Bern, Switzerland


Bern, Switzerland
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Krahenbuhl S.,University of Basel | Pichler W.J.,ADR AC GmbH
Therapeutische Umschau | Year: 2017

The incidence of drug induced liver injury (DILI) in Switzerland is ca. 10 – 20 cases/100'000 persons/per year. DILI is clinically important as it is an iatrogenic disease, can mimic almost all other liver diseases and therefore must be included in the differential diagnosis in patients with unclear liver damage. The diagnosis can be made only indirectly, by judging the temporal relationship between therapy and liver damage before and after stopping suspected drugs and by exclusion of other liver diseases. In most cases, drug-induced liver injuries are idiosyncratic with allergic or metabolic mechanisms. Knowledge of the most important risk factors is important for avoiding drug-induced liver injury. In the case of allergic liver injuries, the eliciting drug can be identified with the lymphocyte transformation test (LTT), which is frequently positive (> 65 %) in systemic reactions (DRESS = DILI combined with exanthema, eosinophilia), while in isolated DILI the LTT is positive in approximately 30 %. Re-exposure can be dangerous and should be avoided. Since there is no specific treatment for most drug-induced liver injuries, early stopping of the administration of suspected drugs is essential. © 2017 Hogrefe.

Thongsri T.,Buddhachinaraj Hospital | Chularojanamontri L.,Mahidol University | Pichler W.J.,ADR AC GmbH
Asian Pacific Journal of Allergy and Immunology | Year: 2017

Objective: Cardiac involvement in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome varies considerably between 4% and 21%. Here we present our case and review literatures for its diagnosis and management. An algorithm for diagnosis of cardiac involvement in DRESS syndrome is proposed in this article. Data sources: Data regarding DRESS-associated myocarditis and eosinophilic myocarditis were gather primarily from MEDLINE database. Results: DRESS syndrome is a hypersensitivity reaction which is due to massive T cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. It is characterized by fever, morbilliform rash, and various systemic symptoms, in particular hepatitis. Hypersensitivity myocarditis (acute eosinophilic myocarditis) which is typically related to a drug reaction can lead to acute necrotizing eosinophilic myocarditis, cardiac thrombosis and fibrotic stage. Cardiac symptoms range from no symptoms to cardiogenic shock. Diagnosis is based on history, clinical findings, cardiac biomarkers and cardiac imaging techniques. Endomyocardial biopsy is done in a minority of patients for definite diagnosis. If suspected, drug discontinuation and suppression of immune reactions are the first therapies. Corticosteroids are the cornerstone of systemic treatments and should be initiated at the time of diagnosis of DRESS syndrome. Additional therapy and ventricular assist devices could be considered in refractory cases. Conclusions: According to its high morbidity and mortality, patients with DRESS syndrome should be carefully monitored or screened for cardiac involvement. Multidisciplinary care is important for a successful treatment outcome. © 2017, Allergy and Immunology Society of Thailand. All rights reserved.

Pichler W.J.,ADR AC GmbH | Adam J.,ADR AC GmbH | Watkins S.,Oregon State University | Wuillemin N.,University of Bern | And 2 more authors.
International Archives of Allergy and Immunology | Year: 2015

Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called 'off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the 'pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from 'conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions. © 2015 S. Karger AG, Basel.

Fux M.,University of Bern | Pecaric-Petkovic T.,ADR AC GmbH | Pecaric-Petkovic T.,University of Bern | Odermatt A.,University of Bern | And 6 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2014

Background IL-33 enhances FcεRI-induced mediator release in human basophils without inducing degranulation itself. In contrast, studies in mice suggested that in the presence of high IgE levels, IL-33 triggers degranulation and anaphylaxis of similar severity as specific allergen. Consistent with this view, sera of atopic patients contain elevated levels of IL-33 after anaphylaxis. In this study, we determined whether IL-33 is potentially anaphylactogenic in humans with high IgE levels by regulating exocytosis independent of FcεRI cross-linking. Furthermore, we investigated whether IL-33 is released upon allergen provocation in vivo. Methods In subjects with high serum IgE levels, we measured IL-33-induced histamine/LTC4 in vitro, CD63 translocation ex vivo, and responsiveness of mast cells in vivo by skin prick test (SPT). In asthma patients, release of IL-33 and its correlation with early (tryptase)- and late-phase markers (IL-13 levels, eosinophil numbers) of the allergic response were assessed in bronchoalveolar lavage fluids (BALFs) after allergen challenge. Results IL-33 itself does not trigger basophil degranulation in vitro and ex vivo, even in subjects with high serum IgE levels, and negative SPTs demonstrate that skin mast cells do not degranulate in response to IL-33. However, in response to allergen challenge, IL-33 is rapidly released into BALFs at levels that do not correlate with other immediate- and late-phase parameters. Conclusion IL-33 is unlikely an independent trigger of anaphylaxis even in subjects with high IgE levels. However, the rapid release of IL-33 upon allergen provocation in vivo supports its role as a mediator of immediate allergic responses. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hausmann O.V.,University of Bern | Seitz M.,University of Bern | Villiger P.M.,University of Bern | Pichler W.J.,University of Bern | Pichler W.J.,ADR AC GmbH
Medical Clinics of North America | Year: 2010

