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1
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Line J, Saville E, Meng X, Naisbitt D. Why drug exposure is frequently associated with T-cell mediated cutaneous hypersensitivity reactions. FRONTIERS IN TOXICOLOGY 2023; 5:1268107. [PMID: 37795379 PMCID: PMC10546197 DOI: 10.3389/ftox.2023.1268107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Cutaneous hypersensitivity reactions represent the most common manifestation of drug allergy seen in the clinic, with 25% of all adverse drug reactions appearing in the skin. The severity of cutaneous eruptions can vastly differ depending on the cellular mechanisms involved from a minor, self-resolving maculopapular rash to major, life-threatening pathologies such as the T-cell mediated bullous eruptions, i.e., Stevens Johnson syndrome/toxic epidermal necrolysis. It remains a significant question as to why these reactions are so frequently associated with the skin and what factors polarise these reactions towards more serious disease states. The barrier function which the skin performs means it is constantly subject to a barrage of danger signals, creating an environment that favors elicitation. Therefore, a critical question is what drives the expansion of cutaneous lymphocyte antigen positive, skin homing, T-cell sub-populations in draining lymph nodes. One answer could be the heterologous immunity hypothesis whereby tissue resident memory T-cells that express T-cell receptors (TCRs) for pathogen derived antigens cross-react with drug antigen. A significant amount of research has been conducted on skin immunity in the context of contact allergy and the role of tissue specific antigen presenting cells in presenting drug antigen to T-cells, but it is unclear how this relates to epitopes derived from circulation. Studies have shown that the skin is a metabolically active organ, capable of generating reactive drug metabolites. However, we know that drug antigens are displayed systemically so what factors permit tolerance in one part of the body, but reactivity in the skin. Most adverse drug reactions are mild, and skin eruptions tend to be visible to the patient, whereas minor organ injury such as transient transaminase elevation is often not apparent. Systemic hypersensitivity reactions tend to have early cutaneous manifestations, the progression of which is halted by early diagnosis and treatment. It is apparent that the preference for cutaneous involvement of drug hypersensitivity reactions is multi-faceted, therefore this review aims to abridge the findings from literature on the current state of the field and provide insight into the cellular and metabolic mechanisms which may contribute to severe cutaneous adverse reactions.
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Affiliation(s)
| | | | | | - Dean Naisbitt
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
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Rodríguez-Pérez R, de las Vecillas L, Cabañas R, Bellón T. Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions. Int J Mol Sci 2023; 24:12577. [PMID: 37628756 PMCID: PMC10454098 DOI: 10.3390/ijms241612577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/03/2023] [Accepted: 08/06/2023] [Indexed: 08/27/2023] Open
Abstract
Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and identification of the culprit drug is essential to prevent future reactions as well as for the identification of safe treatment alternatives. Nonetheless, the diagnosis can be challenging. In vivo and in vitro tests can be helpful, although none are conclusive; therefore, the tests are not usually performed in isolation but as part of a diagnostic algorithm. In addition, some in vitro tests are only available in research laboratories, and standardization has not been fully accomplished. Collaborating research is needed to improve drug hypersensitivity reaction diagnosis. In this review, we update the current available in vivo and in vitro tools with their pros and cons and propose an algorithm to integrate them into clinical practice.
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Affiliation(s)
- Rosa Rodríguez-Pérez
- Institute for Health Research Hospital Universitario La Paz (IdiPAZ), Paseo Castellana 261, 28046 Madrid, Spain; (L.d.l.V.); (R.C.); (T.B.)
| | - Leticia de las Vecillas
- Institute for Health Research Hospital Universitario La Paz (IdiPAZ), Paseo Castellana 261, 28046 Madrid, Spain; (L.d.l.V.); (R.C.); (T.B.)
- Allergy Department, La Paz University Hospital, Paseo Castellana 261, 28046 Madrid, Spain
- PIELenRed Consortium, 28046 Madrid, Spain
| | - Rosario Cabañas
- Institute for Health Research Hospital Universitario La Paz (IdiPAZ), Paseo Castellana 261, 28046 Madrid, Spain; (L.d.l.V.); (R.C.); (T.B.)
- Allergy Department, La Paz University Hospital, Paseo Castellana 261, 28046 Madrid, Spain
- PIELenRed Consortium, 28046 Madrid, Spain
- Center for Biomedical Research Network on Rare Diseases (CIBERER U754), 28046 Madrid, Spain
| | - Teresa Bellón
- Institute for Health Research Hospital Universitario La Paz (IdiPAZ), Paseo Castellana 261, 28046 Madrid, Spain; (L.d.l.V.); (R.C.); (T.B.)
- PIELenRed Consortium, 28046 Madrid, Spain
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3
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Haukamp FJ, Hartmann ZM, Pich A, Kuhn J, Blasczyk R, Stieglitz F, Bade-Döding C. HLA-B*57:01/Carbamazepine-10,11-Epoxide Association Triggers Upregulation of the NFκB and JAK/STAT Pathways. Cells 2023; 12:cells12050676. [PMID: 36899812 PMCID: PMC10000580 DOI: 10.3390/cells12050676] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/17/2023] [Accepted: 02/18/2023] [Indexed: 02/23/2023] Open
Abstract
Measure of drug-mediated immune reactions that are dependent on the patient's genotype determine individual medication protocols. Despite extensive clinical trials prior to the license of a specific drug, certain patient-specific immune reactions cannot be reliably predicted. The need for acknowledgement of the actual proteomic state for selected individuals under drug administration becomes obvious. The well-established association between certain HLA molecules and drugs or their metabolites has been analyzed in recent years, yet the polymorphic nature of HLA makes a broad prediction unfeasible. Dependent on the patient's genotype, carbamazepine (CBZ) hypersensitivities can cause diverse disease symptoms as maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms or the more severe diseases Stevens-Johnson-Syndrome or toxic epidermal necrolysis. Not only the association between HLA-B*15:02 or HLA-A*31:01 but also between HLA-B*57:01 and CBZ administration could be demonstrated. This study aimed to illuminate the mechanism of HLA-B*57:01-mediated CBZ hypersensitivity by full proteome analysis. The main CBZ metabolite EPX introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Anti-inflammatory pathways and associated effector proteins were downregulated. This disequilibrium of pro- and anti-inflammatory processes clearly explain fatal immune reactions following CBZ administration.
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Affiliation(s)
- Funmilola Josephine Haukamp
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Correspondence: ; Tel.: +49-511-532-9774; Fax: +49-511-532-2079
| | - Zoe Maria Hartmann
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Andreas Pich
- Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Core Facility Proteomics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Joachim Kuhn
- Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Florian Stieglitz
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Christina Bade-Döding
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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4
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Pichler WJ, Brüggen MC. Viral infections and drug hypersensitivity. Allergy 2023; 78:60-70. [PMID: 36264263 DOI: 10.1111/all.15558] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/24/2022] [Accepted: 10/14/2022] [Indexed: 12/30/2022]
Abstract
Virus infections and T-cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i): drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T-cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T-cell activation and symptoms. There is a situation where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity by killing herpes peptide-expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.
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Affiliation(s)
| | - Marie-Charlotte Brüggen
- Allergy Unit, Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.,Faculty of Medicine, University Zürich, Zürich, Switzerland.,Christine Kühne - Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
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5
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In Vitro Assays for Diagnosis of Drug-Induced Nonsevere Exanthemas: A Systematic Review and Meta-Analysis. J Immunol Res 2022; 2022:2386654. [PMID: 36590449 PMCID: PMC9797304 DOI: 10.1155/2022/2386654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/20/2022] [Accepted: 11/23/2022] [Indexed: 12/24/2022] Open
Abstract
Frequent mislabelled causal relationship between drug hypersensitivity reactions and culprit drugs reinforces the need for an accurate diagnosis. The systematic reviews and meta-analyses of in vitro assays published so far focused on immediate reactions and the most severe delayed reactions, while the most frequent drug-induced delayed reactions-nonsevere exanthemas-have been underestimated. We aim to fill this gap. A systematic review of studies on in vitro assays used in the diagnosis of nonsevere drug-induced delayed reactions was conducted following the methodology of Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies Statement. The EMBASE and PubMed databases were searched. We have included 33 studies from which we extracted the data, then performed meta-analysis where possible, or synthesised the evidence narratively. The quality of the analysed studies was assessed with the QUADAS-2 tool. The tests identified the most frequently were lymphocyte transformation test (LTT), ELISpot, and ELISA. In the meta-analysis carried out for LTT in reactions induce by beta-lactams, the pool estimate of sensitivity and specificity amounted to 49.1% (95% CI: 14.0%, 85.0%) and 94.6% (95% CI: 81.7%, 98.6%), respectively. The studies showed heterogeneity in study design and laboratory settings, which resulted in a wide range of specificity and sensitivity of testing.
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Atakul G, Köse SŞ, Atay O, Boyacıoglu OK, Al S, Asilsoy S, Uzuner N, Karaman O. Oral Challenge without Penicillin Skin Tests in Children with Suspected Beta-Lactam Hypersensitivity. JOURNAL OF CHILD SCIENCE 2022. [DOI: 10.1055/s-0042-1757151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Abstract
Objective A misdiagnosed “penicillin allergy” is a common problem in childhood. Recently, skipping skin tests (STs) and performing a direct oral challenge test (OCT) have become an increasingly common approach in children with suspected β-lactam (BL) allergy. In our study, we aimed to evaluate the safety and efficacy of OCT without using ST in children who had a history of hypersensitivity reactions with BL antibiotics.
