß-lactams, all subjects underwent skin tests with cephalexin, cefaclor, cefadroxil, cefuroxime, ceftriaxone, and aztreonam. Subjects with negative responses were challenged with the alternative ß-lactams concerned. RESULTS: All subjects had negative skin test results to cefuroxime, ceftriaxone, and aztreonam and tolerated challenges. Forty (18.7%) of the 214 subjects had positive skin test responses to at least 1 aminocephalosporin. Of the 174 subjects with negative responses, 170 underwent challenges; 1 reacted to cefaclor. CONCLUSIONS: These data demonstrate a rate of cross-reactivity between aminopenicillins and aminocephalosporins (ie, cephalexin, cefaclor, and cefadroxil) of around 20%, as well as the absence of cross-reactivity between penicillins and cefuroxime, ceftriaxone, and aztreonam in all subjects with T cell-mediated hypersensitivity to penicillins, almost exclusively aminopenicillins. Therefore these subjects could be treated with cefuroxime, ceftriaxone, and aztreonam. In those who especially require cephalosporin or aztreonam treatment, however, we recommend pretreatment skin tests because negative responses indicate tolerability.

IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins.

BACKGROUND: Studies regarding the cross-reactivity and tolerability of alternative cephalosporins in large samples of subjects with an IgE-mediated hypersensitivity to cephalosporins are lacking. OBJECTIVE: We sought to evaluate the possibility of using alternative cephalosporins in subjects with cephalosporin allergy who especially require them. METHODS: One hundred two subjects with immediate reactions to cephalosporins and positive skin test results to the responsible drugs underwent serum specific IgE assays with cefaclor and skin tests with different cephalosporins. Subjects were classified in 4 groups: group A, positive responses to 1 or more of ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, and ceftazidime; group B, positive responses to aminocephalosporins; group C, positive responses to cephalosporins other than those belonging to the aforementioned groups; and group D, positive responses to cephalosporins belonging to 2 different groups. Group A subjects underwent challenges with cefaclor, cefazolin, and ceftibuten; group B participants underwent challenges with cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten; and group C and D subjects underwent challenges with some of the aforementioned cephalosporins selected on the basis of their patterns of positivity. RESULTS: There were 73 subjects in group A, 13 in group B, 7 in group C, and 9 in group D. Challenges with alternative cephalosporins (ceftibuten in 101, cefazolin in 96, cefaclor in 82, and cefuroxime axetil and ceftriaxone in 22 subjects) were well tolerated. CONCLUSIONS: Cephalosporin hypersensitivity does not seem to be a class hypersensitivity. Subjects with cephalosporin allergy who especially require alternative cephalosporins might be treated with compounds that have side-chain determinants different from those of the responsible cephalosporins and have negative pretreatment skin test responses.

Clinical management of patients with a history of urticaria/angioedema induced by multiple NSAIDs: an expert panel review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequent causes of drug-induced urticaria/angioedema worldwide. Recent review articles have classified patients experiencing NSAID-induced urticaria/angioedema into different categories, including single reactors, multiple reactors, and multiple reactors with underlying chronic urticaria. Each of these categories requires a different clinical approach. The present article, written by a panel of experts, reports the main recommendations for the practical clinical management of patients with a history of urticaria/angioedema induced by multiple NSAID based on current knowledge.

Lipid transfer protein (Ara h 9) as a new peanut allergen relevant for a Mediterranean allergic population.

BACKGROUND: Nonspecific lipid transfer proteins (LTPs) represent potent pollen and food allergens. However, the allergenic properties of peanut LTP have not been studied. OBJECTIVE: To identify LTP in peanut extract using sera from subjects with peanut allergy and Pru p 3-sensitized subjects from Southern Europe, clone and express this protein, and obtain information on the importance as allergen for these selected patients. METHODS: Peanut LTP (Ara h 9) was cloned and sequenced by using a combination of bioinformatic and molecular biology tools (PCR, immunoblotting, Basic Local Alignment Search Tool [BLAST] searches). The immunologic properties of Ara h 9, Ara h 1, Ara h 2, and Ara h 3 were studied by using sera from subjects with peanut and peach allergy from Italy by immunoblotting and allergen microarray technology. RESULTS: Two Ara h 9 isoforms-Ara h 9.01 and Ara h 9.02-were cloned and expressed. Ara h 9 represented a minor allergen for subjects with peanut allergy. However, including Ara h 9 as single component for serologic detection of sensitization to peanut by component-resolved diagnosis seems crucial, because the frequency of sensitization to the classic major peanut allergens Ara h 1, Ara h 2, and Ara h 3 was low in these patients from Southern Europe. CONCLUSION: Ara h 9 is a new member of the LTP allergen family that seems to play an important role in peanut allergy for patients from the Mediterranean area.

