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Background Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs. Methods Patients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT)analysing the proliferative response in T cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester (CFSE). Results The C-LTT showed a significantly lower sensitivity (29.4%) compared with dDC-LTT (61.8%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (15% vs 47.4%) and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3+ +CD4+ Th 1 or CD3+ +NK cells in SJS-TEN, CD3+ +CD4+ Th 1+NK cells in MPE and CD3+ +NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 68.4% and 100%, respectively, with an overall sensitivity of 87% and 85% of specificity in NIDHR. Conclusions The use of a flow-cytometry-based test, DCs as drug presenting cells, and focusing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test.

Background Analysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX. Methods Fifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay. Results Tolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B. Conclusions Cross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients. Background Betalactams (BLs) are the drugs most frequently involved in immediate (IgE-mediated) hypersensitivity reactions (IHRs) [1,2,3], which could be explained by their ability to act as haptens due to their high chemical reactivity against proteins [4, 5]. BL chemical structure is formed by a 4-membered ring (the so-called BL ring) that in penicillins is fused to a 5-membered thiazolidine ring, and in cephalosporins to a 6-membered dihydrothiazine ring (Fig. 1). These drugs have a side chain (R1) bound to the BL ring; besides, cephalosporins have a second side chain (R2) bound to the dihydrothiazine ring, whose chemical structures distinguish the different compounds [6, 7]. Yes

Background. Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardisation and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs. Methods. Patients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT) analysing the proliferative response in T-cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester. Results. The C-LTT showed a significantly lower sensitivity (33.3%) compared with dDC-LTT (65.2%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (14.3% vs 41.7%), and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3++CD4+Th1 cells in SJS-TEN, CD3++CD4+Th1+NK cells in MPE, and CD3++NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 66.6%, and 100%, respectively. With an overall sensitivity of 87% and 85% of specificity in NIDHR. Conclusions. The use of a flow-cytometry-based test, DCs as drug presenting cells, and focussing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test.

Background: Analysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CX), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX. Methods: Fifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay. Results: Tolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 88.2%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B. Conclusions: Cross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients.

A correct diagnosis of drug hypersensitivity reactions (DHRs) is very important for both the patient and health system. However, DHRs diagnosis is complex, time consuming, requires trained personnel, is not standardized for many drugs, involves procedures not exempt of risk, and in most cases lacks standardized in vivo and in vitro tests. Thus, there is an urgent need for improving the different approaches to diagnose patients with suspected DHRs. In this review, we have analyzed the advances performed in immediate and non-immediate DHRs diagnosis during the last two years and obtained several conclusions: the significant heterogeneity in current practice among centres illustrates the need to re-evaluate, update, and standardize in vivo tests and protocols for the diagnosis and management of patients with suspected drug allergy. Regarding in vitro tests, the latest studies have focused on increasing their sensitivity or on establishing the sensitivity and specificity for the tests performed with new drugs. There seems to be a consensus about combining in vivo and in vitro tests as the best way to increase the diagnostic accuracy.

