Serum Specific IgE Assays Research Articles

Diagnosing Hypersensitivity Reactions to Cephalosporins in Children

The goals were to evaluate the usefulness of skin tests, patch tests, serum specific IgE assays, and challenges in diagnosing hypersensitivity reactions to cephalosporins and to clarify the pathogenic mechanism of such reactions. Children with immediate manifestations (within 1 hour) underwent immediate-reading skin tests with penicillin reagents and any suspect cephalosporins, serum specific IgE assays, and challenges; some children underwent reevaluations. Children with nonimmediate manifestations (after >1 hour) were assessed with patch tests, delayed-reading skin tests, and challenges. We evaluated 148 children with hypersensitivity reactions to cephalosporins, mainly cefaclor and ceftriaxone; 105 had experienced nonimmediate manifestations (mostly urticarial eruptions and maculopapular rashes) and 43 immediate manifestations (anaphylactic shock, urticaria and/or angioedema, and erythema). None of the nonimmediate reactors demonstrated positive results in patch tests and/or delayed skin tests; only 1 subject displayed immediate positive responses to penicillin skin-test reagents. Among the 104 patients with negative results, 96 underwent challenges; 95 tolerated the challenges, and 1 reacted to the cefaclor pediatric suspension and tolerated the challenge with a cefaclor capsule. In the first allergologic evaluation, 33 of the 43 children with immediate reactions displayed skin-test positivity. Of the 10 patients with negative results, 7 underwent challenges, followed by therapeutic courses and reevaluations for 4. All challenges and therapeutic courses were tolerated; in the reevaluation, 1 girl demonstrated positive skin-test results for both the responsible cephalosporin and penicillin reagents. Overall, IgE-mediated hypersensitivity was diagnosed for 34 (79%) of 43 subjects. Extremely few nonimmediate manifestations associated with cephalosporin therapy are actually hypersensitivity reactions, whereas most immediate reactions to cephalosporins are IgE-mediated. Cephalosporin skin testing is a useful tool for evaluating such reactions.

The need for a biological diagnosis of penicillin allergy

According to the Nomenclature Review Committee of the World Allergy Organization, drug allergies refer to drug hypersensitivity reactions where a definite immunological mechanism [1] can be demonstrated. The prevalence of self-reported penicillin allergy is high; indeed, a crosssectional survey in Portugal found a 4.5% adult population self-reported penicillin allergy [2]. The prevalence rate of true penicillin allergy is, however, much lower [3, 4], and therefore a firm diagnosis is needed [5]. The clinical picture of drug allergy is very heterogeneous, encompassing distinct diseases such as morbilliform or bullous exanthema, urticaria and angiooedema, pustular exanthemas, fixed drug eruptions, anaphylaxis, blood cell dyscrasia, fever, interstitial lung disease, hepatitis, nephritis, vasculitis, DRESS (drug reaction with eosinophilia and systemic symptoms) and various forms of autoimmune diseases. However, it is important to distinguish between immediate and non-immediate reactions. The former occur within the first hour after the last drug administration and are manifested clinically by urticaria, angiooedema, rhinitis, bronchospasm or anaphylactic shock. The diagnosis of drug allergy often relies on clinical histories, skin tests and a few validated in vitro tests, such as serum-specific IgE assays, which are available only for a few drugs. The sensitivity of these tests is not 100% and, in selected cases, provocation tests are therefore necessary. However, new diagnostic tools, such as the basophil activation test (BAT), have been developed and are still under validation. Their routine use could increase the sensitivity of diagnostic work-ups, thus reducing the need for drug provocation tests and filling the gap between the high number of non-allergic drug allergy suspicions and the lack of specialized centres in all countries, which would enable confirmation or elimination of the diagnosis. There is evidence now that the BAT can contribute to the diagnosis of anaphylactic reactions due to several drugs, particularly muscle relaxants and b-lactams [6, 7]. At present, the most commonly used antigens in BATs are CD63 and CD203c. CD63, the gp53 or lysosyme-associated membrane protein (LAMP)-3, is one of the most reported markers for flow cytometric determination of basophil activation. CD63 is deeply anchored into the basophilic intracytoplasmic granules and is generally weakly expressed on the surface of basophils, monocytes, macrophages and platelets. In cases of allergic inflammation, as a result of fusion between the granule and the plasma membrane, CD63 is expressed with a high density on activated basophils and mirrors histamine release [8]. This up-regulated expression of basophilic CD63 can be detected by multi-colour flow cytometry using specific monoclonal antibodies [9]. As far as b-lactams are concerned, the CD63-based BAT was first evaluated in two studies [7, 10] including, respectively, 58 and 70 patients with immediate reactions to these antibiotics. BAT sensitivity was about 50% and specificity was over 90%. However, unlike the study by Sanz et al. [7], the one by Torres et al. [10] assessed not only patients with positive histories and positive skin tests and/or CAP-FEIA but also patients negative to both these tests and positive to challenges. It is interesting to note that one of the seven patients of the latter group was BAT positive. This group of patients with true allergy and negative skin tests is of crucial importance. They account for up to 33% of b-lactam-allergic patients and are only diagnosed by potentially harmful and cumbersome oral provocation tests [11]. Another more basophil-specific marker, CD203c (neural cell surface differentiation antigen E-NPP3, ecto-nucleotide pyrophosphatase/phosphodiesterase 3), is a multifunctional ectoenzyme exclusively and constitutively expressed on the surface of basophils [12]. Five years Correspondence: Prof. Pascal Demoly, Allergy Department, Hopital Arnaud de Villeneuve, University Hospital of Montpellier and Inserm U657, 34295 Montpellier, Cedex 5, France. E-mail: pascal.demoly@inserm.fr doi: 10.1111/j.1365-2222.2008.02981.x Clinical and Experimental Allergy, 38, 869–871