Materials and Methods We retrospectively evaluated direct OCT outcomes in children with both nonimmediate and immediate-type reaction history with BL antibiotics. STs were not performed before the challenge test. The patients were monitored for 4 hours after the challenge and continued using the drug in two divided doses for 3 days at home.
Results In this study, 72 patients were included, with median age of 7 years (interquartile range: 4; min: 1 year to max: 16 years), and of these, 56% were male. Forty-five subjects (63%) reported immediate-type adverse reactions. The most common clinical manifestation was urticaria/angioedema (51%, n: 37) and maculopapular exanthema in 46% (n: 33) of patients, respectively. The most commonly suspected drug was 71% amoxicillin-clavulanate. A 3-day OCT without preceding ST was performed in all patients. Only three patients (4.2%) showed a positive response to the oral drug challenge test. None of these reactions observed was more severe than index reactions.
Conclusion Performing OCT without STs is a safe and convenient method to exclude BL hypersensitivity in the pediatric age group.
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Affiliation(s)
- Gizem Atakul
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Seda Şirin Köse
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Ozge Atay
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Ozge Kangallı Boyacıoglu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Serdar Al
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Suna Asilsoy
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Nevin Uzuner
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Ozkan Karaman
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
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Srinoulprasert Y, Kumkamthornkul P, Tuchinda P, Wongwiangjunt S, Sathornsumetee S, Jongjaroenprasert K, Kulthanan K. Differential cytokine profiles produced by anti-epileptic drug re-exposure of peripheral blood mononuclear cells derived from severe anti-epileptic drug patients and non-allergic controls. Cytokine 2022; 157:155951. [DOI: 10.1016/j.cyto.2022.155951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/01/2022] [Accepted: 06/20/2022] [Indexed: 12/01/2022]
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Mixed T Helper1/T Helper2/T Cytotoxic Profile in Subjects with Chronic Chagas Disease with Hypersensitivity Reactions to Benznidazole. Microbiol Spectr 2022; 10:e0135722. [PMID: 35938810 PMCID: PMC9430713 DOI: 10.1128/spectrum.01357-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Dermatitis is the most common adverse event during treatment with benznidazole in chronic Chagas disease and is probably mediated by T cells. A set of molecules representative of the different type IV hypersensitivity reactions was evaluated in the circulation and skin biopsies of Trypanosoma cruzi-infected subjects presenting dermatitis during benznidazole administration. Through cytometric bead assays and enzyme-linked immunosorbent assay capture techniques, the serum levels of cytokines, chemokines, proapoptotic molecules, and mediators of the activation and migration of eosinophils and T cells were measured in subjects infected with Trypanosoma cruzi who exhibited skin adverse events (n = 22) and compared with those without adverse events (n = 37) during benznidazole therapy. Serum levels of interleukin- 5 (IL-5), soluble Fas cell surface death receptor ligand (FAS-L), and interferon γ-induced protein (IP-10) significantly increased at 7 to 30 days posttreatment with benznidazole and decreased thereafter in subjects with dermatitis but not in those without dermatitis. Circulating eotaxin levels were lower in subjects with dermatitis than in those without. Two patterns emerged in the skin biopsies: a T helper 1/T cytotoxic profile and a T helper 2/T cytotoxic profile with the presence of CD4+ and CD8+ T cells. Increased low-density lipoprotein (LDL), glutamic-oxaloacetic transaminase (GOT), uremia, and T cell activation emerged as risk factors for the development of dermatitis during benznidazole administration. These results support a delayed-type hypersensitivity reaction to benznidazole, involving CD4+ and CD8+ T cells and eosinophils, and a mixed cytokine profile. This study provides new insights for better management of adverse drug reactions to benznidazole. IMPORTANCE This study identified the risk factors for the development of adverse reactions to benznidazole and identified a set molecule to monitor the appearance of these reactions. This knowledge might improve the safety of benznidazole administration.
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Zhou LF, Lu R. Compound-honeysuckle-induced drug eruption with special manifestations: A case report. World J Clin Cases 2022; 10:8018-8024. [PMID: 36158492 PMCID: PMC9372860 DOI: 10.12998/wjcc.v10.i22.8018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 06/22/2022] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The clinical manifestations of drug eruption are complex and diverse, which can lead to missed diagnosis or misdiagnosis. The clinical manifestations of drug eruption caused by compound honeysuckle have not been reported.
CASE SUMMARY A 20-year-old man was admitted to our department of dermatology due to erythema and papules on the chest and abdomen with pruritus for 3 d. The next day after taking compound honeysuckle granules, the patient suddenly developed a rash and intense itching on his chest and abdomen. Physical examination revealed diffuse red needle-cap size macules and papules with well-defined borders on the chest and abdomen, and discoloration after finger pressure. No abnormality was observed in other areas of the skin. Back skin scratch was positive. White blood cells, eosinophil count and eosinophil ratio were higher than normal. Histopathological examination of the skin lesions on the left abdomen revealed intercellular edema, blurred focal basal cell layers, and focal lymphocyte infiltration in the superficial dermis and perivascular areas. Immunohistochemistry showed CD3+, CD4+ and CD8+ T lymphocytes. The diagnosis was drug eruption with special manifestations induced by compound honeysuckle. The skin lesions completely subsided without pruritus after 2 wk of antihistamine and hormone therapy. Follow-up for > 1 mo showed no recurrence.
CONCLUSION Chinese patent medicine compound honeysuckle granules can induce allergic reaction and rare skin damage.
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Affiliation(s)
- Li-Feng Zhou
- Department of Dermatology, The 942nd Hospital of the People's Liberation Army Joint Logistic Support Force, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Rong Lu
- Department of Pathology, The 942nd Hospital of the People's Liberation Army Joint Logistic Support Force, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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Antibiotic Allergy De-Labeling: A Pathway against Antibiotic Resistance. Antibiotics (Basel) 2022; 11:antibiotics11081055. [PMID: 36009924 PMCID: PMC9404790 DOI: 10.3390/antibiotics11081055] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/29/2022] [Accepted: 07/30/2022] [Indexed: 12/10/2022] Open
Abstract
Antibiotics are one of the most frequently prescribed drugs. Unfortunately, they also are the most common cause for self-reported drug allergy, limiting the use of effective therapies. However, evidence shows that more than 90% of patients labeled as allergic to antibiotics are not allergic. Importantly, the label of antibiotic allergy, whether real or not, constitutes a major public health problem as it directly impacts antimicrobial stewardship: it has been associated with broad-spectrum antibiotic use, often resulting in the emergence of bacterial resistance. Therefore, an accurate diagnosis is crucial for de-labeling patients who claim to be allergic but are not really allergic. This review presents allergy methods for achieving successful antibiotic allergy de-labeling. Patient clinical history is often inaccurately reported, thus not being able to de-label most patients. In vitro testing offers a complementary approach but it shows limitations. Immunoassay for quantifying specific IgE is the most used one, although it gives low sensitivity and is limited to few betalactams. Basophil activation test is not validated and not available in all centers. Therefore, true de-labeling still relies on in vivo tests including drug provocation and/or skin tests, which are not risk-exempt and require specialized healthcare professionals for results interpretation and patient management. Moreover, differences on the pattern of antibiotic consumption cause differences in the diagnostic approach among different countries. A multidisciplinary approach is recommended to reduce the risks associated with the reported penicillin allergy label.
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11
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Glässner A, Dubrall D, Weinhold L, Schmid M, Sachs B. Lymphocyte Transformation Test for drug allergy detection: when does it work? Ann Allergy Asthma Immunol 2022; 129:497-506.e3. [PMID: 35732204 DOI: 10.1016/j.anai.2022.06.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/09/2022] [Accepted: 06/14/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND The lymphocyte transformation test (LTT) is an in vitro test system for the detection of a sensitization in the context of allergies to drugs. Its reported sensitivity varies largely and seems to be affected by different parameters. In review articles, the average LTT performance was often calculated by combining overall mean sensitivities of various published studies, but without considering different patient characteristics or varying patient numbers per publication. OBJECTIVE This meta-analysis aims to investigate the impact of different patient-specific and methodical parameters on the sensitivity of the LTT based on data on the level of the individual patient extracted from single studies. METHODS We performed an advanced literature search in Pubmed and screened the identified publications according to previously defined inclusion criteria. In total, individual patient data from 721 patients were extracted from 30 studies. Random-effects meta-regression analyses were performed. RESULTS The analysis indicate that the ELISA-based read-out is more sensitive compared to the classical radioactivity method (ELISA: 80% vs. radioactivity: 66%;p=0.084). Interestingly, DRESS/DHISS is associated with a higher probability of a positive LTT test result compared to other investigated clinical phenotypes ("DRESS/DHISS" vs. "bullous reaction"; OR: 2.52;p-value=0.003). Our analysis also revealed an impact of the time to testing period after the occurrence of the allergic event ("<2 weeks" vs. "2 weeks-2 months"; OR: 2.12;p-value=0.034). CONCLUSION The read-out method and relevant clinical parameters affect the sensitivity of the LTT. These findings are based on a meta-analysis providing a higher level of evidence than a single study or previous reviews not considering individual patient data.