[EN] BACKGROUND: Quinolones are the second most frequent cause of hypersensitivity reactions (HSRs) to antibiotics. A marked increase in the number of patients with HSRs to quinolones has been detected. OBJECTIVE: To describe the clinical characteristics of patients with HSRs to quinolones and present methods for their diagnosis. METHODS: Patients attending the allergy unit due to reactions suggestive of HSRs to quinolones were prospectively evaluated between 2005 and 2018. Diagnosis was achieved using clinical history, skin tests (STs), basophil activation tests (BATs), and drug provocation tests (DPTs) if ST and BAT results were negative. RESULTS: We included 128 subjects confirmed as having HSRs to quinolones and 42 found to be tolerant. Anaphylaxis was the most frequent entity in immediate HSRs and was most commonly induced by moxifloxacin. Patients were evaluated a median of 150 days (interquartile range, 60-365 days) after the reaction. Of patients who underwent ST and BAT, 40.7% and 70%, respectively, were positive. DPT with a quinolone was performed in 48 cases, giving results depending on the culprit drug: when moxifloxacin was involved, 62.5% of patients gave a positive DPT result to ciprofloxacin, whereas none reacted to levofloxacin. The risk of HSR was 96 times higher in subjects who reported moxifloxacin-induced anaphylaxis and 18 times higher in those reporting immediate reactions compared with clinical entities induced by quinolones other than moxi-floxacin and nonimmediate reactions. CONCLUSIONS: The diagnosis of HSR to quinolones is complex. The use of clinical history is essential as a first step. BAT shows higher sensitivity than STs. DPTs can be useful for finding safe alternative quinolones., The present study has been supported by the Institute of Health "Carlos III" of the Ministry of Economy and Competitiveness (grants cofounded by European Regional Development Fund: RETIC ARADYALRD16/0006/0001, RD16/0006/0010, RD16/0006/0019, and RD16/0006/0030). I.D. is a clinical investigator (B0001-2017) from Consejeria de Salud of the Andalusian government, Junta de Andalucia. N.P.-S. holds a Rio Hortega research contract (CM17/0014), and E.B. a Juan Rodes research contract (JR18/00049), both from the Institute of Health "Carlos III," Spanish Ministry of Economy and Competitiveness (grants cofounded by the European Social Fund).

Background The measurement of nasal specific IgE (NsIgE) in local allergic rhinitis (LAR) patients is challenging and shows variability. The objective of this work was to evaluate a minimally-invasive method of direct detection of NsIgE in patients with LAR to Dermatophagoides pteronyssinus (DP) using an automated immunoassay. Methods Fifty patients participated (LAR, n = 14; allergic rhinitis (AR), n = 20; healthy controls [HC], n = 16). Detection of NsIgE was performed by direct application of the solid phase of a commercial DP ImmunoCAP® test 24 hours after DP nasal provocation. Results There was no difference in the median volume of secretion absorbed by the solid phase of the ImmunoCAP test in the 3 studied groups (p = 0.17). According to receiver operating characteristic (ROC) curve analysis, NsIgE ≥0.1450 was the optimal cutoff point, obtaining in LAR patients 42.86% sensitivity with the highest specificity (100%), and 75% sensitivity and 100% specificity for AR. Conclusion This study demonstrates the detection of NsIgE to DP in LAR by using a simple, commercial device with high specificity.

Non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (NERD) is defined by the combination of chronic rhinosinusitis, nasal polyps, bronchial asthma, and hypersensitivity reactions involving upper and/or lower airways after the exposure to acetylsalicylic acid (ASA) and other NSAIDs. However, airway inflammation occurs even in the absence of exposure to these drugs, leading to disease progression with aggressive polyp formation and non-optimal controlled asthma and rhinosinusitis. In this review, we discuss current and potential management strategies of NERD. This management should be multidisciplinary and comprise medical and surgical treatment of the underlying diseases. In order to prevent reactions due to NSAIDs, avoidance of COX-1 inhibitors with provision of safe therapeutic alternatives should be indicated. However, avoidance of NSAIDs does not ensure disappearance of the airway inflammation and this progresses and persists for life. ASA desensitization followed by daily ASA therapy remains the gold standard of NERD treatment. It is indicated in patients with uncontrolled bronchial and nasal symptoms as well as in patients who require NSAID treatment for specific diseases, such as rheumatic or cardiovascular conditions. ASA desensitization improves upper and lower respiratory symptoms, reduces the need for new nasal surgeries and increases quality of life. Different ASA desensitization protocols have been reported, although the addition of intranasal ketorolac and lysine aspirin prior to an oral ASA schedule has made ASA desensitization safer and more efficient. New therapeutic strategies are being investigated and may provide an alternative treatment for those patients in which ASA desensitization are contraindicated or continuous ASA therapy is discontinued because of adverse effects. Among them, biologic agents are an important treatment option, useful for controlling symptoms of the upper and lower airways. More investigation studies into the mechanisms involved in NERD are needed in order to identify additional therapeutic targets.

