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Rechallenge test was performed for patients with negative skin tests. We reviewed 39 medical records of patients with suspected FDE during the period from to The culprit drug was identified in 35 patients. There were 14 males and 21 females. The number of episodes varies between one and five times and 23 patients have had at least two episodes.

Multiple eruptions was diagnosed in 32 patients and bullous eruptions were observed in 12 cases. FDE lesions were seen in one case in genital areas. The most common offending drugs were mefenamic acid in eight The determination of the culprit drug was made possible by a positive patch test in 24 out of 39 patients.

For the remaining cases, accidental rechallenge or oral provocation helped to establish the culprit drug. We demonstrated in our study that NSAIDs are the most causative drugs of FDE and pointed out the usefulness of drug patch tests in identifying the culprit drug.

Raising awareness of this side effect and its elicitor drugs will increase the likelihood of prompt diagnosis and resolution after the drug withdrawal.

Diltiazem is a calcium channel blocker that has been used topically for the treatment of anal fissures or hemorrhoids. Few cases of allergic contact dermatitis, and a single case of systemic contact dermatitis to diltiazem have been report. The patient had never used topical or systemic diltiazem neither any other calcium channel blocker and she never suffered local or systemic symptoms from local anesthesia in dental treatments.

Diltiazem used systemically can also cause of delayed drug eruptions often with positive patch tests. This example of diltiazem further strengthens the relation between allergic contact dermatitis and T-cell mediated drug reactions, where systemic contact dermatitis can be considered one type of such drug eruptions.

Acute generalized exanthematous pustulosis AGEP is a rare and severe cutaneous adverse reaction. Recent studies have suggested an association between mutations in interleukin receptor antagonist gene ILRN and the onset of pustular generalized such as generalized pustular psoriasis GPP and AGEP.

In literature, only one case of AGEP induced by dihydrocodeine phosphate in a patient with psoriasis vulgaris and a heterozygous IL36RN mutation has been reported. Two weeks later, she developed fever and pruritic skin eruption.

Physical examination showed a diffuse erythema marked in the intertriginous folds dotted with nonfollicular pustules. Histopathological examination was in accordance with AGEP. After obtaining informed consent from patient, a sequential oral provocation tests were separately performed.

After informed consent, genomic DNA was extracted from venous blood sample. The four coding exons of IL36RN gene including its intron—exon boundaries were amplified by polymerase chain reaction PCR and Sanger sequencing was performed. No IL36RN mutations were found. We have reported an unusual case of AGEP caused by codeine in a patient with a history of psoriasis and confirmed by an oral provocation test. Clinicians should be aware of this side effect of codeine especially in patients with a history of psoriasis.

We reviewed patch test data of patients referred to our dermatology clinic between and for the study of a well-characterized DRESS. We describe eight patients 6 males and 2 females; mean age Antibiotics are frequently administered during DRESS, due to the initial prodrome, which mimics an acute bacterial infection.

It has been suggest that during DRESS, exposure to non-related drugs, such as antibiotics, amitriptyline and acetaminophen, could induce a neosensitization, with a new DRESS episode occurring during re-challenge with the second drug, even in the absence of the initial culprit. The suggested mechanism is a massive nonspecific activation of the immune system, after the initial immunosuppression stage, which enables antigen presentation leading to the development of specific T cells and neosensitization.

Reproducibility of positive patch test reactions to antibiotics, even after several years, seems to support the strength of this T cell reaction. Symmetrical drug related intertriginous and flexural exanthema SDRIFEformerly named baboon syndrome, is an uncommon cutaneous reaction that occurs after the systemic administration of drug-related allergens. A type IV delayed hypersensitivity immune response is thought to be involved, thus patch tests are used to identify the causative drug.

However they are negative in one-third to one-half of the patients. In most cases beta-lactam antibiotics are the trigger, but other drugs may be involved.

On the other hand, allergic reactions to macrolide antibiotics appear to be relatively uncommon 0. Often a drug reaction is empirically attributed to a drug and a confirmation study is not requested. The lesions evolved with a little peeling and slowly improved with oral corticoid, topical corticosteroid and skin hydration leaving lesions of hyperpigmentation. The patient remembered having a similar reaction some years ago, which was attributed to an antibiotic prescribed for pneumonia.

Amoxicillin—clavulanate plus azithromycin were prescribed at that time and amoxicillin was taken as the culprit drug. LTT was negative for amoxicillin—clavulanate, but and positive for azithromycin. Lymphocyte transformation test LTT played a key role in the diagnosis, considering the negativity of patch tests. Assuming culprit drugs based on frequency criteria must be avoided and an allergic work-up must be performed.

Adverse cutaneous drug reactions ACDR are drug-induced response of the skin in regards of its structure or function, appendages or mucous membranes. Husain, Drug provocation tests DPTs are often needed when evaluating patients with suspected drug hypersensitivity reactions. Drug skin pacth tests can reproduce delayed hypersensitivity to drugs and entail a moderate reexposure of patients to offending drugs Barbaud, and considered as a good choice for evaluating the patients with severe drug reaction including DRESS.

She was suspected cephadroxil and mefenamic acid as a causative drugs. Those drugs was administered after she underwent the breast tumors resection. Three weeks after consumed those drugs, she had a skin rash all over the body and fever. Based on the physical examination she had a lympnode enlargement, lymphocytosis with atypical lymphocyte, trombocytopenia and hepatic problems Patients was diagnosed with probable DRESS and RegiScar score 5. In this case report, we reported a years-old female with the history of DRESS possibly due to cephadroxil and mefenamic acid.