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Affiliation(s)
- Andreas Glässner
- Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
| | - Diana Dubrall
- Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
| | - Leonie Weinhold
- Institute for Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
| | - Matthias Schmid
- Institute for Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
| | - Bernhardt Sachs
- Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany; Department for Dermatology and Allergy, University Hospital Aachen, Aachen, Germany
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12
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Drug-Induced vs. Viral Maculopapular Exanthem—Resolving the Dilemma. Dermatopathology (Basel) 2022; 9:164-171. [PMID: 35645232 PMCID: PMC9149972 DOI: 10.3390/dermatopathology9020021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/28/2022] [Accepted: 04/30/2022] [Indexed: 02/04/2023] Open
Abstract
Maculopapular exanthem is a commonly encountered presentation in routine clinical practice, and differentiation between its two most common etiologies, i.e., viral- and drug-induced, often poses a diagnostic dilemma. Clinical, hematological and biochemical investigations are seldom reliable in distinguishing between a drug reaction and a viral exanthem. Certain key histopathological features such as the presence of a moderate degree of spongiosis, extensive basal cell damage with multiple necrotic keratinocytes and dermal infiltrate rich in eosinophils or lymphocytes and histiocytes may favor a drug exanthem, while distinctive epidermal cytopathic changes and lymphocytic vasculitis point towards a viral etiology. Similarly, notable immunohistochemical markers such as IL-5, eotaxin and FAS ligand may support a diagnosis of a drug-induced maculopapular eruption. Histopathological and immunohistochemical evaluations may help in distinguishing between the two etiologies when faced with a clinical overlap, especially in patients on multiple essential drugs when drug withdrawal and rechallenge is not feasible.
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13
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Chiu TM, Chu SY. Hypersensitivity Reactions to Iodinated Contrast Media. Biomedicines 2022; 10:1036. [PMID: 35625773 PMCID: PMC9138609 DOI: 10.3390/biomedicines10051036] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
At present, iodinated contrast media (ICM) are mostly non-ionic, have low osmolality, and are safe. Even if adverse drug reactions (ADRs) occur, most are chemo-toxic symptoms and require only observation or H1 antihistamines. However, rare, unpredictable, and even life-threatening hypersensitivity can still occur. The aim of this review is to summarize the issues that all relevant staff need to know about and be able to respond to. The most significant risk factor for ICM hypersensitivity is a history of ICM hypersensitivity. For high-risk populations, we must cautiously weigh the advantages and disadvantages of premedication and be aware that breakthrough reactions may still occur. The best policy for patients with a history of severe ICM hypersensitivity is to avoid the same ICM. If ICM are inevitable, skin tests, in vitro tests, and drug provocation tests may help to find a feasible alternative that is safer. The severity of the hypersensitivity is correlated with the positivity rate of these tests, so there is no need for further investigations for patients with only mild reactions. We should also keep in mind that even excipients in ICM may induce hypersensitivity. Detailed, standardized documentation is essential for correct diagnosis and the prevention of future occurrence.
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Affiliation(s)
- Tsu-Man Chiu
- Department of Dermatology, Changhua Christian Hospital, Changhua City 50073, Taiwan;
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Sung-Yu Chu
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 33305, Taiwan
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14
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Radiocontrast Media Hypersensitivity Reactions in Children. Medicina (B Aires) 2022; 58:medicina58040517. [PMID: 35454356 PMCID: PMC9028608 DOI: 10.3390/medicina58040517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/26/2022] [Accepted: 04/04/2022] [Indexed: 11/23/2022] Open
Abstract
Hypersensitivity reactions to radiocontrast media seem to be rare in children. Furthermore, the use of radiocontrast media in children remains quite safe in terms of the severity of reactions. Since pediatric guidelines are lacking, the diagnostic workup employed in adults could be adapted to children, taking into account that results have not yet been validated in this age group. Specific protocols for risk stratification and management of severe reactions have been proposed so far.
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Kinoshita M, Ogawa Y, Hama N, Ujiie I, Hasegawa A, Nakajima S, Nomura T, Adachi J, Sato T, Koizumi S, Shimada S, Fujita Y, Takahashi H, Mizukawa Y, Tomonaga T, Nagao K, Abe R, Kawamura T. Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis. Sci Transl Med 2021; 13:13/600/eaax2398. [PMID: 34193610 DOI: 10.1126/scitranslmed.aax2398] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 12/13/2020] [Accepted: 06/10/2021] [Indexed: 12/14/2022]
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions.
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Affiliation(s)
- Manao Kinoshita
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Youichi Ogawa
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
| | - Natsumi Hama
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Inkin Ujiie
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Saeko Nakajima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Nomura
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Jun Adachi
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.,Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Takuya Sato
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Schuichi Koizumi
- Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinji Shimada
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuyuki Fujita
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hayato Takahashi
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Yoshiko Mizukawa
- Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.,Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Keisuke Nagao
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD, USA
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tatsuyoshi Kawamura
- Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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16
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Fernandez‐Santamaria R, Bogas G, Palomares F, Salas M, Fernandez TD, Jimenez I, Barrionuevo E, Doña I, Torres MJ, Mayorga C. Dendritic cells inclusion and cell-subset assessment improve flow-cytometry-based proliferation test in non-immediate drug hypersensitivity reactions. Allergy 2021; 76:2123-2134. [PMID: 33523478 DOI: 10.1111/all.14755] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 12/09/2020] [Accepted: 01/04/2021] [Indexed: 12/13/2022]
Abstract
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.
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Affiliation(s)
| | - Gador Bogas
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
| | - Francisca Palomares
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA Málaga Spain
| | - Maria Salas
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
| | - Tahia D. Fernandez
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA Málaga Spain
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
| | - Isabel Jimenez
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA Málaga Spain
| | | | - Inmaculada Doña
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
| | - Maria Jose Torres
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA Málaga Spain
- Medicine Department Universidad de Málaga‐UMA Málaga Spain
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
- Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory Centro Andaluz de Nanomedicina y Biotecnología‐BIONAND Málaga Spain
| | - Cristobalina Mayorga
- Allergy Research Group Instituto de Investigación Biomédica de Málaga‐IBIMA Málaga Spain
- Allergy Unit Hospital Regional Universitario de Málaga‐HRUM Málaga Spain
- Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory Centro Andaluz de Nanomedicina y Biotecnología‐BIONAND Málaga Spain
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17
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Srinoulprasert Y. Lymphocyte transformation test and cytokine detection assays: Determination of read out parameters for delayed-type drug hypersensitivity reactions. J Immunol Methods 2021; 496:113098. [PMID: 34216607 DOI: 10.1016/j.jim.2021.113098] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 06/23/2021] [Accepted: 06/29/2021] [Indexed: 12/15/2022]
Abstract
Drug hypersensitivity reactions (DHRs) occur in certain people and are often not predictable. DHRs can be classified as immediate and delayed reactions regarding to onset of clinical manifestations. Both reactions are considered to be an important public health problem because they can lead to life-threatening conditions; however, this review article will focus on delayed DHRs. The most important points for diagnosis of delayed DHRs are the recognition of drug hypersensitivity characteristics and culprit drug identification. While it is usually difficult to identify a culprit drug; clinical evaluation using the causality assessment method, a non-invasive process, can identify the culprit drug without the need for intensive investigation. Delayed DHRs can cause life-threatening conditions; therefore, in vivo skin tests, as well as drug provocation tests, have to be cautiously performed by a drug allergist and have not been recommended in uncontrolled conditions. ENDA/EAACI has recommended that in vitro tests (if available) be performed prior to any in vivo tests. Therefore, in vitro diagnostic tests can be alternative methods to identify a culprit drug for delayed DHR diagnosis as there is no or very low risk for patients under investigation. There are many testing approaches to identify causative agents for delayed DHRs such as: the lymphocyte transformation test (LTT), cytokine/mediator detection assays (i.e. ELISA and flow cytometry-based bead assays), multiplex bead-based immunoassay and ELISpot. The LTT is the most standardized method whereas it has been available in medical schools affiliated with university hospitals. Other in vitro tests, like cytokine detection assays, have also been used, even though they are still being evaluated. They could supplement LTT results that would provide drug allergist's with documentary evidence and prevent risk to patients by avoiding in vivo or drug provocation testing. Hence, the in vitro tests have been promising tests contributing to the management of the delayed DHR work-up process in clinical practice.
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Affiliation(s)
- Yuttana Srinoulprasert
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Salaya, Thailand.
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18
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Identifying the Culprit Drug in Severe Cutaneous Adverse Reactions (SCARs). CURRENT TREATMENT OPTIONS IN ALLERGY 2021. [DOI: 10.1007/s40521-021-00291-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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19
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Delabeling Delayed Drug Hypersensitivity: How Far Can You Safely Go? THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 8:2878-2895.e6. [PMID: 33039012 DOI: 10.1016/j.jaip.2020.07.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/01/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022]
Abstract
Delayed immune-mediated adverse drug reactions (IM-ADRs) are defined as reactions occurring more than 6 hours after dosing. They include heterogeneous clinical phenotypes that are typically T-cell-mediated reactions with distinct mechanisms across a wide spectrum of severity from benign exanthems through to life-threatening cutaneous or organ-specific diseases. For mild reactions such as benign exanthem, considerations for delabeling are similar to immediate reactions and may include a graded or single-dose drug challenge with or without preceding skin or patch testing. Evaluation of challenging cases such as the patient who is on multiple drugs at the time a severe delayed IM-ADR occurs should prioritize clinical ascertainment of the most likely phenotype and implicated drug(s). Although not widely available and validated, procedures such as patch testing, delayed intradermal skin testing, and laboratory-based functional drug assays or genetic (human leukocyte antigen) testing may provide valuable information to further help risk stratify patients and identify the likely implicated and/or cross-reactive drug(s). The decision to use a drug challenge as a diagnostic or delabeling tool in a patient with a severe delayed IM-ADR should weigh the risk-benefit ratio, balancing the severity and priority for the treatment of the underlying, and the availability of alternative efficacious and safe treatments.