Betalactams are the most widely used drugs against infections and the primary cause of antibiotic hypersensitivity reactions. Reaction patterns for different betalactams have been changing in accordance with consumption trends, and vary among countries. As a consequence, in vivo and in vitro tests have had to change with to keep up with new tendencies. Areas covered: This review is focused on advances in betalactam hypersensitivity diagnosis. Changes in in vivo methods have been limited to the inclusion of new haptens. In contrast, major progress has been achieved for in vitro tests since the 1960s, from the first description of immunoassays, the basophil activation test and the lymphocyte transformation test, to the more sophisticated assays developed in last years. Expert commentary: Issues with diagnosis are related to test sensitivity. In vivo tests show higher sensitivity, however they can be risky, especially in severe and life-threatening reactions. Therefore, we believe that in vitro tests should be the preferred method. Current efforts are under way to enhance their sensitivity. Only multidisciplinary approaches involving immunology, proteomics, nanotechnology and chemistry can help us to fully understand conjugate structures and mechanisms involved in hypersensitivity reactions to betalactams, and consequently lead to advances in in vitro methods.

Nasal provocation test (NPT) with allergens is a simple and safe technique recommended in different diagnostic and research settings. In the daily practice, NPT has proved to be very useful when there are discrepancies between patient’s symptoms and the results of skin or blood testing, for confirming the clinical relevance of a certain allergen in polysensitized patients and also for the diagnosis of new rhinitis phenotypes such as local allergic rhinitis (LAR). In the research field, nasal provocation test with allergens has been widely used in the study of mechanisms of inflammation and allergic response in subjects with allergic rhinitis (AR) and LAR and the study of pathophysiological mechanisms of response allergens to evaluate the therapeutic effect of drugs or immunotherapy in controlled clinical trials. There are key aspects necessary to achieve the best safety and reproducibility of the test, such as the characteristics of the allergen, application techniques, and measurement of the response that must be as objective as possible. The use of short protocols and simple methods of measurement allows the use of NPT in the daily practice as a diagnostic aid and not only a research tool reserved for clinical trials.

In the past years, several investigators have demonstrated the existence of local nasal responses in some patients with typical allergic rhinitis symptoms but without atopy and have defined a new phenotype called local allergic rhinitis (LAR) or 'entopy'. In a percentage of LAR subjects, the upper airway disease is also associated with lower airway symptoms. After the description of this phenotype, the differential diagnosis between LAR and nonallergic rhinitis (NAR) has become a challenge for the clinician. To correctly identify LAR patients is of high importance for treatment and management of these patients, and for an appropriate inclusion of patients in clinical trials and genetics studies. The treatment of LAR patients, in contrast with NAR, is oriented to allergen avoidance and specific treatment. Allergen immunotherapy, the aetiological treatment for allergic respiratory diseases, has demonstrated to be an effective and safe treatment in LAR, increasing immunological tolerance, and reducing the clinical symptoms and the use of medication. In this article, the important and novel aspects of LAR in terms of mechanisms, diagnosis and treatment will be discussed. Also, the involvement of the lower airway and the potential role of IgE in the bronchial disease will be also reviewed.