Covalent binding of flucloxacillin to proteins, followed by antigen processing and presentation of drug-derived antigenic determinants, may drive the adverse event. Currently, little is known about the proteins that are haptenated by flucloxacillin, and whether the modification of intracellular proteins leads to the presentation of functional antigenic drug-modified peptides. A flucloxacillin-specific antibody was used as a precise tool for pinpointing intracellular haptenated proteins that were subsequently identified by state-of-the-art LC—MS.

This approach was also used to study the uptake, distribution and protein binding of flucloxacillin in immortalised and primary cells from liver and the immune system.

Flucloxacillin modified proteins were detected, and their potential contribution to the development of iDILI will be explored. Flucloxacillin-modified peptides were successfully synthesized and purified, to be used in functional T-cell assays.

Formation of covalently modified drug-protein adducts is thought to be the molecular initiating event in many immunological drug reactions. However, our data are the first to fully characterize the nature of the drug-derived antigens presented to the immune system in the context of a HLA molecule. The diagnosis of delayed-type drug hypersensitivity DH is based on patient history, skin testing, challenge tests and in vitro tests. The lymphocyte transformation test LTT is the most commonly used in vitro tool for this purpose bearing a high specificity.

However, limited sensitivity and the use of radioactivity restrict its use and demand for alternatives. In our work, we could demonstrate an enhanced sensitivity by quantification of multiple mediators in supernatants of well-defined drug allergic patients. Granzyme B is sensitive for rather cytotoxic reactions e. We could demonstrate that some cytokine release occurs in the absence of strong proliferation, which explains the better sensitivity of cyto - LTT compared to conventional LTT.

The cyto - LTT is a simple approach which improves the sensitivity of in vitro assays by analyzing several mediators at once, and still retains excellent specificity. In addition, by carefully choosing phenotype-specific cytokines the cyto - LTT helps in defining the clinical picture of DH. The main disadvantage is the rather high cost of reagents and equipment.

Severe delayed-type hypersensitivity reactions occur in certain patients upon treatment with sulfamethoxazole SMX.

T-cells are activated through binding of the metabolite to proteins or through the direct modification of MHC-bound peptides. In vitro, SMX-NO has been shown to modify cysteine residues in glutathione, designer peptides and proteins; however, the presence of these adducts have not yet been identified in patient serum. HSA was depleted from patient serum and from cell culture media using affinity chromatography. In addition to the known cysteine adducts, multiple haptenic structures were found on lysine and tyrosine residues when SMX-NO was incubated with HSA in vitro.

On lysine residues two haptenic structures were identified including an arylazoalkane adduct and a Schiff base adduct. On tyrosine residues a direct displacement of the nitroso functional group by the hydroxyl side chain was observed. Interestingly, these adducts are labile to heat and susceptible to hydrolysis as shown by the presence of allysine. Multiple haptenic adducts were successfully identified in vitro and in patient serum.

Also, the degradation of these adducts to allysine could indicate signal 2 required for T-cell activation. Mass spectrometric identification of modified proteins could have a role in the diagnosis of drug hypersensitivity. Hepatitis C virus HCV is a potentially life-threatening viral infection. Most infected patients develop chronic HCV infection ultimately resulting in severe liver disease including hepatocellular carcinoma, liver fibrosis and cirrhosis.

Treatment with teleprevir, an NS3. These manifestations, along with the delayed onset and slow resolution after drug discontinuation are indicative of a T-cell mediated hypersensitivity reaction. Due to competition from newer and safer therapies, telaprevir was withdrawn from use; however, it remains an interesting model compound to study mechanisms of drug hypersensitivity reactions.

After priming, cultures were restimulated with a second batch of dendritic cells and analysed for drug-antigen specific proliferation by [ 3 H]-thymidine incorporation.

Cultures were then serially diluted to perform T-cell cloning, Stará Garda - Limetal - Limetal (CD. From two healthy donors, we identified T-cell clones responsive to telaprevir and the R-diastereomer.

In this study, we identify the propensity of telaprevir to generate skin-homing cytotoxic T-cells that may induce the cutaneous reactions observed in patients. Proton pump inhibitors PPI has been known to induce type I hypersensitivity reactions.

We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. The LAT by measuring granulysin showed a sensitivity of Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross-hypersensitivity reactions to alternative structurally similar PPI.

In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered. Basophil activation tests BATs have been shown to be a useful research tool in the assessment of allergy, with many reported cases of how they can be used to assess responses to anaesthetics, antibiotics and venoms. We validated the assay for for routine clinical use in patients attending Sheffield Allergy clinic by performing the test on patients presenting with likely anaesthetic, antibiotic drug allergy.

The assay detects CD63 expression after allergen stimulation to assess basophil response. The results of all the basophil activation tests performed since the assay was introduced in were compared to the clinical outcome where available. Clinical outcomes were obtained via patient notes, letters and at clinical multidisciplinary team MDT meetings. In total tests were performed on patients. Therefore a total of results were evaluable for different allergens 29 removed which were tested on non-responders and external requests.