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named α, β, γ, δ, and ε{lunate}, reflecting overstimulation (high cytokine values, type α), hypersensitivity (type β), immune deviation (including immunodeficiency, type γ), cross-reactivity (type δ), and nonimmune mediated side effects (type ε{lunate}). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs. © 2010 Elsevier Inc. All rights reserved.

Pichler W.J.,Clinic for Rheumatology and Clinical Immunology Allergology | Pichler W.J.,ADR AC GmbH | Adam J.,Clinic for Rheumatology and Clinical Immunology Allergology | Daubner B.,Clinic for Rheumatology and Clinical Immunology Allergology | And 3 more authors.
Medical Clinics of North America | Year: 2010

Small molecules, used as drugs, can induce immune reactions by binding covalently as haptens to a carrier protein, which is thereby modified and immunogenic. In addition, drugs bind to proteins via hydrogen bonds, electrostatic force, and van der Waals forces, and may directly interact with immune receptors such as T cell receptors or major histocompatibility complex molecules (pharmacologic interaction with immune receptors, so-called p-i concept). Even this noncovalent interaction may stimulate T cells. The ensuing immune response based on hapten-peptide presentation or direct drug-receptor interaction results in many distinct clinical situations. Based on progress in T cell immunology, this heterogeneity of T cell reaction is now also reflected in a subclassification of type IVa to IVd reactions. © 2010 Elsevier Inc. All rights reserved.

Hausmann O.V.,University of Bern | Gentinetta T.,University of Bern | Gentinetta T.,ADR AC GmbH | Fux M.,University of Bern | And 4 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Background: Basophil activation tests (BAT) rely on different combinations of basophil selection and activation markers. Whereas activation markers, especially CD63, are widely validated, the most suitable and robust marker for basophil selection is still a matter of debate. Aims: Comparison of cell surface expression of two commonly used basophil selection markers (IgE, CD123/HLA-DR) with CCR3 in an unselected group of atopic and nonatopic donors in resting and activated basophils. Methods: EDTA blood of 94 healthy adults, about half of them atopic by history, was analyzed using two different staining strategies: anti-CD123-PE/anti-HLA-DR-PerCP/anti-lin1-FITC and anti-IgE-FITC/anti-CD3-PerCP/ anti-CCR3-PE. Additionally 40 pollen-allergic patients were recruited for the assessment of CCR3 expression after basophil activation. Results: In resting basophils, cell surface expression of the three basophil selection markers was most constant for CCR3. IgE gating strategy showed the highest variation and up to 80% of nonbasophils in the selected gate in certain donors. During basophil activation, a shift of the mean fluorescence intensity for CCR3 toward the lower third of the CCR3-positive population could be demonstrated, but neither were CCR3-positive cells significantly lost for further analysis nor was differentiation between CCR3-positive and CCR3-negative cell populations hampered by this shift. Conclusions: CCR3 is a stable and highly expressed basophil selection marker, independent of the atopic background or basophil activation state and allows an accurate identification of basophils without need of a second marker. The basophil markers CD123/HLA-DR and IgE showed significantly higher interindividual variability in cell surface expression and are therefore less suited as selection markers. © 2010 John Wiley & Sons A/S.