Cross-reactive reactions to nonsteroidal anti-inflammatory drugs.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequent causes of adverse drug reactions, particularly in patients with asthma and chronic idiophatic urticaria. Many subjects report cutaneous and/or respiratory symptoms and, less frequently, anaphylactic shock after the administration of one (single-reactors) or different (cross-reactors) drugs of this class. DIAGNOSIS: There are no reliable cutaneous or in vitro tests which allow NSAID hypersensitivity to be identified in patients with cross-reactive reactions; therefore, the challenge test is considered the "gold standard" for establishing or excluding a diagnosis of NSAID hypersensitivity in such patients. MANAGEMENT: Culprit drugs should always be avoided by patients with suspected or well-established multiple hypersensitivity to NSAIDs. The therapeutic options range from the administration of alternative drugs - such as weak cyclooxygenase (COX)-1 inhibitors and/or preferential or highly selective COX-2 inhibitors to desensitization to the culprit ones. CONCLUSION: In patients with different NSAID-induced reactions, the challenge test with both culprit drugs and alternative ones is the only method to establish a reliable diagnosis of NSAID hypersensitivity and to find some alternative therapeutic options, respectively. In specific cases, drug desensitization can also be performed. However, further studies are required to improve management of such patients.

Etoricoxib tolerability in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem in clinical practice. Our aim was to investigate the clinical tolerability of etoricoxib, a new selective cyclooxygenase-2 inhibitor, in a group of patients with well-established NSAID hypersensitivity. METHODS: We assessed 31 adults (21 women and 10 men) who reported one or more adverse reactions to NSAIDs, manifested as cutaneous, respiratory or anaphylactic symptoms. Sixteen of them reported reactions to a single NSAID (single reactors) and 15 to more than one NSAID (multiple reactors); the most frequently involved drug was acetylsalicylic acid. First, each patient underwent allergologic tests (skin and/or oral challenge tests) with culprit NSAIDs and then tolerability tests with increasing doses of etoricoxib up to 120 mg. All challenges were performed under single-blind, placebo-controlled conditions. RESULTS: NSAID hypersensitivity was diagnosed in all 31 patients: 3 displayed positive results to pyrazolone skin tests and the other 28 to challenges with culprit NSAIDs. None reacted to either placebos or etoricoxib. CONCLUSIONS: Etoricoxib seems to be a safe alternative for patients with well-demonstrated NSAID hypersensitivity.

Celecoxib tolerability in patients with hypersensitivity (mainly cutaneous reactions) to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed in clinical practice, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem for both general practitioners and allergists. METHODS: We assessed 120 patients (83 women and 37 men) who had experienced adverse reactions to one or more NSAIDs; 64 (53.3%) of them had reacted to only one NSAID (single reactors) and 56 (46.7%) to multiple NSAIDs (multiple reactors). Among our subjects, 76.7% reported cutaneous reactions, 8.3% respiratory symptoms, 10.8% both cutaneous and respiratory symptoms, and 4.2% anaphylaxis. All patients were subjected to a single-blind, placebo-controlled oral challenge with two different doses of celecoxib (50 + 150 mg 1 h later = cumulative dose of 200 mg). RESULTS: None of the patients reacted to the placebo and only one (0.8%) suffered a reaction (urticaria) after the second dose of celecoxib. CONCLUSIONS: Celecoxib showed a 98.9% rate of tolerability in the 92 patients with exclusively cutaneous reactions and was well tolerated by all 28 subjects with NSAID-related respiratory or anaphylactic symptoms.

Tolerability of rofecoxib in patients with adverse reactions to nonsteroidal anti-inflammatory drugs: a study of 216 patients and literature review.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria or asthma. The identification of an alternative safe and reliable drug is a common problem in clinical practice. OBJECTIVE: To assess the tolerability of rofecoxib, a new NSAID that selectively inhibits the inducible isoform of cyclooxygenase, in a large group of NSAID-sensitive patients. METHODS: We studied 216 patients (164 females and 52 males) who had suffered adverse reactions to one or more NSAIDs; 98 subjects (45.4%) had experienced reactions to only one NSAID (single hypersensitivity) and 118 subjects (54.6%) had reacted to multiple NSAIDs (multiple hypersensitivity). Cutaneous reactions were reported by 79.6% of the subjects, respiratory symptoms by 10.7%, cutaneous and respiratory symptoms by 8.3%, anaphylaxis by 1.4%. All the subjects underwent a single-blind, placebo-controlled oral challenge with divided therapeutic doses of rofecoxib (6.25 mg +18.75 mg 1 h later = cumulative dose of 25 mg). RESULTS: No reactions to the placebo were observed; only 1 subject (0.46%) experienced an urticarial reaction, after the second dose of rofecoxib. CONCLUSIONS: Considering previous studies and our own data, rofecoxib was well tolerated by all of the 174 patients with exclusively NSAID-related respiratory symptoms. Rofecoxib also had a very low rate (1.6%) of cross-reactivity in the 600 patients with exclusively cutaneous reactions to NSAIDs.