Awaiting challenge test. They share similar problems of false negativity and false positivity with sIgE, and skin testing. Interpretation requires considerable allergy experience but they can aid in decision making when conventional allergy tests give conflicting results. BATs are a complementary diagnostic tool in the study of immediate hypersensitivity reactions and may make it possible to avoid challenges in some cases. Chlorhexidine CHX is a widely utilized disinfectant for skin and mucosal surfaces as well as medical devices.

CHX is a biguanide compound with two chlorophenyl endings linked by a hexamethylene chain. CHX can cause rarely IgE-mediated anaphylaxis. Alexidine ALXanother biguanide with similar hexamethylene center but 2-ethyl-hexyl-end groups instead of the aromatic endings, has similar bactericidal properties and represents a potential substitute for CHX.

The allergic potential of ALX is unknown and was the focus of this study. Non-specific binding of IgE in in vitro IgE allergy tests contribute to false-positive Stará Garda - Limetal - Limetal (CD. Anaphylaxis to antiseptics is a rare complication in chronic wound care.

Most of the cases are due to a chlorhexidine allergy with single cases reacting to polyhexanide. So far, no anaphylactic reaction to the antiseptic octenidine has been reported. We present a case of a year old woman suffering from repeated severe anaphylaxis requiring hospitalization after wound care with lidocain as well as an octenidine containing wound gel.

During the acute phase, tryptase levels rose to max. Skin prick test and basophil activation test BAT were positive to octenidine. Additional testing with structurally related compounds showed positivity to chlorhexidine, alexidine and polyhexanide as well.

The broad cross-reactivity as well as the negative result for metformin containing biguanide motives but no hexamethylene structure points towards a hexamethlyene specificity of the involved IgE.

To our knowledge, it is the first report of an anaphylactic reaction to octenidine, based on a reactivity to the hexamethylene motif explaining the broad cross-reactivity to topical antiseptics.

Our case report shows that not only the classical biguanide structure of chlorhexidine can be a sensitizer. Octenidine as well as polyhexanide might be emerging allergens and structurally unrelated topical antiseptics are important as safe alternatives.

Risk-stratification protocols using in vivo skin tests and desensitization protocols may enable patients with such HSRs to still receive first-line chemotherapy treatment relatively safely. However, allergy skin testing is invasive and has limited clinical specificity and sensitivity. We validated the sIgE test using 3 different groups of patients and evaluated during chemotherapy the biomarkers in sera of two patients with carboplatin-induced HSRs. Based on sIgE measurements in group C, the analytical cut-off setting for both haptens was set at 0.

No sIgE against both the haptens could be detected in group B above the cut-off. Serum samples around HSRs of the patients in group A demonstrated measurable IgEs against at least one of the haptens patient 1: 6. The presence of sIgG4 could not be proven in group B except for one patient.

The approach looks promising and should be evaluated in groups with larger sample sizes. Ondansetron Hydrochloride is a selective serotonin 5-HT3 receptor antagonist used as an antiemetic drug, being generally well tolerated. Hypersensitivity reactions to ondansetron have been reported in either perioperative or emetogenic chemotherapy settings. The wider use of the drug for example in Emergency Pediatric Department, may increase the frequency of reactions. Skin tests are positive in most reported allergic patients and the maximal non-irritating concentration was defined.

The Basophil Activation Test BAT has been studied for the past decade and showed to be useful particularly in the study of allergy to some antibiotics, neuromuscular blockers and pyrazolones. Our aim was to evaluate BAT as a tool to study ondansetron allergy.

BAT was also executed in every case. Two patients were from pediatric ages. BAT was positive in two cases, one of them a child with negative skin tests. BAT may be a useful tool to support Stará Garda - Limetal - Limetal (CD final diagnosis particularly in patients with life-threatening reactions. Currently, the antigenic determinants are anchored to mono or polydisperse polymers or proteins that are embedded in hydrogels with which the test is performed.

The tests are carried out in expensive bulky autoanalyzers that analyze only 5 BLCs, one by one, and display low sensitivity and false negative and positive results. This is probably because the tests use determinants that are not specifically recognized by the IgEs.

Also, the differences between IgEs of different patients make very difficult to have a constant response. Moreover, validation of the tests is a challenging task to perform. For all these reasons, the development of reliable, portable and cost-effective in vitro test is a highly demanded solution for primary and secondary care.

The development of i n vitro methods require multidisciplinary approaches that take into account the chemical structure of the determinant, the way how the determinants are anchored, IgE exposition and the patient immune response. A mass consumer electronic DVD system, offering advantages to serve as basis of health devices for diagnosis of allergy, is presented.

The system incorporates a disc drive as a portable optical detector, and digital versatile compact discs on which a set of determinants in microarray format are covalently immobilized.

The anchoring is carried out through different reactive sites of the BLCs, following the carbodiimide and carbohydrazide chemistry. The centrifugal system on disc is a striking and promising multiplex alternative easily transferable into clinical practice for the rapid diagnosis of allergy to all BLCs families in a selective and sensitive manner because of its cost efficiency, scalability to different scenarios, minimal sample volume and reagent consumption.

Toxic epidermal necrolysis TEN is a life-threatening and blistering adverse drug reaction, characterized by massive epidermal necrosis. To further characterize the phenotype of skin-infiltrating lymphocytes at the acute phase of TEN, we conducted a prospective study on the blood and blister fluids from 16 TEN patients, using flow and mass cytometry, as well as next generation TCR sequencing.

