Current Pharmaceutical Design - Volume 14, Issue 27, 2008

Like the previous one published in 2006 [1], this volume addresses literature regarding the pathogenic mechanisms, diagnosis, and prevention of drug hypersensitivity reactions, in order to improve the management of a problem in constant evolution. Specifically, the present issue provides an update on the main diagnostic methods of such reactions and supplements the information of the previous volume [1], discussing some topics, such as hypersensitivity reactions to biologic agents, nonaromatic anticonvulsants, macrolide antibiotics, anticoagulants, and antineoplastic drugs, not included in the latter. Also like the previous one [1], the present volume often refers to the general guidelines for diagnosing drug hypersensitivity reactions devised by the European Network for Drug Allergy (ENDA), the European Academy of Allergology and Clinical Immunology interest group on drug hypersensitivity; it contains articles by researchers and clinicians belonging to the ENDA and to the American Academy of Allergy, Asthma and Immunology Committee on Adverse Reactions to Drugs and Biologicals. In preparing this volume, we have taken into account the needs of readers who wish to keep abreast of the latest developments regarding hypersensitivity reactions to drugs, particularly those concerning their diagnosis and prevention. In the first article, Guéant and coworkers [2] focus their attention on the genetic risk factors of hypersensitivity reactions to drugs such as β-lactams, carbamazepine, and abacavir. Most studies regard HLA haplotype association, single nucleotide polymorphisms, or polymorphisms in genes encoding drug-metabolizing enzymes. With regard to β-lactams, the genetic factors involved in IgE-mediated mechanisms appear to be connected with TNFA -308G>A, class switching to IgE by B cells (variants of IL13 and of IL4RA), and expression of IgE receptors on target cells (variant of the FcηRIβ gene). As far as delayed T-cell-mediated reactions to drugs are concerned, an association of HLA-B*1502 and HLA-B*5801 has been observed in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis connected with carbamazepine and HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701 seems to be a strong predictor in whites, and the prospective HLA-B*5701 screening enables HIV patients at risk for abacavir hypersensitivity reactions to be identified, thus playing a crucial role in the effective prevention of such reactions. 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 sulphamethoxazole in prohapten. The pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcηRIα gene, and variants in genes of enzymes from arachidonic acid pathway. The following three articles [3-5] provide data on the main in vivo and in vitro diagnostic tests. The review by Brockow and Romano [3] addresses literature data regarding the diagnosis of drug hypersensitivity reactions by skin (prick, intradermal) and patch tests. Even though these tests are the most readily available tools for the evaluation of drug hypersensitivity reactions, their diagnostic value for many drugs have not been fully established yet. However, reliable skin test procedures for the diagnosis of drug hypersensitivity have been defined, and test concentrations have been validated for many drugs, such as β- lactams, neuromuscular blocking agents (NMBAs, or muscle relaxants), and iodinated contrast media. In many cases, skin tests can provide information about the culprit drug and the mechanism involved in certain reactions, and allow the physician to avoid hazardous provocation tests. Skin tests should be performed according to the clinical features of hypersensitivity reactions. In immediate reactions (i.e., occurring within one hour after the last drug administration), an IgE-mediated mechanism can be demonstrated by a positive skin prick and/or intradermal test after 20 minutes, whereas in non-immediate reactions (i.e., occurring more than one hour after the last drug administration), a T-cell involvement can be found by a positive patch test and/or a delayed-reading intradermal test. The predictive value of skin tests varies with the drug tested and is especially high with β-lactams (penicillins, cephalosporins, carbapenems, and monobactams), NMBAs, insulins, platins, streptokinase, and chymopapain. For this reason, these tests have also been carried out in order to identify the patients at risk, such as candidates for chemonucleolysis with chymopapain, or patients undergoing sequential therapeutic courses with platins. Moreover, skin testing with cephalosporins and carbapenems has proved to be a useful tool for finding safe alternatives in the patients with a well-demonstrated IgE-mediated hypersensitivity to penicillins.

