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Werner J. Pichler - One of the best experts on this subject based on the ideXlab platform.
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acute liver failure in a patient treated with metamizole
Frontiers in Pharmacology, 2019Co-Authors: Philipp Krisai, Werner J. Pichler, Deborah Rudin, David Grunig, Kathrin Scherer, Luigi Terracciano, Stephan KrahenbuhlAbstract:We report on a patient who developed acute liver failure while being treated with metamizole. After liver transplantation, the patient recovered rapidly. Liver biopsy showed massive necrosis and lobular infiltration of Lymphocytes. A Lymphocyte Transformation test performed twenty months after transplantation was positive for metamizole. In vitro investigations with N-methyl-4-aminoantipyrine (MAA) and 4-aminantipyrine (AA), the two active metabolites of metamizole, did not reveal relevant toxicity in HepG2 and HepaRG cells. The demonstration of activated Lymphocytes by the Lymphocyte Transformation test and the absence of relevant cytotoxicity by MAA and AA in hepatocyte cell lines suggest an immunological mechanism of metamizole-associated hepatotoxicity.
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in vitro drug causality assessment in stevens johnson syndrome alternatives for Lymphocyte Transformation test
Clinical & Experimental Allergy, 2013Co-Authors: G Porebski, Tatjana Pecaricpetkovic, M Grouxkeller, M Bosak, Tom Kawabata, Werner J. PichlerAbstract:BACKGROUND Patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are often exposed simultaneously to a few potentially culprit drugs. However, both the standard Lymphocyte Transformation tests (LTT) with proliferation as the assay end-point as well as skin tests, if done, are often negative. OBJECTIVE As provocation tests are considered too dangerous, there is an urgent need to identify the relevant drug in SJS/TEN and to improve sensitivity of tests able to identify the causative drug. METHODS Fifteen patients with SJS/TEN with the ALDEN score ≥ 6 and 18 drug-exposed controls were included. Peripheral blood mononuclear cells (PBMC) were isolated and cultured under defined conditions with drugs. LTT was compared to the following end-points: cytokine levels in cell culture supernatant, number of granzyme B secreting cells by ELISpot and intracellular staining for granulysin and IFNγ in CD3(+) CD4(+), CD3(+) CD8(+) and NKp46(+) cells. To further enhance sensitivity, the effect of IL-7/IL-15 pre-incubation of PBMC was evaluated. RESULTS Lymphocyte Transformation tests was positive in only 4/15 patients (sensitivity 27%, CI: 8-55%). Similarly, with granzyme B-ELISpot culprit drugs were positive in 5/15 patients (sensitivity 33%, CI: 12-62%). The expression of granulysin was significantly induced in NKp46(+) and CD3(+) CD4(+) cells (sensitivity 40%, CI: 16-68% and 53%, CI: 27-79% respectively). Cytokine production could be demonstrated in 38%, CI: 14-68% and 43%, CI: 18-71% of patients for IL-2 and IL-5, respectively, and in 55%, CI: 23-83% for IFNγ. Pre-incubation with IL-7/IL-15 enhanced drug-specific response only in a few patients. Specificities of tested assays were in the range of 95 (CI: 80-99%)-100% (CI: 90-100%). CONCLUSIONS AND CLINICAL RELEVANCE Granulysin expression in CD3(+) CD4(+) , Granzyme B-ELISpot and IFNγ production considered together provided a sensitivity of 80% (CI: 52-96%) and specificity of 95% (80-99%). Thus, this study demonstrated that combining different assays may be a feasible approach to identify the causative drug of SJS/TEN reactions; however, confirmation on another group of patients is necessary.
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multiple drug hypersensitivity proof of multiple drug hypersensitivity by patch and Lymphocyte Transformation tests
Journal of Investigational Allergology and Clinical Immunology, 2005Co-Authors: C Gexcollet, A. Helbling, Werner J. PichlerAbstract:BACKGROUND Multiple drug hypersensitivity (MDH) was first described in 1989 by Sullivan et al. as drug allergies to two or more chemically different drugs. So far, the diagnosis of MDH was associated almost exclusively with antibiotics and was defined based on history alone. AIMS OF THE STUDY The objective of this study was to prove MDH by two independent tests, namely patch (PT) and Lymphocyte Transformation (LTT) tests. METHODS Here we present 7 patients matching the definition of a MDH which were documented by positive LTT as well as PT to different drugs. RESULTS Three of the 7 patients developed sensitization to the different compounds during the same treatment period and had one longer-lasting allergic reaction. For another 4 patients sensitization to the different drugs occurred at distinct time points. CONCLUSIONS Our data support the concept of a MDH syndrome. The multiple sensitizations can be proven by skin and in vitro tests. We propose two subtypes of MDH: MDH, which develops against different drugs given simultaneously, and a second subtype, where the sensitizations develop sequentially. Antibiotics are often involved, but we also found sensitization to antiepileptics, hypnotics, antidepressants, local anesthetics, corticosteroids and other drug classes.