They expressed elevated levels of markers of inflammatory activation and displayed a poly-cytotoxic phenotype since they co-expressed Granulysin, Granzyme B, Granzyme A, Perforin and TWEAK, as demonstrated by unsupervised mass cytometry analysis. By comparison, the TCR repertoire bias and poly-cytotoxic phenotype were far less marked in the cells extracted from the inflamed skin of MPE patients. Deep phenotype analysis and next generation TCR sequencing unveils new potential treatment targets and severity biomarkers.

Drug hypersensitivity reactions can present with various skin manifestations. The role of the skin infiltrating immune cells in the pathogenesis is well characterized, but literature data is conflicting about their distribution in the peripheral blood. In our present study we looked for patterns in the distribution of different subtypes of peripheral blood mononuclear cells PBMCs in different manifestations of drug hypersensitivity reactions.

Forty-five patients with the following acute drug hypersensitivity symptoms were enrolled in the study: urticaria 9drug-induced vasculitis 3maculopapular exanthema 17erythema multiforme 4Stevens—Johnson syndrome 3DRESS 3fixed drug exanthema 3and EBV-associated drug rash 3. With increased patient number, this type of flow cytometric analysis of peripheral blood may prove to be of clinical use.

Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in the multidrug therapy for leprosy. Perioperative anaphylaxis is an acute systemic hypersensitivity reaction occurring during general anesthesia and frequently triggered by neuromuscular blocking agents NMBA. It is considered to rely on specific IgE antibodies against an allergen and histamine release by mast cells and basophils. However, data from animal models and clinical study results NASA study suggest an alternative pathway dependent on specific IgG antibodies and involving platelet-activating factor.

Drug-specific T cells have been well documented mostly in antibiotic allergy, but definitive evidence of NMBA-specific memory T cells as well as data on their clinical relevance is lacking.

ROC curve analysis of CD levels showed an area at 0. Cytokine production analysis showed mainly INFg-producing T cells. We characterize for the first time INF-g producing NMBA-specific T cells and show they could represent an interesting additional diagnostic tool in perioperative anaphylaxis particularly when usual tests are negative. The role of HLA in these adverse reactions have been hypothesised in three main ways; the Hapten model, the Pharmacological Interaction model and the Altered Peptide Repertoire model.

There is therefore growing interest in searching for evidence supporting this model for other ADRs using bioinformatics techniques, including molecular docking. In silico docking was used to assess the utility and reliability of well-known docking programs when addressing challenging HLA—drug interactions.

The other programs used, excluding ROSIE, were able to identify the correct sub-pocket of binding and distinguish between the risk and control alleles. The purpose of this exercise was to compare multiple docking programs to assess their performance with these challenging HLA-ADR cases. It was found that the binding mode could not always be predicted but the programs used were mostly able to identify the correct sub-pocket and distinguish between risk and control alleles.

Furthering our understanding of the potentials and limitations of docking small molecules to HLA is important to aid understanding of the underlying mechanisms. Identifying how the binding varies between risk and control alleles may enable us to make predictions of potential ADRs and identify polymorphisms contributing to direct binding. For T cell mediated delayed-type drug hypersensitivity reactions, assays such as the lymphocyte transformation test are utilised for diagnostic purposes, but an approach that predicts potential immunogenicity of drugs during development would be preferable.

Both the patient and Pharma can be aided by the successful prediction of immunogenic drugs at an early stage. The main challenge is to develop and optimize simplified assays that account for and incorporate the multi-factorial nature of drug hypersensitivity, including: HLA associations, immune checkpoint signaling and different forms of drug antigen.

Aim: To develop and optimise assays that 1 assess the number of individuals and 2 the number of T cells that respond to a given test compound. Responses were determined according to their stimulation index as low 1. Responses to other compounds were detected in a lower number of donors. The T-MWA provided a more detailed picture of the immunogenicity of the test compounds. ELISA experiments for cytokine secretion solidified findings; showing similar levels of response as the proliferation assays.

We have successfully transformed complex laboratory-based T cell priming assays into simplified methods that may in the future be used to screen the intrinsic immunogenicity of drugs and chemicals.

The methods use a traffic light system to identify compounds with a low, moderate or high risk of causing immune reactions when administered widely to patients. Approximately 0. Antigen presenting cell APC fixation assay and APC pulsing were performed to determine the mechanisms of antigen presentation.

DDS-NO protein adducts were characterized by mass spectrometry. Idiosyncratic drug-induced liver injury iDILI has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Considering their known anti-inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development.

Nonsteroidal anti-inflammatory drugs NSAIDsamong the most highly consumed medicines worldwide, are the main triggers of drug hypersensitivity reactions DHRs. According to the cyclooxygenase-1 COX-1 hypothesis, COX-1 inhibition shunts the arachidonic acid metabolism towards the synthesis of cysteinil-leukotrienes, which in turn elicit a hypersensitivity reaction in susceptible individuals.

A total of NIUA patients and healthy controls with no significant age and sex differences were included. Genotyping was perfomed using the iPlex Sequenom MassArray technology. Exposure to the antibiotic amoxicillin AX is associated with the development of several adverse drug reactions including liver and skin injury. AX-specific T-cells have been detected in patients presenting with both liver and skin reactions, suggestive of an immune disease aetiology.

These reactions do not occur in every drug administered patient therefore their origin may be attributed to the individual biology of a patient. Several AX-modified proteins have been found including AX conjugated with human serum albumin. However, as yet, a role for such adducts in the activation of T-cells has not been described.