Pichler W.J.,ADR AC GmbH | Pichler W.J.,University of Bern | Watkins S.,ADR AC GmbH | Watkins S.,University of Bern
Current Immunology Reviews | Year: 2014

Drugs may stimulate the immune system by forming stable new antigenic complexes consisting of the drug or drug metabolite which is covalently bound to a protein or peptide (hapten-carrier complex). Both, B- and T-cell immunity may arise, the latter directed to hapten modified peptides presented by HLA molecules. Beside this immunological stimulation, drugs can also stimulate the immune system through binding by non-covalent bonds to proteins like immune receptors. This so-called “pharmacological interaction with immune receptors” concept (“p-i concept”) may occur with HLA or TCR molecules themselves (p-i HLA or p-i TCR), and not the immunogenic peptide. It is a type of “off-target” activity of the drug on immune receptors, but more complex as various cell types, cell interactions and functionally different T cells are involved. In this review the conditions which lead to activation of T cells by p-i are discussed: important factors for a functional consequence of drug binding is the location of binding (p-i HLA or p-i TCR); the exact site within these immune receptors; the affinity of binding and the finding that p-i HLA can stimulate the immune system like an allo-allele. The p-i concept is able to solve some puzzles of drug hypersensitivity reactions and are a basis to better treat and potentially avoid drug hypersensitivity reactions. Moreover, the p-i concept shows that in contrast to previous beliefs small molecules do interact with immune receptors with functional consequence. But these interactions are not based on “immune recognition”, are at odds with some immunological concepts, but may nevertheless open new possibilities to understand and even treat immune reactions. © 2014 Bentham Science Publishers.

Gentinetta T.,University of Bern | Gentinetta T.,ADR AC GmbH | Pecaric-Petkovic T.,University of Bern | Pecaric-Petkovic T.,ADR AC GmbH | And 6 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Background: The in vivo autologous serum skin test (ASST) is the diagnostic gold standard to detect autoantibodies against FcεRI or IgE itself, as well as other autoreactive serum components, in patients with chronic spontaneous urticaria (CU). Coincubation of patient sera with donor basophils and measuring their degranulation in vitro could be a safe alternative but has shown inconsistent results. Objective: Optimization of the basophil activation test to detect autoreactive serum components in patients with CU. Methods: The ability of patient sera to induce CD63 and CD203c in donor basophils (n = 15) was measured by means of flow cytometry. Sera of 20 patients with CU (10 with positive ASST results), 15 patients with cold urticaria, and 27 healthy control subjects were included to optimize test conditions with donor basophils and a basophil cell line (RBL703/21) followed by testing of 110 consecutive patients from clinical routine. Results: We demonstrate that individual IL-3 priming normalized the initially inconsistent basophil reactivity and led to reproducible and comparable test results irrespective of the basophil donors used. CD203c as an activation marker and the use of a basophil cell line were less suitable for this purpose. Conclusion: The basophil activation test with individualized IL-3 priming for each basophil donor is a reproducible and reliable alternative to the ASST. There are several advantages over the ASST: no risk of accidental infection, no influence of antihistamines on the test result, quantifiable results, and a potential in providing treatment monitoring. The exact nature of the degranulating factor or factors in patient sera remains an open question. © 2011 American Academy of Allergy, Asthma & Immunology.

Srinoulprasert Y.,Mahidol University | Srinoulprasert Y.,University of Bern | Srinoulprasert Y.,ADR AC GmbH | Pichler W.J.,University of Bern | Pichler W.J.,ADR AC GmbH
International Archives of Allergy and Immunology | Year: 2014

Background: The lymphocyte transformation test (LTT) is used for in vitro diagnosis of drug hypersensitivity reactions. While its specificity is over 90%, sensitivity is limited and depends on the type of reaction, drug and possibly time interval between the event and analysis. Removal of regulatory T cells (Treg/CD25hi) from in vitro stimulated cell cultures was previously reported to be a promising method to increase the sensitivity of proliferation tests. Objective: The aim of this investigation is to evaluate the effect of removal of regulatory T cells on the sensitivity of the LTT. Methods: Patients with well-documented drug hypersensitivity were recruited. Peripheral blood mononuclear cells, isolated CD3+ and CD3+ T cells depleted of the CD25hi fraction were used as effector cells in the LTT. Irrelevant drugs were also included to determine specificity. 3H-thymidine incorporation was utilized as the detection system and results were expressed as a stimulation index (SI). Results: SIs of 7/11 LTTs were reduced after a mean time interval of 10.5 months (LTT 1 vs. LTT 2). Removal of the CD25hi fraction, which was FOXP3+ and had a suppressive effect on drug-induced proliferation, resulted in an increased response to the relevant drugs. Sensitivity was increased from 25 to 82.35% with dramatically enhanced SI (2.05 to 6.02). Specificity was not affected. Conclusion: Removal of Treg/CD25hi cells can increase the frequency and strengths of drug-specific proliferation without affecting specificity. This approach might be useful in certain drug hypersensitivity reactions with borderline responses or long time interval since the hypersensitivity reaction. © 2014 S. Karger AG, Basel.

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