Maria J. Torres

Diagnosis of immediate allergic reactions to beta-lactam antibiotics

Allergic reactions to betalactams are the most common cause of adverse drug reactions mediated by specific immunological mechanisms. Reactions may be induced by all betalactams currently available, ranging from benzylpenicillin (BP) to other more recently introduced betalactams, such as aztreonam or the related betalactamase-inhibitor clavulanic acid (Fig. 1) (1–5). Although the production process of betalactams has improved over the years, the number of reactions has not decreased, M. J. Torres, M. Blanca, J. Fernandez, A. Romano, A. de Weck, W. Aberer, K. Brockow, W. J. Pichler, P. Demoly for ENDA, and the EAACI interest group on drug hypersensitivity Allergy Service, Carlos Haya Hospital, Malaga, Spain; Allergy Service, University La Paz, Madrid, Spain; Allergy Section, Dept. Clin. Med., UMH, Elche, Spain; Allergy Service, Catholic University of Rome, Italy; Fondation Gerimmun, Beaumont 18, CH1700, Fribourg, Switzerland; Department of Environmental Dermatology, Graz, Austria; Klinik und Poliklinik f5r Dermatologie und Allergologie, Muenchen, Germany; Clinic for Rheumatology and Clinical Immunology/Allergy, Inselspital, Bern, Switzerland; Maladies Respiratoires-INSERM U454, Hopital Arnaud de Villeneuve, Montpellier, France

Nasal inflammatory mediators and specific IgE production after nasal challenge with grass pollen in local allergic rhinitis

BACKGROUND Evidence exists of a new form of local allergic rhinitis (LAR) with local production of specific IgE (sIgE) and a positive response to nasal allergen provocation test (NAPT) in patients previously diagnosed with idiopathic rhinitis. However, the immunologic mechanisms involved are still poorly understood. OBJECTIVE We explored the involvement of nasal sIgE, eosinophil, and mast cell activation in the response to NAPT with grass pollen (NAPT-grass) in a group of patients already classified with LAR. METHODS Out-of-spring NAPT-grass was performed in 30 patients with LAR and 30 healthy controls. Nasal symptoms, acoustic rhinometry, and nasal lavage were performed at baseline and 15 minutes and 1, 6, and 24 hours post-NAPT. Tryptase, eosinophilic cationic protein (ECP), and total and sIgE to grass pollen were measured in nasal lavage by immunoassays. RESULTS NAPT-grass was positive in all patients with LAR. We detected significant increases of tryptase and ECP in 40% and 43%, respectively, at 15 minutes and 1, 6, and 24 hours post-NAPT compared with baseline (P < .05). sIgE was increased in 30%, with significant increases at 1 and 6 hours (P < .05) and 24 hours (P = .002) post-NAPT. The maximum release of tryptase was detected 15 minutes after NAPT, whereas the maximum release of ECP and sIgE was detected 24 hours after challenge. NAPT-grass was negative in all healthy controls, with no increase in tryptase, ECP, total IgE, or sIgE. CONCLUSION These results demonstrate that patients with LAR had local production of sIgE and mast cell/eosinophil activation induced by nasal exposure to grass pollen.

Evolution of patients with nonallergic rhinitis supports conversion to allergic rhinitis.

BACKGROUND Nonallergic rhinitis (NAR) affects a significant number of patients in clinical practice. However, the different entities involved within NAR require further study. Once allergy has been ruled out, most of these patients are not usually followed up in allergy clinics, despite the persistence of rhinitis symptoms. Thus few data are available concerning the natural evolution of these patients. OBJECTIVE We sought to re-evaluate over time the severity, accompanying disorders, and possible allergen sensitizations in subjects with NAR. METHODS A representative sample of 180 patients given diagnoses of NAR during 2000-2004 was re-evaluated in 2007 by using sociodemographic and clinical questionnaires, spirometry, skin prick testing, and measurement of specific IgE to common aeroallergens. RESULTS Patients with NAR generally experienced worsening disease (52%), with an increase in the persistence (12%) and severity of nasal symptoms (9%) and new comorbidities (24%) over time. The most frequent comorbidities at the re-evaluation were asthma (increasing from 32% to 55%) and conjunctivitis (from 28% to 43%), followed by chronic rhinosinusitis. Sensitization to aeroallergens not present at the initial evolution was detected by means of skin prick testing, serum specific IgE measurement, or both in 24% of the patients. CONCLUSIONS Persistent moderate-to-severe rhinitis associated with asthma, conjunctivitis, or both and sensitization to aeroallergens are likely to appear at a later date in adults initially given diagnoses of NAR. A periodic re-evaluation of these patients might therefore be necessary.

