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Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.

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.

Lamotrigine and nonaromatic antiepileptic drugs (valproate, gabapentin, and topiramate) are associated with hypersensitivity reactions, mainly cutaneous eruptions. The underlying mechanisms of these manifestations are not yet completely understood. A cell-mediated pathogenic mechanism has been demonstrated in some cases on the basis of positive patch tests and/or lymphocyte transformation tests. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in patients with hypersensitivity reactions to lamotrigine. Subjects with a history of mild hypersensitivity reactions and negative allergologic tests can be challenged with the suspected drugs. Challenge tests can also be useful to identify safe alternatives. Our study reports hypersensitivity reactions to lamotrigine and to nonaromatic antiepileptic drugs, especially those assessed by allergologic tests.

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.

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. 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. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

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.