This study aimed to investigate the role of AX-peptide adducts in the activation of a drug-specific T-cell response. Positional derivatives containing the same anchors with lysine in different TCR contact sites were also generated.

Subsequently, T-cells were cloned by serial dilution and repetitive mitogen stimulation. Well growing clones were tested with AX, AX-modified peptides and unmodified peptides. Clones were expanded and characterized in terms of cellular phenotype and cytokine release.

AX-peptide specific clones proliferated and secreted cytokines such as IFN-g in a dose dependent manner with high specificity to the antigen showing no cross reactivity with free drug, with unmodified peptide or with positional derivatives at different TCR contact sites. Here we present a strategy to study T-cell responses to drug-modified peptides in individuals expressing specific HLA alleles associated with immunological drug reactions.

Further work on designer drug-modified peptides could help 1 elucidate the principal antigenic signals in drug-induced skin and liver injury and 2 develop reagents to improve diagnosis. The effect of the abacavir-induced self-peptides on T-cell activation was further dissected by examining the dose-responsiveness and processing requirements of peptide-pulsed antigen presenting cells. Dose titration experiments revealed an enhanced response to the presence of self-peptides of a small number of clones at low abacavir concentrations.

Similarly, certain clones produced responses to a subset of self-peptides in the absence of abacavir. Antigen presenting cell pulsing and glutaraldehyde fixation assays also revealed a stronger T-cell response to abacavir and a small number of self-peptides, when compared with abacavir alone.

Tolvaptan, a nonpeptide arginine vasopressin V2-receptor antagonist, is associated with idiosyncratic liver injury. The delayed nature and prompt recurrence upon rechallenge indicate that injury results from an adaptive immune attack on the liver. Thus, a hypothesis for tolvaptan-induced liver injury is that the drug or a metabolic derivative s forms antigenic determinants with MHC molecules to activate T-cells.

Peripheral blood mononuclear cells were isolated from 9 tolvaptan-exposed patients with signs of hepatic injury and lymphocyte transformation tests were performed. Lymphocyte transformation tests to all patients were negative for tolvaptan, and to two metabolites, DM and DM Cross-reactivity with tolvaptan or DM was not detected. Only a handful of clones were identified indicating that they likely represent a low frequency population in peripheral blood.

Although the clinical presentation is well established, the role of drug-specific T cells has not been defined. The phenotype and function of drug-specific T cells were then determined.

A total of clones were tested for drug specificity. ILA secretion was not detected. A subset of patients with angioedema AE and urticaria has histamine releasing autoantibodies.

The Album) release test HR-test has been used as a tool in chronic urticaria to define the autoimmune subgroup and may possibly guide the clinician to a more effective therapy like omalizumab and cyclosporine. The prevalence of positive histamine releasing autoantibodies in monosymptomatic AE is sparsely described in the literature. The purpose of the study was to report the prevalence of positive histamine releasing autoantibodies in a cohort of patients with recurrent AE without urticaria and compare it with previously published data.

We performed a retrospective cohort study of AE patients seen at the Department of Dermatology, Odense University Hospital, between and Difference of proportion test and odds ratio calculations were employed when comparing treatment efficacy. HR-test results were available in patients and showed that When monosymptomatic AE patients with positive HR-test were compared with AE patients with concomitant urticaria and positive HR-test, the odds ratio was 2.

Patients with AE and concomitant urticaria more often have a positive HR-test and might gain more treatment benefit from anti-allergic medication than patients with monosymptomatic AE. As the use of iodinated contrast media ICM increases, the adverse reactions are also increasing.

Among them, anaphylaxis is getting more attention according to its fatal consequences. However, there is no effective method for predicting anaphylaxis in patients other than a previous history.

To develop the strategy of risk prediction based on genetic susceptibility, we analyzed the association between severe anaphylaxis to ICM and human leukocyte antigen HLA genotypes. We searched patients who ever experienced anaphylaxis with administration of low osmolar ICM in the Korean registry of ICM adverse reaction. Their genotypes were compared with those of Korean general population.

A total of 23 patients suffering anaphylaxis to ICM were recruited. The risk for the development of ICM-induced anaphylaxis was significantly increased with this allele OR 6. Drug-induced anaphylaxis is caused by various triggers, including binding of antigen specific Immunoglobulin E IgE to mast cells and basophils, and their direct activation. It is possible to investigate whether drug-specific IgE antibodies are involved in the onset of anaphylaxis by measuring their serum levels.

However, this can only be assessed for certain drugs. Recently, the basophil activation test BAT has been established as a tool to detect the causative agent of anaphylaxis. In this study, we aimed to investigate whether drug-induced anaphylaxis by different drugs were IgE dependent or independent by using the BAT. We recruited five patients with perioperative anaphylaxis, for which the culprit drugs were either rocuronium, protamine, cefazolin or cefotiam.

All patients provided us with written informed consent for study participation. Skin tests with all drugs administered during the perioperative period were followed by BATs, with CDc as the activated basophil marker.

BATs were performed using serial dilutions of the culprit agents with and without wortmannin, an inhibitor of phosphoinositide 3-kinase. The percentage inhibition of basophil activation by wortmannin at drug concentrations at which basophils were most activated in each patient was calculated. We used two different positive controls, anti-IgE antibodies and formyl-methionyl-leucyl-phenylalanine fMLPwhich is known to activate basophils through a different pathway from IgE.