Hypersensitivity Reactions to Complementary and Alternative Medicine Products

Complementary and alternative medicine (CAM) is becoming increasingly popular, and is often used for treating hypersensitivity diseases. Virtually all alternative remedies can cause hypersensitivity reactions, but the most frequently involved ones are tea tree oil, members of the Compositae family, propolis, oils used in aromatherapy, substances responsible for photosensitization, and metal-containing compounds. The main target organ is skin, with manifestations ranging from contact dermatitis (the most common) to urticaria-angioedema, maculopapular eruptions, photosensitivity reactions, and the Stevens-Johnson syndrome. Other types of reactions are possible, including respiratory and anaphylactic ones. Different pathogenic mechanisms have been suggested for CAM product reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly contact dermatitis and maculopapular eruptions. Skin tests and serum specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while patch tests and lymphocyte transformation tests are usually performed to evaluate delayed hypersensitivity reactions. Thus clinicians should know about the potential of CAM products for causing adverse reactions. Our study is aimed at highlighting the risk of hypersensitive reactions to CAM remedies on the basis of the numerous cases reported in the literature. Because little is known about adverse reactions to CAM products, further systematic studies and an appropriate regulation by heath authorities are necessary.

Hypersensitivity Reactions to Ophthalmic Products

Adverse reactions after administration of ophthalmic products have frequently been observed. These reactions can be provoked by both active principles and excipients. Different pathogenic mechanisms have been suggested for such reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly conjunctival ones and eyelid dermatitis. Prick tests and immediate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while patch tests are usually performed to evaluate delayed reactions. Other diagnostic tests, such as serum-specific IgE assays in immediate reactions, as well as delayed-reading intradermal tests and/or lymphocyte transformation tests in delayed ones, are rarely performed. In this review, particular attention is addressed to the clinical and practical aspects of both cell-mediated and IgE-mediated hypersensitivity reactions to ophthalmic products.

Diagnosing immediate reactions to cephalosporins

After penicillins, cephalosporins are the betalactams that most often induce IgE-mediated reactions. The development of diagnostic tests has been delayed, however, because the cephalosporin allergenic determinants have not been properly identified. To evaluate the usefulness of skin tests, serum specific IgE assays, and challenges in diagnosing immediate reactions to cephalosporins and to clarify the pathogenic mechanism of such reactions. We studied 76 adults with immediate reactions to cephalosporins, mainly ceftriaxone, cefotaxime, and ceftazidime. Skin tests and serum specific IgE assays were performed for culprit cephalosporins and cefaclor, as well as for penicillin, amoxicillin, and ampicillin. Some subjects with negative results underwent challenges and re-evaluations. Responses to cephalosporins other than the culprit ones were also studied. In the first allergologic work-up, an IgE-mediated hypersensitivity to penicillins and/or cephalosporins was diagnosed in 63 (82.9%) of the 76 patients on the basis of skin-test and/or specific IgE assay positivity. Of the 13 negative patients, eight accepted challenges and underwent re-evaluations. Considering both first- and second-evaluation results, the skin-test-positivity rate increased from 76.3% to 85.5% and that of sepharose-radioimmunoassay positivity from 67.1% to 74.3%. Overall, an IgE-mediated hypersensitivity was diagnosed in 70 patients (in seven after retesting). On the basis of skin-test and CAP-FEIA results, we classified our 76 patients into five groups: group A (three patients), positive only to penicillin reagents; B (17), positive to both cephalosporin and penicillin reagents; C (24), positive to more than one cephalosporin; D (21), positive only to the responsible cephalosporin; E (11) negative to skin tests and CAP-FEIA, including five sepharose-radioimmunoassay positive. Most immediate reactions to cephalosporins appear to be IgE-mediated. Cephalosporin skin testing and sepharose-radioimmunoassay are useful tools for evaluating these reactions. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges.

Immediate allergic reactions to beta-lactams: diagnosis and therapy.

Beta-lactams are the antibiotics which most frequently provoke adverse reactions mediated by specific immunological mechanisms. These reactions, classifiable as immediate or non-immediate, can be produced by the four classes of beta-lactams (penicillins, cephalosporins, carbapenems and monobactams) currently available, which share a common beta-lactam ring structure. Immediate reactions occur within the first hour after drug administration and are characterized by urticaria, angioedema, rhinitis, bronchospasm, and anaphylactic shock. Immediate reading skin tests are the quickest and most reliable method for demonstrating the presence of beta-lactam specific IgE antibodies. It is crucial to use in diagnosis the suspected beta-lactams themselves, particularly cephalosporins, in addition to penicillin determinants. Serum specific IgE assays can be used as complementary tests. Negative test results should be interpreted in light of the time elapsed from the last exposure to the responsible beta-lactam. In fact, both in vivo and in vitro test sensitivity is known to decrease over time. In some diagnostic work-ups, patients with a positive history and negative skin and in vitro tests with classic reagents undergo a controlled administration of the suspected beta-lactam. The management of immediate allergic reactions should take into consideration their severity and type. Adrenaline is the drug of choice in the treatment of anaphylactic shock. In addition to adrenaline, corticosteroids and antihistamines should be administered. Histamine H(1) receptor antagonists are the mainstay of the treatment of immediate allergic reactions such as urticaria, rhinitis and conjunctivitis.