Search

Purpose of review NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders. Recent findings In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the underlying disease. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions. Summary The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entities. As the number of patients affected with NSAIDs is important, further studies are warranted.

OBJECTIVE Cross-intolerance to NSAIDs is a class of drug hypersensitivity reaction, of which NSAIDs-induced urticaria and/or angioedema (NIUA) are the most frequent clinical entities. They are considered to involve dysregulation of the arachidonic acid pathway; however, this mechanism has not been confirmed for NIUA. In this work, we assessed copy number variations (CNVs) in eight of the main genes involved in the arachidonic acid pathway and their possible genetic association with NIUA. MATERIALS AND METHODS CNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3, and PTGER4 were analyzed using TaqMan copy number assays. Genotyping was carried out by real-time quantitative PCR. Individual genotypes were assigned using the CopyCaller Software. Statistical analysis was carried out using GraphPad prism 5, PLINK, EPIDAT, and R version 3.1.2. RESULTS AND CONCLUSION A total of 151 cases and 139 controls were analyzed during the discovery phase and 148 cases and 140 controls were used for replication. CNVs in open reading frames were found for ALOX5, PTGER1, PTGER3, and PTGER4. Statistically significant differences in the CNV frequency between NIUA and controls were found for ALOX5 (Pc=0.017) and PTGER1 (Pc=1.22E-04). This study represents the first analysis showing an association between CNVs in exonic regions of ALOX5 and PTGER1 and NIUA. This suggests a role of CNVs in this pathology that should be explored further.

Metamizole is a NSAID that has been banned in several countries because of its toxicity. It is often involved in selective hypersensitivity reactions and most hypersensitivity patients develop anaphylaxis. Metamizole is rapidly metabolized, and metabolic profiles are related to genetic factors. We analyzed whether genetic determinants of metamizole metabolism influence the risk of developing hypersensitivity in 265 patients diagnosed with hypersensitivity to metamizole and 362 healthy individuals who tolerated metamizole. Slow acetylation is associated with an increased risk of developing selective hypersensitivity to metamizole [odds ratio for slow alleles=2.17 (95% confidence interval=1.44-3.27); P=0.00016], and particularly anaphylaxis [odds ratio=4.77 (95% confidence interval=2.28-9.98); P=0.000006], with a significant gene-dose effect. The association was not identified in patients with cross-hypersensitivity. Cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) genotypes did not influence risk association. Our findings raise the hypothesis of genetically determined metabolic variability as a risk factor for developing anaphylaxis with metamizole.

Purpose of review Innate immune responses are attracting increasing interest from researchers in the field of drug allergy. This review discusses recent advances in the understanding of several innate immune components in delayed cutaneous hypersensitivity reactions to medications, with special attention on severe reactions. Recent findings The mechanism of activation of dendritic cells in response to drugs is being unravelled. Activated monocytes and macrophages have been found in affected skin of bullous diseases. Increased gene expression of monomyeloid cell products including several ‘alarmins’ or endogenous damage-associated molecular patterns has been described in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Natural killer (NK) cells from patients respond to drugs in vitro. In-vivo, NK cells may contribute to severe diseases through the secretion of effector molecules such as granulysin. The innate receptor CD94/NKG2C is expressed by NK cells and cytotoxic T lymphocytes in SJS/TEN and triggers degranulation in response to human leukocyte antigen-E-expressing keratinocytes. T cells with innate activities have been detected in patients during severe acute reactions. Summary Humoral and cellular components of the innate immune response have been identified in association with delayed drug hypersensitivity reactions. Their participation in certain diseases may explain the variability of phenotypes in hypersensitivity reactions to medications.

The purpose of this review is to describe new insights into the pathophysiology and clinical characterization of 'local allergic rhinitis', a new phenotype of rhinitis that may affect individuals previously diagnosed with nonallergic rhinitis.Several studies have shown the existence of local allergic rhinitis with nasal production of specific IgE (sIgE) antibodies in the absence of atopy in over 40% of nonallergic rhinitis patients. Evidence for this entity is supported by the clinical symptoms, the local production of sIgE and a leukocyte-lymphocyte inflammatory pattern, with an increase in the nasal fluids of eosinophils, mast cells and T lymphocytes during natural exposure to aeroallergens, as well as a positive immediate and dual response to a nasal allergen provocation test with local production of tryptase and eosinophil cationic protein and an increase of nasal sIgE to inhalant allergens.On the basis of these new findings, an advanced diagnostic approach is proposed in patients with symptoms suggestive of allergic rhinitis but negative results in skin prick test and serum sIgE. Detection of local sIgE in nasal secretions during natural exposure to aeorallergens and a positive nasal allergen provocation test with local production of tryptase, eosinophil cationic protein and sIgE are useful to detect patients with local allergic rhinitis.