Skin tests showed positive reactions with culprit drugs in all patients. The culprit drugs in all patients resulted in basophil activation. Activation of basophils by culprit agents was inhibited by wortmannin in all patients tested in this study. We confirmed that wortmannin inhibited anti-IgE antibody-induced activation of basophils.

These results suggest that rocuronium- protamine- cefazolin- and cefotiam-induced anaphylaxis are likely caused by IgE antibody-dependent pathways. Type IV DHR have typically a delayed onset after the last drug intake, with diverse clinical manifestations ranging from Steven-Johnson syndrome to maculo-papular eruption.

It has been demonstrated that T cell play a pivotal role in the development of the delayed DHR. In clinical practice, in vitro approaches for this kind of reactions are particularly scarce. We developed an improved, non-radioactive lymphocyte proliferation test for the diagnosis of delayed DHR.

Of note, the concentrations tested were chosen taking into account the volume of distribution of the drug. The test was deemed positive when the proliferation rate of any of the three concentrations tested compared to the control equals or exceeds 2, also called Stimulation Index SI.

In these patients we were able to confirm the diagnosis of delayed DHR. Thus, we either suggested the avoidance of the offending drug, or, if the drug was considered indispensable, we applied a desensitization protocol to administered the drug. In these cases the previously suspected delayed DHR was ruled out. Drug desensitization DS was developed to reintroduce first line therapies in a safe and effective fashion in allergic patients. Mast cells MCs are key effectors and are believed to be the primary target cell in DS.

In vitro model of rapid MCs IgE mediated DS has shown the inhibition of the MC activation hallmarks, reaching at the end of the protocol the antigen target dose. This study presents a humanized in vitro model of DS showing the microscopy phenotype difference between activated-desensitized MCs and the variable hyporesponsiveness of MC along the DS protocol. Antigen dose was doubled each ten minutes optimal interval time to inhibit MCs degranulationreaching the target dose at the end of the protocol.

Beta-hexosaminidase release during single doses antigen delivery were compared with the same antigen doses added sequentially following the eleven steps of the DS protocol. The beta-hexosaminidase percentage release were significantly lower in desensitized MCs compared to activated MCs.

Challenge with single DS doses induced a sequential increase of beta-hexosaminidase release after the sixth step of the protocol, creating a dose response curve. Sequentially added doses also induced an hyporesponsiveness as shown by lack of degranulation.

Microscopy images prove the presence of MCs mediator granules inside the cells after received the target antigen dose by DS in contrast to activated MCs which lose all the cytoplasmic granules. This fact confirms that desensitization blocks completely MCs degranulation. Comparing the beta-hexosaminidase release during the different DS protocol steps, we confirm the importance of the first sub-optimal DS steps to get a total MC hyporesposiveness at the end of the procedure.

Drug patch tests DPT for diagnostics of delayed cutaneous adverse drug reactions should be highly specific and sensitive, but at the same time non-irritant. The non-irritant concentrations of some active pharmaceutical ingredients APIs were established. However, the data on the lowest concentration of APIs that still produces positive reaction is scarce. Our goal was to assess the content of the active ingredient in the DPT in connection to the results of the DPT and oral provocation test OPT in the routine clinical practice.

A retrospective single-centre study was conducted in adult patients referred to allergy department of University Clinic Golnik between January and May Two allergologists independently assessed the type and probability of allergic reaction described in medical history.

The patients with doubtful delayed cutaneous adverse drug reaction or insufficient data were excluded. However, only patients with 33 negative DPT suited all inclusion criteria. They were performed with 7 different APIs. High percentage of false-negative DPT, though in the small sample, urges better standardization of tests in clinical practise, especially the evaluation of the actual API content for the uncommon drugs.

Besides skin testing, basophil activation test with patient basophils direct BAT is used in the diagnosis of immediate type drug hypersensitivity reactions. IL-3 primed basophils were then stimulated with serial drug dilutions and controls. Further drugs, disinfectants and additives divalent and monovalent tested positive in the indirect BAT were penicillin G, amoxicillin, cefaclor, cefuroxime, ceftriaxone, ceftazidime, cefotaxime, carboxymethylcellulose, ibuprofen, octenidine and proguanil.

We were successful in improving and standardizing the conditions of indirect BAT using sera of drug-allergic patients on non-allergic donor basophils. In addition, indirect BAT increases reproducibility using different sera on the same basophil donor batch analysis and provides a way to overcome the problem of IgE non-responders in BAT.

These methods will help drive the development of targeted therapeutics and screening approaches. Clavulanic acid CLV is a betalactam BL which inhibits betalactamases activity and is frequently administered combined with amoxicillin AX. Both BLs can be independently involved in allergic reactions. Although protein haptenation with BLs is considered necessary to activate the immune system, currently there are no straight-forward detection tools, such as a monoclonal antibody against CLV, for the study of protein haptenation with CLV.

To achieve this aim, CLV was derivatized with biotin, then incubated with either human serum albumin HSA or sera and, finally, the resulting protein adducts were analyzed by different techniques. We sought to define the characteristics of abacavir specific T cells that are recruited to the skin at the site of a positive ABC patch test several years following the acute reaction. For first time we have shown single-cell definition of T cells at the site of a cutaneous response to ABC. Furthermore, these ABC reactive T cells can be cloned from patch test positive skin and are distinctly polyclonal.

This supports the altered peptide repertoire model of T-cell activation and provides a road map for studying drug-specific responses at a tissue level.