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 β-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 FcηRIβ gene). Delayed Tcell- 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 FcηRIα 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*

Adverse drug reactions (ADRs) are an area of concern for pharmaceutical drug development. Among these, drug hypersensitivity reactions are neither dose-dependent nor predictable, and affect only predisposed individuals. Clinical and immunological studies suggest that IgE-mediated (type I) and cell-mediated (type-IV) pathogenic mechanisms are involved in many immediate (i.e., occurring within 1 hour after the last drug administration) and non-immediate (i.e., occurring more than 1 hour after the last drug administration) hypersensitivity reactions, respectively. Skin prick, patch, and intradermal tests are the most readily available tools for the evaluation of hypersensitivity drug reactions. The diagnostic value of skin tests for many drugs still has not been fully established. Reliable skin test procedures for the diagnosis of drug hypersensitivity have been defined, and test concentrations have been validated for many drugs. Skin tests should be carried out according to the clinical features of ADRs. In immediate drug reactions, an IgE-mediated mechanism can be demonstrated by a positive skin prick and/or intradermal test after 20 minutes, whereas in non-immediate reactions, a Tcell involvement can be found by a positive patch test and/or a late-reading intradermal test. The predictive value of skin tests varies with the drug tested and is especially high with β-lactams, muscle relaxants, insulins, platinum salts, streptokinase, and chymopapain. Further diagnostic tests are required in the assessment of drug hypersensitivity reactions. However, skin tests can provide information about the culprit drug and the mechanism involved in certain reactions. The present review addresses literature data regarding the diagnosis of drug hypersensitivity reactions by skin tests.

A position paper by the European Network for Drug Allergy (ENDA), the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity, defines drug provocation tests (DPTs) as ‘the controlled administration of a drug in order to diagnose drug hypersensitivity reactions’. The DPT is widely considered to be the ‘gold standard’ to establish or exclude the diagnosis of hypersensitivity to a certain substance, as it not only reproduces hypersensitivity symptoms, but also any other adverse clinical manifestation, irrespective of the mechanism. The DPT can be harmful and thus should only be considered after balancing the risk-benefit ratio in the individual patient. The ENDA position paper specifies two main indications for DPTs with the suspected compounds: 1. to exclude hypersensitivity in non-suggestive histories of drug hypersensitivity and in patients with non-specific symptoms, such as vagal symptoms under local anesthesia; 2. to establish a firm diagnosis in suggestive histories of drug hypersensitivity with negative, non-conclusive, or nonavailable allergologic tests. A positive DPT result optimizes allergen avoidance, while a negative one allows a false label of drug hypersensitivity to be removed. For these reasons, DPTs are often carried out to exclude a diagnosis of hypersensitivity to β-lactams when other allergologic tests are negative. DPTs are also performed when the sensitivity of allergologic tests for evaluating allergic reactions to certain drugs, such as non-β-lactam antibiotics, heparins, and glucocorticoids, is limited. On the other hand, DPTs are also performed to diagnose hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in subjects with the cross-reactive pattern, because both skin tests and in vitro diagnostic methods are ineffective in such patients.

The application of flowcytometry in the study of basophil activation for the diagnosis of allergic diseases has given interesting results in recent years. The quantification of basophil activation by flowcytometry has been proven to be a useful tool for the assessment of the immediate-type response to allergens mediated by IgE or by other mechanisms in drug allergic patients. Up to now, most basophil activation test studies reported in the literature have used CD69 or CD203c as markers to quantify basophil activation after antigen-specific stimulation. Some technical variations such as the use of whole blood or isolated leukocytes, the addition of IL-3, the conditions of storage of the blood sample, the time of incubation with allergens and their concentration can affect the results of the basophil activation tests. The basophil activation test is more sensitive and specific than other in vitro diagnostic techniques in drug allergy. In various studies, its sensitivity in allergy to muscle relaxant drugs ranges between 36 and 97.7%, with a specificity around 95%. For betalactam antibiotics, basophil activation test sensitivity is 50% and its specificity 90%. For NSAIDs, sensitivity varies between 66% and 75%; specificity is about 93%. Basophil activation test reproduces in vitro hypersensitivity mechanisms involved in immediate-type allergic reactions, allows the diagnosis of allergic and pseudo-allergic reactions particularly for drugs, which are often not detectable by serological techniques, such as determination of specific IgE.

Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3 000 to 1 in 110 000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted.

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.

Allergic contact dermatitis (ACD) and photo-ACD are cell-mediated delayed hypersensitivity reactions of the skin caused by a wide range of substances. Topical ketoprofen (KP), a nonsteroidal anti-inflammatory drug (NSAID), can induce ACD and photo-ACD. Patients with ACD and/or photo-ACD to KP frequently show concomitant sensitization to other substances. The aim of this study was to identify the substances most frequently associated with sensitization to KP, and to evaluate, by means of computerized conformational analysis, whether this association could be due to crossallergy. 15 subjects with ACD and photo-ACD to KP were tested with the SIDAPA (Societa Italiana di Dermatologia Allergologica Professionale ed Ambientale) patch test standard series, including fragrance mix and its components (eugenol, isoeugenol, oak moss, geraniol, hydroxycitronellal, amylcinnamaldehyde, cinnamyl alcohol and cinnamaldehyde) and with the SIDAPA photopatch test series. Allergic reactions to cinnamyl alcohol were noted in all patients, whereas some patients also showed positive reactions to fenticlor, octocrylene and benzophenone-10. Computerized conformational analysis demonstrated that the structure of cinnamyl alcohol is similar to that of KP, whereas the structures of benzophenone-10, octocrylene and fenticlor are completely different. These results suggest that in patients with contact allergy to KP, concomitant positive reactions to cinnamyl alcohol are due to cross-sensitization, whereas simultaneous allergic reactions to fenticlor, octocrylene and benzophenone-10 should be regarded as cosensitizations.

Macrolides are characterised by their basic structure which is made up of a lactonic cycle with 2 osidic chains. They are classified according to the number of carbon atoms in the cycle : 14 membered macrolides (erythromicin, roxithromycin, dirithromycin, clarithromycin…), 15 membered (azithromycin) and 16 membered (spiramycin, josamycin, midecamycin…) macrolides. Epidemiological studies show that macrolides are amongst the safest antibiotics, but in these series, no drug allergy work up was performed. An immediate IgE dependent hypersensitivity has been shown with erythromycin in some cases. The mechanism is unknown and the skin tests are negative in most other cases. It would appear that the macrolide allergies are unlikely to be class allergies. Eviction is the treatment of choice. Desensitization has been successful in a few cases.

Drugs with anticoagulant activity, including heparins, hirudins, coumarins, and platelet aggregation inhibitors belong to the most widely used drugs. Hypersensitivity reactions from these agents are rare. However, due to their widespread use, they may have a considerable impact on patient safety and treatment. Accurate diagnosis of potentially lifethreatening adverse events and identification of alternatives is mandatory. We review hypersensitivity reactions caused by the different groups of anticoagulant agents and discuss the pathophysiological mechanisms, diagnostic possibilities and management options. According to patients histories the most common hypersensitivity reaction is intolerance to acetylsalicylic acid (ASA). Also localized erythematous plaques, occurring to subcutaneous application of heparins are rather common. Other hypersensitivity reactions are rare but may be life-threatening, e.g. skin necrosis due to heparin-induced thrombocytopenia. Rarely anaphylactoid reactions have been observed to ASA, heparin, and hirudin. Skin and provocation tests with immediate and late readings are the most reliable diagnostic tools for heparin- or hirudininduced urticaria/anaphylaxis or heparin-induced delayed plaques. Provocation tests may be used to identify safe alternatives. In cases of necrosis from heparins or coumarins, all in vivo tests are contraindicated. Most in vitro tests are not universally available, and with the exception of platelet aggregation tests, they have a low sensitivity. In some anticoagulant-associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. Typically, several tests are needed, and therefore the test procedures are time consuming.