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20
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Torres MJ, Trautmann A, Böhm I, Scherer K, Barbaud A, Bavbek S, Bonadonna P, Cernadas JR, Chiriac AM, Gaeta F, Gimenez‐Arnau AM, Kang H, Moreno E, Brockow K. Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity. Allergy 2021; 76:1325-1339. [PMID: 33170954 DOI: 10.1111/all.14656] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/30/2020] [Accepted: 10/14/2020] [Indexed: 12/17/2022]
Abstract
Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial.
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Affiliation(s)
- María José Torres
- Allergy Unit Regional University Hospital of Malaga‐IBIMA‐UMA‐ARADyAL Malaga Spain
| | - Axel Trautmann
- Department of Dermatology and Allergy University Hospital Würzburg Würzburg Germany
| | - Ingrid Böhm
- Department of Diagnostic, Interventional, and Pediatric Radiology Inselspital University of Bern Bern Switzerland
| | | | - Annick Barbaud
- Service de Dermatologie et Allergologie Sorbonne Université INSERM Institut Pierre Louis d’Epidemiologie et de Sante Publique AP‐HP Sorbonne Universite, Hopital Tenon Paris France
| | - Sevim Bavbek
- Department of Chest Disease Division of Immunology and Allergy School of Medicine Ankara University Ankara Turkey
| | | | | | - Anca Mirela Chiriac
- Department of Pulmonology Division of Allergy Hôpital Arnaud de Villeneuve University Hospital of Montpellier Montpellier France
| | - Francesco Gaeta
- Allergy Unit Columbus Hospital Agostino Gemelli IRCCS University Hospital Rome Italy
| | - Ana M. Gimenez‐Arnau
- Department of Dermatology Hospital del Mar IMIM Universitat Autònoma Barcelona Barcelona Spain
| | - Hye‐Ryun Kang
- Department of Internal Medicine Division of Allergy and Clinical Immunology Seoul National University College of Medicine Seoul Korea
| | - Esther Moreno
- Allergy Unit University Hospital of Salamanca‐IBSAL‐UMA‐ARADyAL Salamanca Spain
| | - Knut Brockow
- Department of Dermatology and Allergy Biederstein School of Medicine Technical University of Munich Munich Germany
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21
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Sachs B, Fatangare A, Sickmann A, Glässner A. Lymphocyte transformation test: History and current approaches. J Immunol Methods 2021; 493:113036. [PMID: 33745950 DOI: 10.1016/j.jim.2021.113036] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 02/07/2023]
Abstract
Drug-induced hypersensitivity reactions encompass a variety of different clinical phenotypes ranging from harmless rashes to fatal reactions. They can be classified into allergic (i.e. drug allergy) and non-allergic reactions (i.e. non-allergic hypersensitivity). Drug allergies in turn can either be antibody (e.g. IgE) or T cell-mediated. One of the diagnostic tools for the in vitro detection of drug allergy is the lymphocyte transformation test (LTT) which is based on the activation and expansion of the drug-specific memory T cells following co-incubation of the patient's peripheral mononuclear cells (PMBC) with the suspected drug in vitro. The read-out parameter in the classical LTT is T cell proliferation which can be measured as counts per minute following the addition of radiolabeled thymidine to the cell culture. However, in the course of time different modifications of the classical LTT with regard to the read-out parameters and methods have been proposed. Likewise, variations of the LTT platform itself have been described in the literature. This review article describes the development of the classical LTT and its use in the context of drug allergy detection and summarizes the modifications which have been published over time.
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Affiliation(s)
- Bernhardt Sachs
- Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany; Department for Dermatology and Allergology, University Hospital Aachen, Germany.
| | - Amol Fatangare
- Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany
| | - Albert Sickmann
- Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany; Medizinische Fakultät, Medizinisches Proteom-Center (MPC), Ruhr-Universität Bochum, 44801 Bochum, Germany; Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen AB243FX, UK
| | - Andreas Glässner
- Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany
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Adair K, Meng X, Naisbitt DJ. Drug hapten-specific T-cell activation: Current status and unanswered questions. Proteomics 2021; 21:e2000267. [PMID: 33651918 DOI: 10.1002/pmic.202000267] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 11/07/2022]
Abstract
Drug haptens are formed from the irreversible, covalent binding of drugs to nucleophilic moieties on proteins, which can warrant adverse reactions in the body including severe delayed-type, T-cell mediated, drug hypersensitivity reactions (DHRs). While three main pathways exist for the activation of T-cells in DHRs, namely the hapten model, the pharmacological interaction model and the altered peptide repertoire model, the exact antigenic determinants responsible have not yet been defined. In recent years, progress has been made using advanced mass spectrometry-based proteomic methods to identify protein carriers and characterise the structure of drug-haptenated proteins. Since genome-wide association studies discovered a link between human leukocyte antigens (HLA) and an individual's susceptibility to DHRs, much effort has been made to define the drug-associated HLA ligands driving T-cell activation, including the elution of natural HLA peptides from HLA molecules and the generation of HLA-binding peptides. In this review, we discuss our current methodology used to design and synthesise drug-modified HLA ligands to investigate their immunogenicity using T-cell models, and thus their implication in drug hypersensitivity.
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Affiliation(s)
- Kareena Adair
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Xiaoli Meng
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Dean J Naisbitt
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
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23
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Villani AP, Rozieres A, Bensaid B, Eriksson KK, Mosnier A, Albert F, Mutez V, Brassard O, Baysal T, Tardieu M, Allatif O, Fusil F, Andrieu T, Jullien D, Dubois V, Giannoli C, Gruffat H, Pallardy M, Cosset FL, Nosbaum A, Kanagawa O, Maryanski JL, Yerly D, Nicolas JF, Vocanson M. Massive clonal expansion of polycytotoxic skin and blood CD8 + T cells in patients with toxic epidermal necrolysis. SCIENCE ADVANCES 2021; 7:7/12/eabe0013. [PMID: 33741590 PMCID: PMC7978430 DOI: 10.1126/sciadv.abe0013] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 02/02/2021] [Indexed: 05/22/2023]
Abstract
Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient's blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.
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Affiliation(s)
- Axel Patrice Villani
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
- Drug Allergy Reference Center, Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Dermatologie, Lyon, France
| | - Aurore Rozieres
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Benoît Bensaid
- Drug Allergy Reference Center, Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Dermatologie, Lyon, France
| | - Klara Kristin Eriksson
- Department of Rheumatology, Immunology and Allergology, Drug Allergy Research Laboratory, University Hospital of Bern, 3010 Bern, Switzerland
| | - Amandine Mosnier
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Floriane Albert
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Virginie Mutez
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Océane Brassard
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Tugba Baysal
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Mathilde Tardieu
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Omran Allatif
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Floriane Fusil
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Thibault Andrieu
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
- SFR Biosciences Gerland, US8, UMS3444, Lyon, France
| | - Denis Jullien
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
- Drug Allergy Reference Center, Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Dermatologie, Lyon, France
| | | | | | - Henri Gruffat
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | | | - François-Loïc Cosset
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Audrey Nosbaum
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
- Département d'Allergologie et d'immunologie Clinique, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Osami Kanagawa
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
| | - Janet L Maryanski
- Unité de Thérapie Cellulaire et Génique (UTCG), Centre Hospitalier Universitaire de Nice, 06101 Nice, France
| | - Daniel Yerly
- Department of Rheumatology, Immunology and Allergology, Drug Allergy Research Laboratory, University Hospital of Bern, 3010 Bern, Switzerland
- ADR-AC GmbH, Holligenstrasse 91, 3008 Bern, Switzerland
| | - Jean-François Nicolas
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France
- Département d'Allergologie et d'immunologie Clinique, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Marc Vocanson
- Centre International de Recherche en Infectiologie (CIRI); INSERM, U1111; Université de Lyon 1; Ecole Normale Supérieure de Lyon; and CNRS, UMR 5308, Lyon, France.
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Copaescu A, Gibson A, Li Y, Trubiano JA, Phillips EJ. An Updated Review of the Diagnostic Methods in Delayed Drug Hypersensitivity. Front Pharmacol 2021; 11:573573. [PMID: 33597867 PMCID: PMC7883592 DOI: 10.3389/fphar.2020.573573] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 10/23/2020] [Indexed: 12/19/2022] Open
Abstract
Delayed drug hypersensitivity reactions are clinically diverse reactions that vary from isolated benign skin conditions that remit quickly with no or symptomatic treatment, drug discontinuation or even continued drug treatment, to the other extreme of severe cutaneous adverse reactions (SCARs) that are associated with presumed life-long memory T-cell responses, significant acute and long-term morbidity and mortality. Diagnostic "in clinic" approaches to delayed hypersensitivity reactions have included patch testing (PT), delayed intradermal testing (IDT) and drug challenges for milder reactions. Patch and IDT are, in general, performed no sooner than 4-6 weeks after resolution of the acute reaction at the maximum non-irritating concentrations. Functional in vitro and ex vivo assays have largely remained the province of research laboratories and include lymphocyte transformation test (LTT) and cytokine release enzyme linked ImmunoSpot (ELISpot) assay, an emerging diagnostic tool which uses cytokine release, typically IFN-γ, after the patient's peripheral blood mononuclear cells are stimulated with the suspected drug(s). Genetic markers such as human leukocyte antigen have shown recent promise for both pre-prescription screening as well as pre-emptive and diagnostic testing strategies.