The vast majority of patients present with non-immediate rashes, arthralgia and fever. Patient management is especially complicated in the multi-allergic patient group where alternative treatment strategies have often been exhausted. In these patients, desensitisation represents a well-tolerated method of reintroducing the drug by gradually increasing a suboptimal dose until a therapeutic dose is achieved.

Despite this, little is known about the immunological basis of a successful non-immediate desensitisation. Aim: To conduct lymphocyte transformation tests on hypersensitive patient PBMC before, during and after tazocin desensitisation to assess whether a graded increase in drug exposure modulates the drug-specific T-cell response. PBMC were isolated and cultured with piperacillin 0. PBMC from all nine hypersensitive patients were stimulated to proliferate in a concentration-dependent manner with piperacillin prior to commencement of the desensitisation protocol.

These data show that the drug-specific T-cell response is inhibited in b-lactam hypersensitive patients with non-immediate symptoms undergoing an established desensitisation protocol. Allergic reactions to b-lactams are the most frequent cause of Adverse Drug Reactions ADRs mediated by specific immunological mechanisms.

Amoxicillin, widely used for the treatment of bacterial infections, belongs to this drug class. In clinical practice, detection of b-lactam-specific IgE levels CAP System offers a complementary approach to diagnose allergy to antibiotics. Its sensitivity is rather low, although specificity is high. The positive predictive value of this test might also be influenced by the total amount of serum IgE. To clarify the clinical diagnosis of suspected ADR to amoxicillin, we used the 0.

We observed 5 patients with suspected, although ambiguous, immediate ADR to amoxicillin. In all patients the levels were slightly above the current threshold limit i. Notably, this ratio was below 0. That suggested that the 5 patients were not sensitized to amoxicillin. To validate this hypothesis, we performed an oral drug provocation test with amoxicillin. Moreover, the drug was administered for 3 consecutive days, following the provocation test day.

All the patients tolerated the drug provocation procedure. No adverse reactions were observed, thus excluding the possible amoxicillin hypersensitivity that could have been suspected formerly, based on crude RAST results. The ratio between amoxicillin-specific IgE and total IgE threshold 0. We propose that total IgE levels should be always assessed when amoxicillin-specific IgE are evaluated.

Betalactam antibiotics are the most frequently prescribed antibiotics to treat infections. However, they are the most common cause of drug hypersensitivity reactions mediated by a specific immunological mechanism. Amoxicillin AX is the most often elicitor, which was originally prescribed alone, and is now often prescribed alongside clavulanic acid Clav. The diagnosis is complex, based on skin testing and drug provocation test, methods not risk-free.

In vitro testing can be used, however their sensitivity is low, probably due to the use of chemical structures that are not optimally recognized by the immune system. The aim of this study was to generate and characterize AX- and Clav-specific T-cell clones from blood of hypersensitive patients to be used as tool to study the immunological recognition of new chemical structures derived from AX and Clav to be included in in vitro diagnostic tests. Drug-specific T-cell clones were Album) from PBMC by serial dilution and repetitive mitogen stimulation.

AX- and Clav-specific T-cell clones required the presence of drug and antigen presenting cells to proliferate. They are activated by AX or Clav only in the presence of antigen presenting cells, supporting the hapten hypothesis for the recognition and presentation of betalactam antibiotics. The specific T-cell clones generated are an immunologically characterized tool that can be used for the analysis of new structures derived from AX and Clav to be included in in vitro diagnostic tests. Eighteen abacavir analogues were synthesised with modifications to the cyclopropyl moiety, namely derivatives of the azetidine group.

This approach may provide a platform towards the design of safer therapeutics known to interact selectively with HLA molecules. Patient-reported antibiotic allergies so-called antibiotic allergy labels [AALs] are frequently encountered in hospitalized patients, however the correct assessment of these AALs are often poor. We validated an antibiotic allergy assessment tool AAAT to aid non-allergist in phenotyping and management of patients with reported beta-lactam AALs.

The AAAT utilizes patient-reported symptoms and signs associated with an index beta-lactam allergy label Fig. The phenotypic outcomes of the AAAT were classified as; i severe immediate IgE-mediatedii non-severe immediate IgE-mediatediii severe delayed T-cell-mediatediv non-severe delayed T-cell-mediatedv potential immune mediated e.

Each phenotype was allocated a corresponding management recommendation of either; i direct de-labelling with removal from electronic health record ii direct oral rechallenge iii inpatient point-of-care antibiotic allergy skin testing, or iv outpatient antibiotic allergy assessment potentially including skin testing and oral challenge. The tool was initiatelly reviewed for content and usability, utilizing hypothetical case scenarios and the final validation involved a range of medical participants utilizing the AAAT, in real-patient case studies from the Austin Health Antibiotic Allergy Database.

The AAAT demonstrated an overall sensitivity of The highest sensitivity and specificity was for the identification of severe immediate hypersensitivities, The AAAT demonstrated a sensitivity and specificity of The beta-lactam AAAT proved a useful tool for a range of healthcare workers in the identification of antibiotic allergy phenotypes, and designating appropriate management.

Lower sensitivity for severe delayed hypersensitivity identifies this as a safety concern and a target for education of healthcare personnel. Dapsone hypersensitivity syndrome DHSas a life-threatening condition, is the most serious adverse reaction associated with dapsone intake and one of the major causes of death in leprosy patients. All the subjects were followed up for two months to monitor the adverse events. Immunological tests were done to distinguish DHS from leprosy reactions and reactions to other drugs.