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.

A new class of drugs, produced with the hybridoma technique, has been introduced and employed to treat many immunological diseases. This class consists of recombinant monoclonal antibodies, which can be chimeric, humanized or human. Predictably, there has been a rise in adverse hypersensitivity reactions to these therapeutic agents, whose pathogenic mechanisms are not yet well understood. Specific IgE has been demonstrated in a very few cases, and only in some of these recombinant antibodies. Skin tests are not done as a clinical routine screening. In the present article the mechanisms underlying hypersensitivity reactions to these drugs are analyzed, also in the light of the personal experience and that reported in the literature, with the aim of identifying potential risk factors and means of prevention of these reactions. For some drugs, infusion reactions may be prevented thanks to the the use of premedication. Moreover, symptoms of acute hypersensitivity during infusion can be successfully managed in the majority of cases by slowing the speed of administration. All these findings seem to confirm that the pathogenesis is not related to a true immediate (IgE-mediated) hypersensitivity in most cases. When the substitution of the drug that has triggered a hypersensitivity reaction is required, this is only possible if such an alternative drug exists (i.e., replacement of a chimeric antibody with a humanized or human antibody sharing the same target). As an alternative, desensitization protocols have been employed to induce a state of temporary tolerance to the drug in some cases, yielding successful results for infliximab and trastuzumab.

The need to offer first line therapy for primary and recurrent cancers has spurred the clinical development of rapid desensitizations for chemotherapy and monoclonal antibodies. Rapid desensitizations allow patients to be treated with medications to which they have presented with hypersensitivity reactions (HSRs), including anaphylaxis. Rapid desensitization achieves temporary tolerization to full therapeutic doses by slow administration of incremental doses of the drug inducing the HSR. Protocols are available for most chemotherapy agents, including taxanes, platins, doxorubicin, monoclonal antibodies, and others. Candidate patients include those who present with type I HSRs, mast cell/IgE dependent, including anaphylaxis, and non-IgE mediated HSRs, during the chemotherapy infusion or shortly after. Idiosyncratic reactions, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are not amenable to rapid desensitization. The recommendation for rapid desensitization can only be made by allergy and immunology specialists and can only be performed in settings with one-to-one nurse-patient care and where resuscitation personnel and resources are readily available. Repeated desensitizations can be safely performed in outpatient settings with similar conditions, which allow cancer patients to remain in clinical studies. We have generated a universal 12-step protocol that was applied to 413 cases of intravenous and intraperitoneal rapid desensitizations using taxanes, platins, liposomal doxorubicin, doxorubicin, rituximab, and other chemotherapy drugs. Under this protocol all patients were able to complete their target dose, and 94% of the patients had limited or no reactions. No deaths or codes were reported, indicating that the procedure was safe and effective in delivering first line chemotherapy drugs.

Signs supporting antiinflammatory effects of H1-antihistamines were first reported long ago, but their clinical relevance remains controversial, especially with respect to their ability to inhibit the release of histamine and other preformed mediators. Experimental studies have documented that H1-antihistamines may affect several inflammatory events, including chemotaxis and the survival of eosinophils, the expression of adhesion molecules, and the release of chemokines and cytokines from different sources, thus highlighting the potential for a modulation of chronic inflammation and immune responses. Interestingly, a specific inhibitory effect on Th2-type cytokine secretion has been demonstrated for some new generation antihistamines. The mechanisms responsible for the antiinflammatory activity of H1-antihistamines are still unclear, but are presumed to be both receptor-dependent and receptor-independent. Recent findings have indicated the ability of these drugs to down-regulate intracellular signaling pathways, i.e., NF-κB. In this article, the current knowledge and novel findings about the antiinflammatory action and mechanisms of H1-antihistamines are briefly reviewed and critically analyzed, from the standpoint of possible clinical implications with special reference to skin disorders.