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Affiliation(s)
- Ana Copaescu
- Department of Infectious Diseases, Austin Health, Center for Antibiotic Allergy and Research, Heidelberg, VIC, Australia
| | - Andrew Gibson
- Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia.,Clinical Immunology and Allergy, McGill University Health Center, Montréal, Canada
| | - Yueran Li
- Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia
| | - Jason A Trubiano
- Department of Infectious Diseases, Austin Health, Center for Antibiotic Allergy and Research, Heidelberg, VIC, Australia.,Department of Oncology, Sir Peter MacCallum Cancer Center, The University of Melbourne, Parkville, VIC, Australia.,Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, VIC, Australia.,The National Center for Infections in Cancer, Peter MacCallum Cancer Center, Melbourne, VIC, Australia
| | - Elizabeth J Phillips
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia.,Department of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, United States
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Srinoulprasert Y, Rerkpattanapipat T, Sompornrattanaphan M, Wongsa C, Kanistanon D. Clinical value of in vitro tests for the management of severe drug hypersensitivity reactions. Asia Pac Allergy 2020; 10:e44. [PMID: 33178569 PMCID: PMC7610079 DOI: 10.5415/apallergy.2020.10.e44] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
Drug hypersensitivity reactions (DHRs) occasionally present with severe cutaneous adverse reactions (SCARs) which result in a high risk of morbidity and mortality. Although SCARs are rare, the occurrence could lead to a significant increase in healthcare and economic burden, especially when more than one possible culprit drug is implicated. Therefore, the accurate identification of the culprit drug(s) is important for correct labeling and subsequent patient education and avoidance. To date, clinical evaluation using causality assessment has limitations because the assessment may be inaccurate due to the overlapping timelines when multiple drugs are initiated/continued. Moreover, drug provocation tests (DPTs) which is the gold standard in diagnosis, are contraindicated, and in vivo skin tests may also be associated with risks of triggering SCAR. The European Network for Drug Allergy recommended that in vitro tests, if available, should be performed before any in vivo tests. Basophil activation tests and lymphocyte transformation tests, could serve as reliable in vitro tests for both immediate and delayed-type DHR. Many academic medical centers with affiliated laboratory services offer these tests in the diagnostic evaluation of SCARs in clinical practice. This not only complements identification of the culprit drug(s), but may also be used to test for potentially non cross-reactive alternatives, hence avoiding DPTs. In this review, we summarize the roles of in vitro tests in identifying the culprit drug(s) in SCARs, issues with utilization and interpretation of test results, and our experience in clinical practice.
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Affiliation(s)
- Yuttana Srinoulprasert
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ticha Rerkpattanapipat
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Mongkhon Sompornrattanaphan
- Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chamard Wongsa
- Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Duangjit Kanistanon
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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26
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Mori F, Fili L, Sarti L, Capone M, Liccioli G, Giovannini M, Barni S, Novembre EM, Parronchi P. Sensitivity and specificity of lymphocyte transformation test in children with mild delayed hypersensitivity reactions to beta-lactams. Allergy 2020; 75:2696-2699. [PMID: 32392390 DOI: 10.1111/all.14358] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Francesca Mori
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Lucia Fili
- Department of Clinical and Experimental Medicine University of Florence Florence Italy
| | - Lucrezia Sarti
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Manuela Capone
- Department of Clinical and Experimental Medicine University of Florence Florence Italy
| | - Giulia Liccioli
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Mattia Giovannini
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Simona Barni
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Elio M. Novembre
- Allergy Unit Department of Pediatrics Anna Meyer Children's University Hospital Florence Italy
| | - Paola Parronchi
- Department of Clinical and Experimental Medicine University of Florence Florence Italy
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27
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Santiago LG, Morgado FJ, Baptista MS, Gonçalo M. Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits. Contact Dermatitis 2020; 82:290-296. [DOI: 10.1111/cod.13462] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 12/29/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Luis G. Santiago
- Department of DermatologyCoimbra University Hospital Coimbra Portugal
| | | | | | - Margarida Gonçalo
- Department of DermatologyCoimbra University Hospital Coimbra Portugal
- Faculty of MedicineUniversity of Coimbra Coimbra Portugal
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28
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Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS): How Far Have We Come? Am J Clin Dermatol 2019; 20:217-236. [PMID: 30652265 DOI: 10.1007/s40257-018-00416-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome (DiHS), is an uncommon severe adverse reaction to medications. It is important to recognize it as it is potentially fatal and can cause significant morbidity. From the first reports of drug reactions related to certain anticonvulsants characterized by fever, liver enzyme elevation, and skin changes, our continuously growing understanding of this entity has allowed us to describe its physiopathology and clinical features even further. The relationship of genetic factors, viral activation, and specific drug exposure is now known to play a role in this disease. There is still not a widely accepted marker for DReSS/DiHS, but the spectrum of clinical and laboratory features has now been better outlined. The mainstay of treatment is the use of systemic corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and cyclophosphamide have been described. We present a comprehensive review of the literature on DReSS/DiHS, focusing on its history, etiopathogenesis, diagnosis, therapeutic approach, and outcome.
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29
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Torres M, Mayorga C, Fernández T, Cornejo-García J, Antúnez C, Valenzuela M, Prado MD, Rodriguez-Pena R, Blanca M. T Cell Assessment in Allergic Drug Reactions during the Acute Phase According to the Time of Occurrence. Int J Immunopathol Pharmacol 2018. [DOI: 10.1177/205873920601900112] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Allergic drug reactions can be classified as immediate, accelerated or delayed. This classification usually correlates with the mechanism involved: immediate reactions are IgE mediated and delayed reactions are T cell dependent. We analyzed lymphocyte involvement in patients with these reactions by determining cell subpopulations, activation state and skin homing receptor expression (CLA) in blood and skin. Patients with immediate, accelerated and delayed reactions were evaluated during the acute phase and after resolution. Controls taking drugs were included. Phenotypic immunofluorescence analysis was done by flow cytometry in peripheral blood, and by immunohistochemistry in skin for delayed reactions. Forty-six patients were included, 17 with immediate reactions, 10 accelerated and 19 delayed. At the acute phase CLA was significantly increased in delayed reactions and HLA-DR in all three types of reaction. In the severest delayed reactions, Steven-Johnson/Lyell syndromes, the CD4 subsets were increased in peripheral blood and skin compared to maculopapular exanthemas and urticaria and HLA-DR when compared with urticaria. In maculopapular exanthemas CLA was significantly increased in peripheral blood and skin compared to urticaria and the severe reactions. We found that T-cells are implicated, besides delayed reactions, in immediate and accelerated reactions. In delayed reactions there is a parallelism between results found in skin and peripheral blood with a higher participation of CD4+ cells the more severe the reaction.
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Affiliation(s)
- M.J. Torres
- Allergy Service, Carlos Haya Hospital, Malaga, Spain
| | - C. Mayorga
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | - T.D. Fernández
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | - J.A. Cornejo-García
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | - C. Antúnez
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | - M. Valenzuela
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | | | - R. Rodriguez-Pena
- Research Laboratory for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain
| | - M. Blanca
- Allergy Service, Carlos Haya Hospital, Malaga, Spain
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30
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Kumkamthornkul P, Udnaen S, Tansit T, Tuchinda P, Srinoulprasert Y. Evaluation of a lymphocyte transformation test and cytokine detection assay to identify phenytoin and carbamazepine provoked DRESS or SJS/TEN in epilepsy patients. Int Immunopharmacol 2018; 63:204-210. [DOI: 10.1016/j.intimp.2018.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 07/24/2018] [Accepted: 08/08/2018] [Indexed: 01/12/2023]
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31
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Villani AP, Gamradt P, Nosbaum A, Laoubi L, Jullien D, Nicolas JF, Vocanson M. Immune-mediated skin diseases induced by chemicals and drugs. CURRENT OPINION IN TOXICOLOGY 2018. [DOI: 10.1016/j.cotox.2018.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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32
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Cabañas R, Calderón O, Ramírez E, Fiandor A, Caballero T, Heredia R, Herranz P, Madero R, Quirce S, Bellón T. Sensitivity and specificity of the lymphocyte transformation test in drug reaction with eosinophilia and systemic symptoms causality assessment. Clin Exp Allergy 2018; 48:325-333. [DOI: 10.1111/cea.13076] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/26/2017] [Accepted: 10/24/2017] [Indexed: 12/17/2022]
Affiliation(s)
- R. Cabañas
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
- PIELenRed Consortium; Madrid Spain
| | - O. Calderón
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - E. Ramírez
- PIELenRed Consortium; Madrid Spain
- Department of Clinical Pharmacology; School of Medicine; La Paz University Hospital Health Research Institute (IdiPAZ); Autonomous University of Madrid; Madrid Spain
| | - A. Fiandor
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
- PIELenRed Consortium; Madrid Spain
| | - T. Caballero
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - R. Heredia
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - P. Herranz
- PIELenRed Consortium; Madrid Spain
- Department of Dermatology; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - R. Madero
- Department of Statistics; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - S. Quirce
- Department of Allergy; La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
| | - T. Bellón
- PIELenRed Consortium; Madrid Spain
- La Paz University Hospital Health Research Institute (IdiPAZ); Madrid Spain
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33
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Porebski G. In Vitro Assays in Severe Cutaneous Adverse Drug Reactions: Are They Still Research Tools or Diagnostic Tests Already? Int J Mol Sci 2017; 18:E1737. [PMID: 28796198 PMCID: PMC5578127 DOI: 10.3390/ijms18081737] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/07/2017] [Accepted: 08/04/2017] [Indexed: 12/25/2022] Open
Abstract
Severe cutaneous adverse drug reactions (SCARs) represent life-threatening medical conditions and an appropriate causative diagnosis of these conditions is of the highest importance. Existing in vivo diagnostic methods are risky or are just contraindicated in these patients. Therefore, in vitro tests take on greater significance. In this survey, the studies on in vitro assays in SCARs were identified with a defined searching strategy and strict eligibility criteria. Different methods in the particular clinical manifestations and the groups of drugs were compared in respect to the diagnostic parameters obtained. The lymphocyte transformation test and IFNg-ELISpot (Interferon γ-Enzyme-linked immunospot assay) appeared to have the best evidence currently available. Further diagnostic assays, which are based mostly on distinct mechanisms of SCARs, may outdo previous assays but they still need confirmation in a larger group of patients and in more research centers. Data from pediatric populations and acute generalized exanthematous pustulosis (AGEP) patients are scarce. Some technical issues, limitations, and modifications of routine laboratory methods are also discussed.