In contrast, based upon the historic incidence, 11—33 patients of DHS would be expected. We prospectively collected and analyzed demographic data of patients with a penicillin allergy admitted to the internal medicine residency service at Mayo Clinic Florida between August 1 and August 30, We implemented an educational initiative including use of a validated antibiotic selection algorithm to aid physicians in prescribing beta lactams based on history of drug hypersensitivity.

No inpatient penicillin skin testing was performed. In the day post-intervention re-measurement phase, 23 patients with penicillin allergy were admitted of which Post-intervention drug allergy history documentation increased by Cephalosporin use increased by Mean length of stay was unchanged 3.

No adverse drug reactions were reported. A significant proportion of hospitalized patients with penicillin allergy receive unnecessary broad-spectrum antibiotics partly due to poor penicillin allergy evaluation.

This quality improvement initiative focused on educating primary providers to take a thorough drug allergy history is safe and effective at increasing uptake of beta lactams without increasing healthcare utilization. Immediate and delayed drug hypersensitivity reactions DHR to beta lactams can be directed to both the shared beta lactam ring and to specific side chains. DHR to flucloxacillin are less common than those to aminopenicillins.

Data analyzed included patient demographics, index reaction details, outcomes of skin prick SPTintradermal IDT testing with penicillin determinants PPL and MD, Diaterbenzylpenicillin, amoxicillin and flucloxacillin and oral drug provocation tests with flucloxacillin. One of two patients with a positive delayed IDT was also positive to benzylpenicillin and amoxicillin.

In 8 patients with negative skin tests allergy was confirmed by oral drug provocation with flucloxacillin, using a 1—3 step protocol.

Flucloxacillin allergy is more common in women than in men. Oral drug provocation testing in skin test negative patients, using a shortened protocol, was safe in the specialist setting. Beta-lactam allergy can currently be diagnosed based on positive skin testing, serum-specific IgE and provocation challenge. However, in the context of distant reactions, large paediatric cohort studies assessing the sensitivity and specificity of skin testing and serum-specific IgE are few. The role of extended antibiotic challenges remains unclear.

Children with a clear history of anaphylaxis e. All children received an OPC regardless of reaction history, or preceding skin and serum test results. Children were challenged with the culprit beta-lactam antibiotic; if unknown, amoxicillin was used. Six children reacted immediately to the OPC 2. One of these children had a positive IDT.

One child with a positive skin-prick test passed OPC. Five additional children had a positive IDT 1. Of the children who went home on a 5-day EC, 20 6. The most common reactions to the EC were rashes In our study, skin testing and serum beta-lactam specific IgEs were poor predictors of positive reactions to oral provocation testing. This provides further data that oral provocation testing in children with distant reactions is safe and that skin testing and testing for specific IgE were poor predictors of true allergy.

Tackling spurious penicillin allergy labels is a key target for improving antimicrobial stewardship. The label results in use of broad spectrum alternatives, and is associated with higher rates of Clostridium difficileVRE and MRSA, increased hospital stay and critical care admission. In elective surgical patients, the potential consequences of the allergy label carry significant health cost implications.

Current testing guidelines are laborious and expensive, requiring skin tests prior to oral challenge. All patients attending for pre-operative assessment who self-reported penicillin allergy, completed a screening questionnaire. Patients completed a 3-day amoxicillin course, and were then contacted by phone. De-labelling was confirmed in writing, with GP and hospital records updated accordingly. Of patients screened, 45 were eligible for inclusion, ineligible.

To date, 37 patients have been de-labelled, and where knownreceived appropriate penicillin prophylaxis uneventfully. No patient had a reaction on initial challenge. Elective surgical patients at low risk of penicillin allergy can be identified and de-labelled pre-operatively, as part of their existing surgical care pathway. Patients appear keen to be tested, providing this pathway is simple and quick.

Unverified penicillin allergy leads to adverse downstream clinical and economic sequelae. Penicillin allergy evaluation can be used to identify true, IgE-mediated allergy. Beta-lactam antibiotics are the drugs that most frequently produce adverse reactions mediated by a specific immunological mechanism. Within these, penicillins are the group most involved and best studied. Currently, amoxicillin, probably due to its high consumption, has displaced benzylpenicillin in terms of the number of reactions.

We have obtained a positive result in 17 patients out of 90 with reported penicillin allergy Less than a quarter of patients have personal history of atopy They had a personal history of drug allergy 7. Most of the patients had taken one The clinic was predominantly cutaneous Most of patients did not go to the emergency room The In our study, skin prick test was positive in the 4. Drug challenge was positive in the 4. We have obtained a positive result in the Inpatients who have unconfirmed history of allergy to betalactam antibiotics and who need antibiotics pose a challenge.

Avoiding betalactamic antibiotics suppose therapeutic limitations, the use of second line drugs, a prolonged hospital stay, an increase of risk of adverse effects and more expenditure. A majority of the patients who report allergy to betalactam antibiotics tolerate this drugs.

Objectives: To confirm or to rule out betalactam allergy with allergy tests in inpatients of two university hospitals with an unconfirmed history of betalactam allergy an who need antibiotic treatment.

Skin tests with betalactam antibiotics, following ENDA guidelines, were done on demand of the physician responsible of the inpatient. The protocol was approved by the infectious diseases committee. Skin tests were negative in From the Album Limetal.

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