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the Lymphocyte Transformation test for the diagnosis of drug allergy sensitivity and specificity
Clinical & Experimental Allergy, 1997Co-Authors: Beat Nyfeler, Werner J. PichlerAbstract:BACKGROUND: The diagnosis of a drug allergy is mainly based upon a very detailed history and the clinical findings. In addition, several in vitro or in vivo tests can be performed to demonstrate a sensitization to a certain drug. One of the in vitro tests is the Lymphocyte Transformation test (LTT), which can reveal a sensitization of T-cells by an enhanced proliferative response of peripheral blood mononuclear cells to a certain drug. OBJECTIVE: To evaluate the sensitivity and specificity of the LTT, 923 case histories of patients with suspected drug allergy in whom a LTT was performed were retrospectively analysed. METHODS: Based on the history and provocation tests, the probability (P) of a drug allergy was estimated to be > 0.9, 0.5-0.9, 0.1-0.5 or 0.9) had a positive LTT, which indicates a sensitivity of 78%. If allergies to betalactam-antibiotics were analysed separately, the sensitivity was 74.4%. Fifteen of 102 patients where a classical drug allergy could be excluded (P < 0.1), had nevertheless a positive LTT (specificity thus 85%). The majority of these cases were classified as so-called pseudo-allergic reaction to NSAIDs. Patients with a clear history and clinical findings for a cotrimoxazole-related allergy, all had a positive LTT (6/6), and in patients who reacted to drugs containing proteins, sensitization could be demonstrated as well (i.e. hen's egg lysozyme, 7/7). In 632 of the 923 cases, skin tests were also performed (scratch and/or epicutaneous), for which we found a lower sensitivity than for the LTT (64%), while the specificity was the same (85%). CONCLUSION: Although our data are somewhat biased by the high number of penicillin allergies and cannot be generalized to drug allergies caused by other compounds, we conclude that the LTT is a useful diagnostic test in drug allergies, able to support the diagnosis of a drug allergy and to pinpoint the relevant drug.
Paul H Hayashi - One of the best experts on this subject based on the ideXlab platform.
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development of a modified Lymphocyte Transformation test for diagnosing drug induced liver injury associated with an adaptive immune response
Journal of Immunotoxicology, 2017Co-Authors: Jessica Whritenour, Mira Ko, Qing Zong, Jianying Wang, Karrie Tartaro, Patricia Schneider, Ellen Olson, Maria Van Volkenburg, Jose Serrano, Paul H HayashiAbstract:AbstractDrug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The Lymphocyte Transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive i...
Jessica Whritenour - One of the best experts on this subject based on the ideXlab platform.
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development of a modified Lymphocyte Transformation test for diagnosing drug induced liver injury associated with an adaptive immune response
Journal of Immunotoxicology, 2017Co-Authors: Jessica Whritenour, Mira Ko, Qing Zong, Jianying Wang, Karrie Tartaro, Patricia Schneider, Ellen Olson, Maria Van Volkenburg, Jose Serrano, Paul H HayashiAbstract:AbstractDrug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The Lymphocyte Transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive i...
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Development of a modified Lymphocyte Transformation test for diagnosing drug-induced liver injury associated with an adaptive immune response
Taylor & Francis Group, 2017Co-Authors: Jessica Whritenour, Qing Zong, Jianying Wang, Karrie Tartaro, Patricia Schneider, Ellen Olson, Jose Serrano, Maria Van Volkenburg, Paul HayashiAbstract:Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The Lymphocyte Transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate Lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH
Natalija Novak - One of the best experts on this subject based on the ideXlab platform.
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positive Lymphocyte Transformation test in a patient with allergic contact dermatitis of the scalp after short term use of topical minoxidil solution
Contact Dermatitis, 2005Co-Authors: Tobias Hagemann, Brigitte Schlutterbohmer, Jeanpierre Allam, Thomas Bieber, Natalija NovakAbstract:Topical 2,4-diamino-6-piperidino-pyrimidine-3-oxide (minoxidil) solution has been widely used for the treatment of androgenetic alopecia for over 15 years now and the substance is currently approved for this indication in 2% and 5% formulation. Typical side effects of this topical treatment include irritative dermatitis going along with pruritus, erythema, scaling and dryness, which occur especially at the onset of the therapy. In some cases, allergic contact dermatitis or exacerbation of sebor-rhoic dermatitis has been reported. While most of the patients with allergic contact dermatitis described in the literature showed a positive sensitization to the vehicle substance propylene glycol evaluated by patch testing, reactions to the active ingredient minoxidil are rare. Here, we report a case of allergic sensitization to minoxidil, which we evaluated and differentiated from an irritative reaction by a combination of patch testing and Lymphocyte Transformation test. The differentiation of allergic and irritative adverse effects and the identification of the causative allergen are of major relevance for the proceeding and adjustment of the therapy. Patients with sensitizations against propylene glycol are candidates for preparations with alternative solvents but can proceed treatment with minoxidil. In contrast, patients with allergies to the active ingredient itself are no longer candidates for treatment with minoxidil and should undergo alternative therapeutic options.
Ian Kimber - One of the best experts on this subject based on the ideXlab platform.
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The Lymphocyte Transformation test in allergic contact dermatitis: New opportunities
Journal of Immunotoxicology, 2016Co-Authors: Amy Popple, Rebecca Jane Dearman, Gavin Maxwell, Nichola Gellatly, Jason Williams, Ian KimberAbstract:Allergic contact dermatitis (ACD) is driven by the activation and proliferation of allergen-specific memory T-Lymphocytes and is currently diagnosed by patch testing with a selected panel of chemical allergens. The Lymphocyte Transformation test (LTT) can be used to monitor ex vivo T-Lymphocyte responses to antigens, including contact allergens. The LTT is not viewed as being an alternative to patch testing, but it does seek to reflect experimentally skin sensitization to specific chemicals. The LTT is based on stimulation in vitro of antigen-driven T-Lymphocyte proliferation. That is, exposure in culture of primed memory T-Lymphocytes to the relevant antigen delivered in an appropriate configuration will provoke a secondary response that reflects the acquisition of skin sensitization. The technical aspects of this test and the utility of the approach for investigation of immune responses to contact allergens in humans are reviewed here, with particular emphasis on further development and refinement of the protocol. An important potential application is that it may provide a basis for characterizing those aspects of T-Lymphocyte responses to contact allergens that have the greatest influence on skin sensitizing potency and this will be considered in some detail.