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Affiliation(s)
- Grzegorz Porebski
- Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Sniadeckich 10, 31-531 Krakow, Poland.
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34
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Illing PT, Purcell AW, McCluskey J. The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions. Immunogenetics 2017; 69:617-630. [DOI: 10.1007/s00251-017-1007-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 05/29/2017] [Indexed: 12/17/2022]
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35
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Romano A, Valluzzi RL, Caruso C, Maggioletti M, Gaeta F. Non-immediate Cutaneous Reactions to Beta-Lactams: Approach to Diagnosis. Curr Allergy Asthma Rep 2017; 17:23. [PMID: 28382604 DOI: 10.1007/s11882-017-0691-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Non-immediate cutaneous reactions (i.e., occurring at least 1 h after the initial drug administration), particularly maculopapular exanthemas and urticarial eruptions, are common during beta-lactam treatments. A T cell-mediated pathogenic mechanism has been demonstrated in some cutaneous reactions, such as maculopapular exanthema, fixed drug eruption, acute generalized exanthematous pustulosis, and drug-induced hypersensitivity syndrome. In the diagnostic work-up, patch testing is useful, together with delayed-reading intradermal testing. Patch tests are a simple and safe diagnostic tool, which in the case of severe reactions should be used as the first line of investigation. However, patch tests are less sensitive than intradermal tests, which are preferable in subjects with mild reactions. Lymphocyte transformation or activation tests and enzyme-linked immunosorbent spot assays can be used as complementary tests. In selected cases of mild or moderate reactions, displaying negative results in the aforesaid allergy tests, a graded challenge with the implicated beta-lactam can be performed.
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Affiliation(s)
- Antonino Romano
- Allergy Unit, Presidio Columbus, Via G. Moscati, 31, 00168, Rome, Italy. .,IRCCS Oasi Maria S.S, Troina, Italy.
| | - Rocco Luigi Valluzzi
- Allergy Unit, Presidio Columbus, Via G. Moscati, 31, 00168, Rome, Italy.,Department of Pediatrics, Division of Allergy, Pediatric Hospital Bambino Gesù, Rome, Vatican City, Italy
| | - Cristiano Caruso
- Allergy Unit, Presidio Columbus, Via G. Moscati, 31, 00168, Rome, Italy
| | | | - Francesco Gaeta
- Allergy Unit, Presidio Columbus, Via G. Moscati, 31, 00168, Rome, Italy
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36
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Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JKG, Setterfield J, Bunker CB, Ardern-Jones MR, Watson KMT, Wong GAE, Philippidou M, Vercueil A, Martin RV, Williams G, Shah M, Brown D, Williams P, Mohd Mustapa MF, Smith CH. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 2017; 174:1194-227. [PMID: 27317286 DOI: 10.1111/bjd.14530] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2016] [Indexed: 12/11/2022]
Affiliation(s)
- D Creamer
- Department of Dermatology, King's College Hospital NHS Foundation Trust, London, SE5 9RS, U.K
| | - S A Walsh
- Department of Dermatology, King's College Hospital NHS Foundation Trust, London, SE5 9RS, U.K
| | - P Dziewulski
- St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospital Services NHS Trust, Chelmsford, CM1 7ET, U.K
| | - L S Exton
- British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K
| | - H Y Lee
- Dermatology Unit, Singapore General Hospital, Singapore
| | - J K G Dart
- Moorfields Eye Hospital, 162 City Road, London, EC1V 2PD, U.K
| | - J Setterfield
- Mucosa and Salivary Biology, Dental Institute, King's College London, Guy's Campus, Great Maze Pond, London, SE1 9RT, U.K
| | - C B Bunker
- University College Hospital, London, NW1 2BU, U.K
| | - M R Ardern-Jones
- Clinical Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, U.K
| | - K M T Watson
- Department of Dermatology, Orpington Hospital, Orpington, Kent, BR6 9JU, U.K
| | - G A E Wong
- Department of Dermatology, University Hospital of South Manchester NHS Foundation Trust, Manchester, M23 9LT, U.K
| | - M Philippidou
- Department of Histopathology, King's College Hospital NHS Foundation Trust, London, SE5 9RS, U.K
| | - A Vercueil
- Intensive Care Medicine, King's College Hospital NHS Foundation Trust, London, SE5 9RS, U.K
| | - R V Martin
- St Andrews Centre for Plastic Surgery and Burns, Mid Essex Hospital Services NHS Trust, Chelmsford, CM1 7ET, U.K
| | - G Williams
- Late of the Burns Centre, Chelsea and Westminster NHS Foundation Trust, London, SW10 9NH, U.K
| | - M Shah
- Department of Burns and Plastic Surgery, University Hospitals of South Manchester, Southmoor Road, Wythenshawe, Manchester, M23 9LT, U.K
| | - D Brown
- St John's Institute of Dermatology, Guy's and St Thomas NHS Foundation Trust, London, SE1 9RT, U.K
| | - P Williams
- Department of Dermatology, King's College Hospital NHS Foundation Trust, London, SE5 9RS, U.K
| | - M F Mohd Mustapa
- British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K
| | - C H Smith
- St John's Institute of Dermatology, Guy's and St Thomas NHS Foundation Trust, London, SE1 9RT, U.K
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37
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Kinoshita Y, Saeki H. A Review of the Pathogenesis of Toxic Epidermal Necrolysis. J NIPPON MED SCH 2017; 83:216-222. [PMID: 28133001 DOI: 10.1272/jnms.83.216] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Toxic epidermal necrolysis (TEN) is a rare skin condition, most often drug-induced, known for its skin detachment and high mortality. In general, acute TEN is considered a T-cell mediated, type IV hypersensitivity disorder. It mostly results from a cumulative effect of risks from the drug structure, drug metabolism, HLA alleles and T cell clonotypes. However, the precise mechanism of TEN is still unknown. Apoptosis or necroptosis causes keratinocytes to lose their shape and adhesion, and necrosis predominates within a few days. Total epidermal necrosis separates the epidermis from the dermis. TEN is regarded as an immune reaction with predominantly CD8+ T lymphocytes, monocytes/macrophages, and natural killer cells. Impaired regulatory T-cells, T-helper 17 cells, cytotoxic granules such as perforin-granzyme and granulysin, tumor necrosis factor α, annexin, microRNA-18a-5p, and drug metabolites are all thought to be involved. From what is known, it can be assumed their mechanism is complex, and there is still much to be investigated. New findings will contribute to the identification of effective active methods of intervention.
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38
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Mayorga C, Doña I, Perez-Inestrosa E, Fernández TD, Torres MJ. The Value of In Vitro Tests to DiminishDrug Challenges. Int J Mol Sci 2017; 18:ijms18061222. [PMID: 28590437 PMCID: PMC5486045 DOI: 10.3390/ijms18061222] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 05/31/2017] [Accepted: 06/02/2017] [Indexed: 01/30/2023] Open
Abstract
Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and drug provocation testing, which is not risk-free for the patient, especially in severe reactions. In vitro tests could help to identify correctly the responsible agent, thus improving the diagnosis of these reactions, helping the physician to find safe alternatives, and reducing the need to perform drug provocation testing. However, it is necessary to confirm the sensitivity, specificity, negative and positive predictive values for these in vitro tests to enable their implementation in clinical practice. In this review, we have analyzed these parameters from different studies that have used in vitro test for evaluating drug hypersensitivity reactions and estimated the added value of these tests to the in vivo diagnosis.
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Affiliation(s)
- Cristobalina Mayorga
- Research Laboratory-Allergy Unit, Biomedical Institute of Málaga-IBIMA, Regional University Hospital of Malaga-UMA, Málaga 29009, Spain.
- Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, Málaga 29009, Spain.
| | - Inmaculada Doña
- Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, Málaga 29009, Spain.
| | - Ezequiel Perez-Inestrosa
- Department of Organic Chemistry, University of Málaga, Biomedical Institute of Málaga-IBIMA, Málaga 29071, Spain.
- Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Málaga 29590, Spain.
| | - Tahia D Fernández
- Research Laboratory-Allergy Unit, Biomedical Institute of Málaga-IBIMA, Regional University Hospital of Malaga-UMA, Málaga 29009, Spain.
| | - Maria J Torres
- Allergy Service, IBIMA-Regional University Hospital of Malaga-UMA, Málaga 29009, Spain.
- Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Málaga 29590, Spain.