Purpose of review A number of studies over recent years have shown the relevance of nonimmediate immunological reactions to drugs and emphasized the need for these reactions to be studied in greater depth, including both in-vivo and in-vitro tests and provocation studies. Recent findings Several clinical entities are involved, ranging from mild to severe reactions. Nonimmediate reactions have a special tropism for the skin, although other organ-specific or systemic reactions may also occur. In the affected organ, the drug acts as a hapten or protohapten, originating an immunological stimulus that is followed by recruitment of T lymphocytes and other types of cells, depending on the reaction. This involves a trafficking phenomenon in which these cells use different receptors that interplay with their corresponding ligands in the tissue. In addition, a number of activation and cytotoxic markers are also expressed, which are related with disease severity. Summary Current studies provide overwhelming evidence of the interaction between the organ involved, very often the skin, and immunocompetent cells. This is of relevance for diagnostic and therapeutic approaches.

Purpose of review Selective immediate reactions to NSAIDs imply that patients develop a urticarial/ anaphylactic response to a single drug with good tolerance to other compounds. No systematic review of these reactions has yet been made. Recent findings With the increase in consumption of NSAIDs, these have become one of the most common drugs inducing hypersensitivity reactions. Although cross-intolerance reactions are the most common, a significant proportion is selective responses. As specific IgE antibodies are not always found, there is only indirect evidence supporting an IgE-mediated mechanism in selective NSAID reactors. Summary Selective immediate reactions to NSAIDs must be considered when a patient develops urticaria or anaphylaxis after intake of one drug with good tolerance to drugs from other groups or even a drug from the same group with a slightly different chemical structure. Further research is required to identify the antigenic determinant structures recognized.

Purpose of review Maculopapular exanthema is a common cutaneous manifestation of many diseases produced by several agents able to activate the immune system, the most common of which are drugs and viruses. In spite of its high frequency, knowledge of the molecular mechanisms involved remains scarce. Recent findings The cytokine patterns in maculopapular exanthema have a Th1 or Th0 pattern, according to whether the reaction is induced by a drug or a virus, respectively. Additionally, the involvement of CD4 T-lymphocytes with cytotoxic capabilities has been shown in the former. Different chemokines and their receptors are also involved in skin homing, such as CCL20, CCL27, CXCL9 or CXCL10, and oxidative stress can help exacerbate the symptoms. Summary These findings may be very important for the diagnostic evaluation of these entities and for the development of new tools for diagnosis and treatment.

Purpose of review To analyse the available data in the field of immediate allergic reactions to beta-lactams, with particular emphasis on more recent studies, and to comment on the future role of this group of antibiotics. Recent findings The world of beta-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. Summary Results indicate that evaluation of immediate reactions to beta-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.

Although fluoroquinolones (FQs) are generally well-tolerated antibiotics, increasing numbers of hypersensitivity reactions have been reported. These can be evaluated in vitro by basophil activation tests (BATs); however, sensitivity is not optimal. Many factors could influence sensitivity such as basophil activation markers. The objective of this study was to evaluate the influence of 2 different activations markers, CD63 and CD203c, on the sensitivity of BAT to FQ. We studied 17 patients with immediate allergic reactions to FQ. BAT was performed with moxifloxacin and ciprofloxacin using CD193 (CCR3) for basophil selection and CD203c or CD63 as activation markers. Stimulation with ciprofloxacin induced a significantly higher expression of CD63 in ciprofloxacin-allergic patients compared to moxifloxacin-allergic patients (P = 0.002). In patients allergic to moxifloxacin with anaphylactic shock, we have observed an increase in the percentage of cells that upregulate CD203c, whereas patients with anaphylaxis preferentially upregulate CD63. The best sensitivity–specificity was obtained using a cutoff of 3 and the culprit FQ, using CD203c for moxifloxacin-allergic patients (sensitivity = 36.4%; specificity = 94.4%), and CD63 for ciprofloxacin-allergic patients (sensitivity = 83.3%; specificity = 88.9%). A negative correlation was found between the upregulation of CD63 and CD203c and the time interval between the reaction occurrence and the performance of the test (Spearman r = −0.446; P

In this new issue of Current Opinion in Allergy and Clinical Immunology, five major areas of research in the field of hypersensitivity reactions to drugs in the past year are reviewed. The manuscript of Blanca-Lopez et al.[1] is devoted to hypersensitivity reactions to NSAIDs. NSAIDs are the drugs most frequently involved in hypersensitivity drug reactions [2,3]. In a study published recently, it has been shown that almost 50% of the cases had confirmed NSAIDs hypersensitivity followed by 20% with beta-lactam hypersensitivity. Both groups of drugs together contributed to more than the 70% of drug hypersensitivity reactions [2]. These results are consistent with data published by other groups [3]. There has been increasing interest in the nonpulmonary manifestations of NSAID hypersensitivity, which have not been studied in detail. An expert group from the European Academy of Allergy Asthma and Clinical Immunology has provided a consensus document, carefully defining these reactions [4]. Five major clinical entities are now recognized, and it is expected that in the future major subgroups will be identified making genome-wide association studies more specific to each clinical entity [5–7].