Fluoroquinolones (FQs) are important antibiotics for the treatment of a wide range of infectious diseases. However, while FQs are generally well-tolerated, both IgE and T cell-mediated hypersensitivity reactions can occur. Moreover, there has been an increase in the prevalence of these reactions in recent decades, probably due to higher levels of consumption. The diagnosis of allergy to FQs is complex and is based on clinical history, skin tests (STs), and determination of the drug-specific IgE using both immunoassays and basophil activation tests (BATs). However, these approaches have sub-optimal sensitivity and specificity: clinical history can be unreliable and overestimate the incidence of reactions, STs show a high rate of false positives, and in vitro tests have low sensitivity. Therefore, drug provocation testing is currently the best method to establish diagnosis; however, it carries certain risks and should be avoided for cases with a history of severe reactions. In order to improve the sensitivity and specificity of in vivo and in vitro methods, it is crucial to fully characterize the FQ antigenic determinants that are recognized by the immunological system. Current data indicate that groups at the C2–C6 positions of their chemical structure may form part of the antigenic determinant recognized by IgE. Moreover, their photostability can affect protein reactivity and therefore the formation of the hapten-carrier. All of these factors influence IgE and T cell recognition, the clinical response, and cross-reactivity and are the key for improving diagnostic methods. Additionally, a previous diagnosis of hypersensitivity to β-lactams has been reported to be a risk factor for FQ hypersensitivity, and this significantly decreases the therapeutic options for treating infectious diseases. Therefore, further studies are needed to obtain an accurate diagnosis, taking into account cross-reactivity, and to find alternative treatments.

Background and objective Suspicion of an acute allergic reaction is a common reason for attending the emergency department (ED). However, there are few comparisons between the initial diagnosis of suspected allergic reaction made in the ED with the definitive diagnosis made subsequently in the allergy department (AD). Objective: To compare details of the initial diagnosis made in the ED relating to allergy with the final diagnosis made in the AD. Methods Patients attending the ED of 2 hospitals with suspected allergic reactions were prospectively enrolled based on key words. A certified allergy specialist reviewed the ED records of these patients and, if these were suggestive of an allergic reaction, the patients were scheduled for further evaluation at the allergy clinic. Results In total, 2000 patients were enrolled between April 2013 and October 2015. Of these, 1333 passed the initial assessment and underwent further evaluation. Of the 1333 patients, 528 underwent an allergological study, and 206 were confirmed as being allergic. With respect to drug allergy, nonsteroidal anti-inflammatory drugs were the most common triggers, followed by β-lactams; in food allergy, plant-based foods were the most common. Only 16.4% of patients confirmed as having anaphylaxis in the AD were initially diagnosed with the condition in the ED. Conclusion Of the 528 patients who finally underwent the full allergological study, fewer than half were confirmed as allergic. Moreover, anaphylaxis appears to be underdiagnosed in the ED. Better communication between the ED and the AD is necessary to improve the diagnosis and management of these patients.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross-reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p

Quinolones represent an important category of antibiotics that are generally safe and well tolerated. However, in the last 12 years, there has been an increase in the incidence of hypersensitivity reactions to these antibiotics. Allergic reactions to quinolones can be classified as either immediate or delayed reactions. A precise diagnosis can be difficult as history is often unreliable and test reagents are not standardized; therefore drug provocation testing is generally accepted as the gold standard. There are currently no commercial in vitro tests for the evaluation of quinolones allergy, although determination of specific IgE, basophil activation test, and lymphocyte transformation test have been shown to be useful for in vitro evaluation. Patients with a diagnosis of hypersensitivity to quinolones must avoid the culprit drug; however, when it is the only therapeutic option available, drug desensitization may be required.

Local allergic rhinitis (LAR) is characterized by the presence of a nasal Th2 inflammatory response with local production of specific IgE antibodies and a positive response to a nasal allergen provocation test (NAPT) without evidence of systemic atopy. The prevalence has been shown to be up to 25% in subjects affected with rhinitis with persistence, comorbidity and evolution similar to allergic rhinitis. LAR is a consistent entity that does not evolve to allergic rhinitis with systemic atopy over time although patients have significant impairment in quality of life and increase in the severity of nasal symptoms over time. Lower airways can be also involved. The diagnosis of LAR is based mostly on demonstration of positive response to NAPT and/or local synthesis of specific IgE. Allergens involved include seasonal or perennial such as house dusts mites, pollens, animal epithelia, moulds (alternaria) and others. Basophils from peripheral blood may be activated by the involved allergens suggesting the spill over of locally synthesized specific IgE to the circulation. LAR patients will benefit from the same treatment as allergic patients using antihistamines, inhaled corticosteroids and IgE antagonists. Studies on immunotherapy are ongoing and will determine its efficacy in LAR in terms of symptoms improvement and evolution of the natural course of the disease.