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39
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Incidence and Risk Factors for Gadolinium-Based Contrast Agent Immediate Reactions. Top Magn Reson Imaging 2017; 25:257-263. [PMID: 27748714 DOI: 10.1097/rmr.0000000000000109] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Since their clinical introduction in 1988, gadolinium-based contrast agents (GBCAs) have demonstrated an excellent safety profile with a reported acute adverse reaction rate ranging from 0.01% to 2%. By comparison, the acute adverse reaction rate of low osmolar nonionic computed tomography contrast agents (CTCs) ranges from 0.7% to 3.1%. Many of the risk factors associated with CTC reactions (drug allergies, asthma, atopy, prior contrast reaction) also point toward an increased incidence of acute adverse events to GBCAs. With CTCs, an increased adverse event rate was associated with ionic preparations and high osmolality. In response to concerns for nephrogenic systemic fibrosis, GBCAs are now selected for their augmented chemical stability. These agents possess some combination of macrocyclic chelates or ionic preparations. With their improved chemical stability, these agents also possess higher osmolality and the increased potential to elicit an acute adverse reaction. In light of these concerns, researchers are now focusing greater efforts on reexamining acute adverse reactions to GBCAs and whether there is an increased association with certain agents. In addition to hypersensitivity reactions, this article will also discuss contrast extravasations, safety of GBCAs for pregnant and nursing patients, and the potential nephrotoxic effects of GBCAs.
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40
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Pichler WJ, Srinoulprasert Y, Yun J, Hausmann O. Multiple Drug Hypersensitivity. Int Arch Allergy Immunol 2017; 172:129-138. [PMID: 28315874 PMCID: PMC5472211 DOI: 10.1159/000458725] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms.
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Affiliation(s)
- Werner J. Pichler
- Department of Immunology, ADR-AC, Bern, Siriraj Hospital, Mahidol University, NSW, Australia
| | - Yuttana Srinoulprasert
- Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - James Yun
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Oliver Hausmann
- Department of Immunology, ADR-AC, Bern, Siriraj Hospital, Mahidol University, NSW, Australia
- Department of Immunology, Löwenpraxis, Luzern, Switzerland, NSW, Australia
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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist. Curr Rheumatol Rep 2017; 19:3. [DOI: 10.1007/s11926-017-0626-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Dodiuk-Gad RP, Chung WH, Shear NH. Adverse Medication Reactions. CLINICAL AND BASIC IMMUNODERMATOLOGY 2017. [PMCID: PMC7123512 DOI: 10.1007/978-3-319-29785-9_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Cutaneous adverse drug reactions (ADRs) are among the most frequent adverse reactions in patients receiving drug therapy. They have a broad spectrum of clinical manifestations, are caused by various drugs, and result from different pathophysiological mechanisms. Hence, their diagnosis and management is challenging. Severe cutaneous ADRs comprise a group of diseases with major morbidity and mortality, reaching 30 % mortality rate in cases of Toxic Epidermal Necrolysis. This chapter covers the terminology, epidemiology, pathogenesis and classification of cutaneous ADR, describes the severe cutaneous ADRs and the clinical and laboratory approach to the patient with cutaneous ADR and presents the translation of laboratory-based discoveries on the genetic predisposition and pathogenesis of cutaneous ADRs to clinical management guidelines.
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Ye YM, Hur GY, Kim SH, Ban GY, Jee YK, Naisbitt DJ, Park HS, Kim SH. Drug-specific CD4 + T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome. Br J Dermatol 2016; 176:378-386. [PMID: 27373553 DOI: 10.1111/bjd.14839] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. OBJECTIVES To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. METHODS We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. RESULTS Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. CONCLUSIONS This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.
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Affiliation(s)
- Y-M Ye
- Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea
| | - G-Y Hur
- Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea
| | - S-H Kim
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - G-Y Ban
- Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea
| | - Y-K Jee
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, South Korea
| | - D J Naisbitt
- MRC Centre for Drug Safety Science, Department of Clinical and Molecular Pharmacology, The University of Liverpool, Liverpool, U.K
| | - H-S Park
- Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea
| | - S-H Kim
- Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea.,Translational Research Laboratory for Inflammatory Disease, Clinical Trial Center, Ajou University Medical Center, Suwon, South Korea
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Konvinse KC, Phillips EJ, White KD, Trubiano JA. Old dog begging for new tricks: current practices and future directions in the diagnosis of delayed antimicrobial hypersensitivity. Curr Opin Infect Dis 2016; 29:561-576. [PMID: 27753687 PMCID: PMC5113146 DOI: 10.1097/qco.0000000000000323] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Antimicrobials are a leading cause of severe T cell-mediated adverse drug reactions (ADRs). The purpose of this review is to address the current understanding of antimicrobial cross-reactivity and the ready availability of and evidence for in-vitro, in-vivo, and ex-vivo diagnostics for T cell-mediated ADRs. RECENT FINDINGS Recent literature has evaluated the efficacy of traditional antibiotic allergy management, including patch testing, skin prick testing, intradermal testing, and oral challenge. Although patch and intradermal testing are specific for the diagnosis of immune-mediated ADRs, they suffer from drug-specific limitations in sensitivity. The use of ex-vivo diagnostics, especially enzyme-linked immunospot, has been highlighted as a promising new approach to assigning causality. Knowledge of true rates of antimicrobial cross-reactivity aids empirical antibiotic choice in the setting of previous immune-mediated ADRs. SUMMARY In an era of increasing antimicrobial resistance and use of broad-spectrum antimicrobial therapy, ensuring patients are assigned the correct 'allergy label' is essential. Re-exposure to implicated antimicrobials, especially in the setting of severe adverse cutaneous reaction, is associated with significant morbidity and mortality. The process through which an antibiotic label gets assigned, acted on and maintained is still imprecise. Predicting T cell-mediated ADRs via personalized approaches, including human leukocyte antigen-typing, may pave future pathways to safer antimicrobial prescribing guidelines.
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Affiliation(s)
- Katherine C Konvinse
- aDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA bInstitute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia cDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA dDepartment of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA eDepartment of Infectious Diseases, Austin Hospital, Victoria, Australia fDepartment of Infectious Diseases, Alfred Hospital, Victoria, Australia gDepartment of Infectious Diseases, Peter MacCallum Cancer Centre, Victoria, Australia hDepartment of Medicine, University of Melbourne, Victoria, Australia
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Klaewsongkram J, Thantiworasit P, Suthumchai N, Rerknimitr P, Sukasem C, Tuchinda P, Chularojanamontri L, Srinoulprasert Y, Rerkpattanapipat T, Chanprapaph K, Disphanurat W, Chakkavittumrong P, Tovanabutra N, Srisuttiyakorn C. In vitro test to confirm diagnosis of allopurinol-induced severe cutaneous adverse reactions. Br J Dermatol 2016; 175:994-1002. [PMID: 27106261 DOI: 10.1111/bjd.14701] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2016] [Indexed: 11/29/2022]
Abstract
BACKGROUND Allopurinol is a frequent cause of severe cutaneous adverse reactions (SCARs), such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The reactions can potentially be fatal. As drug rechallenge in patients with a history of drug-induced SCARs is contraindicated, in vitro testing may have a diagnostic role as a confirmation test. OBJECTIVES To study the diagnostic value of interferon (IFN)-γ enzyme-linked immunospot (ELISpot) assay as a confirmatory test in patients with a history of allopurinol-induced SCARs. METHODS Peripheral blood mononuclear cells (PBMCs) from 24 patients with a history of allopurinol-induced SCAR (13 DRESS, 11 SJS/TEN) and 21 control subjects were incubated with allopurinol or oxypurinol in the presence or absence of antiprogrammed death ligand 1 antibody (anti-PD-L1). The numbers of IFN-γ-releasing cells after stimulation in each group were subsequently measured with ELISpot. RESULTS The numbers of IFN-γ-releasing cells in allopurinol-allergic subjects were significantly higher than in control subjects when stimulating PBMCs with oxypurinol 100 μg mL-1 , especially when adding anti-PD-L1 supplementation. According to the receiver operating characteristic curve results, the optimal discriminatory power of IFN-γ ELISpot in confirming diagnosis of allopurinol-induced SCARs can be obtained using 16 spot-forming cells per 106 PBMCs as a cut-off value upon oxypurinol/anti-PD-L1 stimulation (79·2% sensitivity and 95·2% specificity). CONCLUSIONS The measurement of oxypurinol/anti-PD-L1-inducing IFN-γ-releasing cells yields a high diagnostic value in distinguishing between allopurinol-allergic and control subjects. This technique is beneficial in confirming diagnosis of allopurinol-induced SCARs in patients whose reaction develops while taking multiple drugs.