Cephalosporin chemical reactivity and its immunological implications.

Purpose of reviewThe aim of this article is to analyze the chemical reactivity of cephalosporins resulting in the epitope responsible for recognition by IgE antibodies and to establish the basis of the allergenicity. Recent findingsIncreasing evidence supports the role of cephalosporins in IgE hypersensitivity reactions. Third and fourth generation cephalosporins appear to be more involved in specific IgE reactions and often no cross-reactivity with traditional benzyl penicillin determinants exists. In some instances selective responses to unique cephalosporins occur and in others common side-chain similarities exist. SummaryLack of knowledge of the exact chemical structure of cephalosporin antigenic determinants has hindered clinical interpretation of allergic reactions to these drugs and hampered understanding of the specific recognition by IgE molecules of these determinants. Data indicate that R2 is not present in the final conjugate and that recognition by IgE antibodies is mainly directed to the R1 acyl side chain and to the β-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation process.

Immediate allergic reactions to betalactams: facts and controversies.

Purpose of reviewTo analyse the available data in the field of immediate allergic reactions to β-lactams, with particular emphasis on more recent studies, and to comment on the future role of this group of antibiotics. Recent findingsThe world of β-lactams has become more complex than initially thought, due to the increased number of chemical structures available, the wide variety of indications for their use in treating different infectious diseases, and possibly also due to the interaction of other as yet undetermined factors. Benzyl penicillin, the original inducer of allergic reactions, has now largely been replaced by amoxicillin and, to a lesser extent, by cephalosporins in inducing IgE-mediated allergic reactions. These structures often share extensive cross-reactivity, eliciting clinical reactions to many compounds, especially amongst penicillins. In other circumstances selective responses are observed which are restricted to one group or one single compound, as occurs in the group of cephalosporins. The application of new determinants for skin testing and the use of adapted in-vitro studies have enabled these findings to be confirmed in detail. SummaryResults indicate that evaluation of immediate reactions to β-lactams requires the use of several determinants for both in-vitro and in-vivo testing, and which must reflect the relevant drug involved in eliciting the response. This tendency will be strengthened in the future if use of benzyl penicillin continues to decrease as a drug to which populations are exposed.

Dendrimerized cellulose as a scaffold for artificial antigens with applications in drug allergy diagnosis.

Cellulose-based dendrimerized material was prepared and its quality was assessed by determining the number of amine functional groups incorporated. Based on the results for a series of preparations, the material was obtained in a highly reproducible manner thanks to the particular chemical construction method used. The number of amine groups incorporated and the amount of dendrimer attached are directly related to the dendrimer generation. The combination of the properties of the cellulose polymer and those of the dendrimeric state provides biocompatible materials amenable to easy chemical characterization. The proposed method provides an effective tool for developing clinically testable materials with a view to studying adverse immunological responses to drugs in humans.

Nonimmediate reactions to betalactams

Purpose of reviewNonimmediate reactions to β-lactams include several clinical entities, from maculopapular rash to severe reactions such as Steven-Johnson syndrome. Toxic epidermal necrolysis and organ-specific reactions may also occur. Recent findingsProgress has been made in understanding the role of the immunological system in nonimmediate reactions to β-lactams. Different T-cell subsets recognize β-lactams after haptenation of serum or cell proteins in the context of major histocompatibility complex. Studies using T-cell lines and clones have shown that a heterogeneous response is generated, with the expression of different cytokine profiles. Betalactams also act on dendritic cells, inducing changes that enable them to interact with naïve lymphocytes, becoming memory T cells. Tissue-activated CD4 and CD8 cells express perforin and other cytotoxic mediators that elicit the lesions. Studies on the clinical course of these entities indicate that cells migrate, establishing a recirculation with homing to the skin and back to the circulation. These cells thus participate not only in skin lesions but probably also in the repair process. SummaryUnderstanding the immunological mechanisms involved in nonimmediate reactions to β-lactams has improved over the last few years, with better definition of the different T-cell subpopulations involved. Experimental studies and monitoring of the response support the implication of different cell subsets.

Urticaria and Anaphylaxis due to Betalactams (Penicillins and Cephalosporins)

Anaphylaxis and urticaria are the main clinical entities associated with betalactam allergy. They usually occur within 1 h of drug exposure, although urticaria may occasionally appear later. The sh

Polymorphisms in CEP68 gene associated with risk of immediate selective reactions to non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.