Summary Hypersensitivity drug reactions (HDRs) encompass a wide spectrum of unpredictable clinical entities. They represent an important health problem, affecting people of all ages, and lead to a large strain on the public health system. Here, we summarize experiments that use high-throughput genomics technologies to investigate HDRs. We also introduce the field of systems biology as a relatively recent discipline concerned with the integration and analysis of high-throughput data sets such as DNA microarrays and next-generation sequencing data. We describe previous studies that have applied systems biology techniques to related fields such as allergy and asthma. Finally, we present a number of potential applications of systems biology to the study of HDRs, in order to make the reader aware of the types of analyses that can be performed and the insights that can be gained through their application.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent triggers of drug hypersensitivity with NSAIDs-induced urticaria/angioedema (NIUA) the most common phenotype. Loss of hypersensitivity has been reported for IgE-mediated reactions; however, it has not been assessed in nonimmunological reactions such as NIUA. We evaluated NSAID-hypersensitivity over time in NIUA patients. Methods Patients confirmed as NIUA by positive drug provocation test (DPT) with acetylsalicylic acid (ASA) during 2005-2012 (V1) were included (n=38). Subjects were prospectively re-evaluated by DPT with ASA/other NSAIDs at two time points between 2013 and 2015 (V2 and V3). Atopy was assessed by skin prick test (SPT) using inhalant and food allergens. Results Patients were evaluated at V1 and re-evaluated after 60 months (V2; IR:48-81) and a further 18 months (V3; IR:14-24). At V2, the majority (24; 63.15%) tolerated ASA and other NSAIDs (Group A) while 14 (36.84%) still reacted (Group B). At V3, all Group A patients remained tolerant; all Group B patients remained hypersensitive. The number of previous episodes reported at V1 and the percentage of reactions induced by ASA/ibuprofen were significantly lower in Group A (P=.005 and P=.006, respectively). Group A patients developed tolerance 72 months (IR:45-87) after their last evaluated reaction (V1); this interval was shorter in nonatopics (P=.003), patients who experienced reactions over 1 hour after NSAIDs administration (P=.001), and those who experienced isolated urticaria after NSAID intake (P=.024). Conclusions NIUA patients may develop tolerance to NSAIDs over time, a process that seems to be influenced by atopy and type of clinical reaction.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most commonly involved in hypersensitivity drug reactions. Such reactions can be due to the release of inflammatory mediators in the absence of specific immunologic recognition, or immunoglobulin E (IgE)- or T-cell-selective responses. The former include upper and lower airway symptoms in patients with chronic underlying respiratory disease, the exacerbation of chronic spontaneous urticaria, and the induction of cutaneous symptoms. The latter include selective responses to a single NSAID with good tolerance to strong cyclooxygenase-1 inhibitors, with a putative IgE or T-cell mechanism proposed. These reactions can be acute or delayed.

Background Patients can react to amoxicillin (AX) and clavulanic acid (CLV) taken in combination because of selective reactions to either drug. However, scant information exists concerning patients who react simultaneously to both compounds. Objective To analyze the mechanisms involved in 4 patients who developed allergic reactions to AX-CLV administration (3 with immediate IgE-mediated reaction and 1 with nonimmediate T-cell–mediated reaction) and who responded specifically to both AX and CLV. Methods Skin tests with benzylpenicillin (BP), AX, and CLV were done and, if necessary, drug provocation tests with BP/penicillin V, AX, and AX-CLV were carried out. In immediate reactors, serum specific IgE to benzylpenicilloyl and amoxicilloyl was determined by using the CAP-FEIA system (Pharmacia Diagnostics, Uppsala, Sweden), and basophil activation test to BP, AX, CLV, and AX-CLV was done. In nonimmediate reactors, immunohistochemistry of skin biopsy and analysis of dendritic cell maturation and T-cell–specific response to BP, AX, CLV, and AX-CLV at both acute and resolution phases of the reaction were conducted. Results All patients with immediate reactions (N = 3) had good tolerance to BP and penicillin V. Two cases also had specific IgE to AX and all had a basophil activation test positive to AX, CLV, and AX-CLV. The patient with a nonimmediate reaction exhibited dendritic cell and T-lymphocyte responses specific to both AX and CLV. Finally, the analysis of the cells infiltrating the skin and peripheral blood during the acute phase indicated a T H 1 pattern response. Conclusions Our study provides evidence that reactions to both AX and CLV can appear in the same patient.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