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Affiliation(s)
- J Klaewsongkram
- Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunology Research Group, Chulalongkorn University, Bangkok, Thailand. .,King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
| | - P Thantiworasit
- Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunology Research Group, Chulalongkorn University, Bangkok, Thailand
| | - N Suthumchai
- Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunology Research Group, Chulalongkorn University, Bangkok, Thailand
| | - P Rerknimitr
- King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Division of Dermatology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunology Research Group, Chulalongkorn University, Bangkok, Thailand
| | - C Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - P Tuchinda
- Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - L Chularojanamontri
- Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Y Srinoulprasert
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - T Rerkpattanapipat
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - K Chanprapaph
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - W Disphanurat
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - P Chakkavittumrong
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - N Tovanabutra
- Dermatological Division, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - C Srisuttiyakorn
- Division of Dermatology, Department of Medicine, Phramongkutklao Hospital, Phramongkutklao College of Medicine, Bangkok, Thailand
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Karami Z, Mesdaghi M, Karimzadeh P, Mansouri M, Taghdiri MM, Kayhanidoost Z, Jebelli B, Shekarriz Foumani R, Babaie D, Chavoshzadeh Z. Evaluation of Lymphocyte Transformation Test Results in Patients with Delayed Hypersensitivity Reactions following the Use of Anticonvulsant Drugs. Int Arch Allergy Immunol 2016; 170:158-62. [PMID: 27560351 DOI: 10.1159/000448284] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 07/11/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIM Administration of the anticonvulsant drugs phenobarbital, phenytoin, carbamazepine and lamotrigine can be associated with severe hypersensitivity reactions. The lymphocyte transformation test (LTT) is a method to determine which drug has caused the hypersensitivity reaction. This study was done to evaluate the results of LTT in patients with delayed hypersensitivity reactions following the administration of anticonvulsants. METHODS Twenty-four patients with hypersensitivity reactions, e.g. drug-induced hypersensitivity syndrome/drug rash and eosinophilia with systemic symptoms (DIHS/DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), following the administration of anticonvulsant drugs, and 24 patients who had used anticonvulsant drugs but did not have hypersensitivity reactions (the control group) were included in this study. Peripheral blood mononuclear cells were isolated. The cells were stimulated with the drugs, phytohemagglutinin as a mitogen and Candida as an antigen (positive controls). Lymphocyte proliferation was measured using the BrdU proliferation assay kit (Roche, Germany). The stimulation index was calculated as the mean ratio of the OD of stimulated cells divided by the OD of unstimulated cells. The results in the case and control groups were compared. RESULTS Of 24 patients in the test group, 14 (58.3%) had positive LTT results and 10 (41.7%) had negative results. Among patients in the control group, 1 (4.2%) had a positive LTT result and 23 (95.8%) had negative results. Among the patients who had received carbamazepine and phenytoin, there was a significant difference between the results of LTT in the case and control groups (p = 0.002 and p = 0.028, respectively). Although patients receiving lamotrigine and phenobarbital had more positive LTT results in the case group than in the control group, these differences were not statistically significant. The sensitivity, specificity, positive predictive value and negative predictive value of LTT were 58.4, 95.8, 93.3 and 69.9%, respectively. CONCLUSIONS Considering the significant difference in LTT results between the case and control groups in patients receiving carbamazepine and phenytoin, and not observing such a difference in patients receiving phenobarbital and lamotrigine, LTT results are more valuable for the diagnosis of hypersensitivity reactions following the administration of carbamazepine and phenytoin. The LTT has good specificity but low sensitivity for the diagnosis of drug hypersensitivity reactions.
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Affiliation(s)
- Zahra Karami
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Rodrigues-Cernadas J, Vultaggio A, Brockow K, Caubet JC, Makowska J, Nakonechna A, Romano A, Montañez MI, Laguna JJ, Zanoni G, Gueant JL, Oude Elberink H, Fernandez J, Viel S, Demoly P, Torres MJ. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016; 71:1103-34. [PMID: 26991315 DOI: 10.1111/all.12886] [Citation(s) in RCA: 188] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2016] [Indexed: 12/15/2022]
Abstract
Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.
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Affiliation(s)
- C. Mayorga
- Research Laboratory; IBIMA-Regional University Hospital of Malaga-UMA; Malaga Spain
- Allergy Unit; IBIMA-Regional University Hospital of Malaga-UMA; Malaga Spain
| | - G. Celik
- Division of Immunology and Allergy; Department of Chest Diseases; Ankara University School of Medicine; Ankara Turkey
| | - P. Rouzaire
- Department of Immunology and ERTICa Research Group; University Hospital of Clermont-Ferrand and Auvergne University; Clermont-Ferrand France
| | - P. Whitaker
- Regional Adult Cystic Fibrosis Unit; St James's Hospital; Leeds UK
| | - P. Bonadonna
- Allergy Unit; Azienda Ospedaliera Universitaria Intergata of Verona; Verona Italy
| | - J. Rodrigues-Cernadas
- Immunoallergology Department; Faculty of Medicine; Centro Hospitalar São João; Porto Portugal
| | - A. Vultaggio
- Immunoallergology Unit; Department of Biomedicine; Careggi Hospital; Florence Italy
| | - K. Brockow
- Department of Dermatology and Allergology Biederstein; Technische Universität München; Munich Germany
| | - J. C. Caubet
- Pediatric Allergy Unit; Department of Child and Adolescent; University Hospitals of Geneva; Geneva Switzerland
| | - J. Makowska
- Department of Immunology, Rheumatology and Allergy; Healthy Ageing Research Center; Medical University of Łódź; Łódź Poland
| | - A. Nakonechna
- Allergy and Immunology Clinic; Royal Liverpool and Broadgreen University Hospital; Liverpool UK
| | - A. Romano
- Allergy Unit Complesso Integrato Columbus; Rome and IRCCS Oasi Maria S.S.; Troina Italy
| | - M. I. Montañez
- BIONAND-Andalusian Centre for Nanomedicine and Biotechnology; Malaga Spain
| | - J. J. Laguna
- Allergy Unit; Hospital de la Cruz Roja; Madrid Spain
| | - G. Zanoni
- Section of Immunology; Department of Pathology and Diagnostics; University of Verona; Verona Italy
| | - J. L. Gueant
- Department of Molecular Medicine and Personalized Therapeutics and Inserm UMRS 954N-GERE (Nutrition-Genetics-Environmental Risks); University Hospital of Nancy and University of Lorraine; Nancy France
| | - H. Oude Elberink
- Department of Allergology; GRIAC Research Institute; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - J. Fernandez
- Allergy Section; Alicante University Hospital; UMH; Alicante Spain
| | - S. Viel
- Laboratory of Immunology; Centre Hospitalier Lyon Sud; Hospices Civils de Lyon; Lyon France
| | - P. Demoly
- Hôpital Arnaud de Villeneuve; University Hospital of Montpellier, and Sorbonne Universités; UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR; Paris France
| | - M. J. Torres
- Allergy Unit; IBIMA-Regional University Hospital of Malaga-UMA; Malaga Spain
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UK guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016. J Plast Reconstr Aesthet Surg 2016; 69:e119-e153. [DOI: 10.1016/j.bjps.2016.01.034] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 01/14/2016] [Indexed: 12/13/2022]
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Jörg-Walther L, Schnyder B, Helbling A, Helsing K, Schüller A, Wochner A, Pichler W. Flare-up reactions in severe drug hypersensitivity: infection or ongoing T-cell hyperresponsiveness. Clin Case Rep 2015; 3:798-801. [PMID: 26509009 PMCID: PMC4614642 DOI: 10.1002/ccr3.346] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 07/14/2015] [Accepted: 07/29/2015] [Indexed: 12/18/2022] Open
Abstract
“Flare-up” reactions are late manifestations of severe T-cell-mediated drug hypersensitivity reactions. Management is anti-inflammatory treatment and avoiding unnecessary medicines. Symptoms like fever, lymph node swelling, and blood count abnormalities may lead to confusion with bacterial infections. For prompt recognition it is important to keep the differential diagnosis in mind.
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Affiliation(s)
- Lukas Jörg-Walther
- Department of Rheumatology, Immunology and Allergology, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Benno Schnyder
- Department of Rheumatology, Immunology and Allergology, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Arthur Helbling
- Department of Rheumatology, Immunology and Allergology, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Karin Helsing
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Alexandra Schüller
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Annette Wochner
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital of Bern Bern, Switzerland
| | - Werner Pichler
- ADR-AC GmbH, Adverse Drug Reactions, Analysis and Consulting Bern, Switzerland
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Trautmann A, Seitz CS, Stoevesandt J, Kerstan A. Aminopenicillin-associated exanthem: lymphocyte transformation testing revisited. Clin Exp Allergy 2015; 44:1531-8. [PMID: 25323308 DOI: 10.1111/cea.12437] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 09/19/2014] [Accepted: 10/13/2014] [Indexed: 11/26/2022]
Abstract
BACKGROUND The lymphocyte transformation test (LTT) has been promoted as in-vitro test for diagnosis of drug hypersensitivity. For determination of statistical LTT sensitivity, series of patients with clinically uniform reactions followed by complete drug hypersensitivity work-up are mandatory. Assessment of LTT specificity requires control patients who tolerated exposure to the drug studied. OBJECTIVE To prospectively determine the diagnostic value of the LTT in a clinically and diagnostically well-defined series of patients. METHODS Patients with exanthematous skin eruptions after ampicillin (AMP) intake were included in this study. After exclusion or confirmation of delayed-onset allergic AMP hypersensitivity by skin and provocation testing, two independent LTTs were performed: one standard LTT and a modified LTT with additional anti-CD3/anti-CD28 monoclonal antibody stimulation. RESULTS By testing, delayed-onset allergic AMP hypersensitivity was diagnosed in 11 patients and definitely ruled out in 26. The standard LTT reached a diagnostic sensitivity of 54.5% while the modified LTT yielded 72.7%. However, the methodical test modification resulted in a decline of specificity from 92.3% (standard LTT) to 76.9%. CONCLUSIONS AND CLINICAL RELEVANCE In cases of AMP-associated exanthems, the diagnostic value of the LTT compared with routine allergy testing is limited. When evaluating such exanthems, provocation testing remains the gold standard. Delayed reading of intradermal skin tests remains most useful to avoid positive provocation reactions.
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Affiliation(s)
- A Trautmann
- Department of Dermatology and Allergy, University Hospital Würzburg, Würzburg, Germany
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