Background Reports of selective reactions to clavulanic acid (CLV) have increased in recent decades because of its increased prescription in combination with amoxicillin (AX) as AX-CLV. Basophil activation test (BAT) is used for diagnosing beta-lactam immediate hypersensitivity and is the only available in vitro assay for diagnosing patients with immediate hypersensitivity to CLV. However, few studies, and with limited numbers of patients have been published. Objective The aim of this study was to establish the sensitivity, specificity, and negativization rates of BAT to AX and CLV. Methods We studied 115 patients with immediate allergic reactions after AX-CLV treatment, 57 with selective reactions to AX (group A), 58 with selective reactions to CLV (group B), and 28 tolerant subjects. BAT was performed with AX in group A and with CLV in group B. A 4-year follow-up study was performed in patients with an initial positive BAT result. Results The overall sensitivity of BAT was 55%, specificity 89%, and positive predictive value (PPV) 96%. For group A, sensitivity was 47%, specificity 93%, and PPV 93%; for group B, sensitivity was 62%, specificity 89%, and PPV 92%. Follow-up study showed a faster negativization rate of BAT for group A, with around 40% of patients becoming negative at 12 months in both groups. Conclusions The high PPV of BAT to CLV shows its potential value as a complementary tool to the allergological workup of patients with immediate allergic reactions after AX-CLV treatment. Importantly, the assay should be done within the first 12 months after the reaction to reduce false-negative results.

Evaluate: the in vivo and in vitro responses to nOle e 1 in allergic rhinitis (AR) and local allergic rhinitis (LAR) patients sensitized to olive tree pollen (OL) confirmed by nasal allergen provocation test (NAPT). Methods: Twelve subjects with AR, 12 with LAR, and 12 subjects as control group (CG) were selected. Skin testing and NAPT with nOle e 1 were performed. ECP and tryptase were measured in nasal lavages before and after NAPT. Serum IgE to OL allergens were measured by ELISA. Basophil activation tests (BAT) with OL and nOle e 1 and dendritic cell maturation/proliferation studies were carried out. Results: All AR (12/12) and 10/12 (83%) of LAR had a +NAPT to nOle e 1. ECP levels in nasal lavages were significantly increased after NAPT in both AR and LAR compared with CG at 15 minutes (p

International audience; Quantitation of specific IgE by immunoassay is a recommended in vitro test for the diagnosis of immediate hypersensitivity reactions to betalactams (BLs), particularly when skin test results are negative. IgE antibodies that recognize the common nuclear structure of all BLs or the specific side chain structure can be mainly distinguished by immunoassays. The aim of this study was to develop an immunoassay system to detect IgE antibodies with different specificities. Cellulose discs conjugated with benzylpenicillin (BP), amoxicillin (AX) or both drugs, with poly-l-lysine (PLL) as carrier molecule, were used as solid phases in the radioallergosorbent test (RAST). Direct and inhibition radioimmunoassay studies were made to verify the structures recognized by serum IgE antibodies from penicillin-allergic patients. Our results indicated that the addition of both haptens did not decrease the capacity to capture IgE when serum specific to either BP or AX was used, at least in terms of sensitivity. In addition, the inclusion of two haptens improved significantly the levels of IgE detection in patients who recognized both BP and AX. Therefore, the use of a solid phase with a carrier molecule conjugated with two determinants (AX and BP) is helpful to recognize IgE antibodies against either of these determinants and is useful for screening sera with different specificities.