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Jiamsathit W, Bunarong K, Papenkort S, Cox AR, Jarernsiripornkul N. Drug-Induced Serious Cutaneous Reactions in Hospitalized Patients: A Cross-Sectional Study. J Clin Med 2025; 14:857. [PMID: 39941527 PMCID: PMC11818606 DOI: 10.3390/jcm14030857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/16/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Serious adverse drug reactions (ADRs) can lead to hospital admission and can be fatal, but some of them are preventable. This study aimed to determine the types and frequencies of serious cutaneous ADRs and the methods employed to manage and prevent them, as well as to assess the factors related to their seriousness. Methods: A cross-sectional study was conducted retrospectively on inpatients and outpatients at a tertiary care hospital. All data were collected from the medical records database over a period of 3 years. Serious cutaneous ADRs were identified in the hospital database using the International Classification of Disease and Related Health Problems, 10th Revision (ICD-10). Results: A total of 2151 cases were retrieved using the ICD-10, and 436 patients were randomly selected for this study. Of these, 218 patients experienced ADRs (50.0%). The major clinical symptoms of the eight serious ADRs included anaphylaxis (38.5%) and urticaria (30.2%). The most commonly suspected drug group was antibiotics (45.0%). The main methods of ADR management were drug treatment (84.4%) and drug withdrawal (81.2%). The primary method of ADR prevention was patient drug allergy cards (52.3%). Factors affecting the severity of ADRs were having an underlying condition (p = 0.031) and the concomitant use of drugs (p = 0.044). Conclusions: Anaphylaxis was the most common serious ADR. Patients with underlying diseases and those taking concomitant drugs are more likely to present with serious ADRs. The prevention of serious ADRs should be promoted at all levels in hospitals to reduce harm and prevent their reoccurrence.
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Affiliation(s)
- Warisara Jiamsathit
- Sirindhorn College of Public Health Khon Kaen, Faculty of Public Health and Allied Health Sciences, Praboromarajchanok Institute, Khon Kaen 40000, Thailand;
| | - Kansuda Bunarong
- Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; (K.B.); (S.P.)
| | - Sonthiya Papenkort
- Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; (K.B.); (S.P.)
| | - Anthony R. Cox
- Department of Pharmacy, School of Health Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK;
| | - Narumol Jarernsiripornkul
- Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; (K.B.); (S.P.)
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2
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Cadot R, Gery P, Lenief V, Nicolas J, Vocanson M, Tauber M. Exploring recent advances in drugs severe cutaneous adverse reactions immunopathology. Allergy 2025; 80:47-62. [PMID: 39295209 PMCID: PMC11724259 DOI: 10.1111/all.16316] [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: 06/26/2024] [Revised: 08/13/2024] [Accepted: 09/03/2024] [Indexed: 09/21/2024]
Abstract
Severe cutaneous adverse reactions to drugs (SCARs) are rare but life-threatening delayed allergies. While they primarily affect the skin, they can also affect internal organs. Accordingly, they present with diverse clinical symptoms that vary not only between SCARs subtypes but also among patients. Despite the availability of topical and systemic treatments, these only address the symptoms and not the cause. To develop more effective therapies, it is necessary to elucidate the complexity of the pathophysiology of SCARs in relation to their severity. In line with the new type IV hypersensitivity reactions nomenclature proposed by the European Academy of Allergy and Clinical Immunology (EAACI), this review highlights the current insights into the intricate immune mechanisms engaged, the interplay between the culprit drug and genetic predisposition in drug presentation mechanisms, but also how external factors, such as viruses, are implicated in SCARs. Their relevance to the development of targeted medicine is also discussed.
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Affiliation(s)
- Romane Cadot
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
| | - Perrine Gery
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
| | - Vanina Lenief
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
| | - Jean‐François Nicolas
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
- Allergology and Clinical Immunology DepartmentLyon Sud University HospitalPierre BéniteFrance
| | - Marc Vocanson
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
| | - Marie Tauber
- CIRI‐Centre International de Recherche en InfectiologieLyonFrance
- INSERM, U1111LyonFrance
- École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1Université de LyonLyonFrance
- CNRS, UMR 5308LyonFrance
- Allergology and Clinical Immunology DepartmentLyon Sud University HospitalPierre BéniteFrance
- Reference center for toxic bullous dermatitis and severe cutaneous adverse reactionsHospices Civils de LyonLyonFrance
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3
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Elzagallaai AA, Rieder MJ. Pathophysiology of drug hypersensitivity. Br J Clin Pharmacol 2024; 90:1856-1868. [PMID: 36519187 DOI: 10.1111/bcp.15645] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022] Open
Abstract
Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one-sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical "hapten" hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p-i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross-reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross-reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs.
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Affiliation(s)
- Abdelbaset A Elzagallaai
- Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Michael J Rieder
- Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Department of Pediatrics and Physiology, University of Western Ontario, London, Ontario, Canada
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4
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Contassot E, Brüggen MC. Sequential proteomic profiling of patients with Stevens-Johnson syndrome or toxic epidermal necrolysis. Allergy 2023; 78:3289-3290. [PMID: 37728116 DOI: 10.1111/all.15888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/21/2023]
Affiliation(s)
- Emmanuel Contassot
- Dermatology Department, University Hospital of Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marie-Charlotte Brüggen
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
- Christine Kühne Center for Allergy Research and Education CK-CARE, Davos, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
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Elzagallaai AA, Rieder MJ. Novel insights into molecular and cellular aspects of delayed drug hypersensitivity reactions. Expert Rev Clin Pharmacol 2023; 16:1187-1199. [PMID: 38018416 DOI: 10.1080/17512433.2023.2289543] [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: 09/18/2023] [Accepted: 11/27/2023] [Indexed: 11/30/2023]
Abstract
INTRODUCTION Delayed drug hypersensitivity reactions (DDHRs) represent a major health problem. They are unpredictable and can cause life-long disability or even death. The pathophysiology of DDHRs is complicated, multifactorial, and not well understood mainly due to the lack of validated animal models or in vitro systems. The role of the immune system is well demonstrated but its exact pathophysiology still a matter of debate. AREA COVERED This review summarizes the current understanding of DDHRs pathophysiology and abridges the available new evidence supporting each hypothesis. A comprehensive literature search for relevant publications was performed using PubMed, Google Scholar, and Medline databases with no date restrictions and focusing on the most recent 10 years. EXPERT OPINION Although multiple milestones have been achieved in our understanding of DDHRs pathophysiology as a result of the development of useful experimental models, many questions are yet to be fully answered. A deeper understanding of the mechanistic basis of DDHRs would not only facilitate the development of robust and reliable diagnostic assays for diagnosis, but would also inform therapy by providing specific target(s) for immunomodulation and potentially permit pre-therapeutic risk assessment to pursue the common goal of safe and effective drug therapy.
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Affiliation(s)
- Abdelbaset A Elzagallaai
- Department of Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Michael J Rieder
- Department of Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
- Department of Paediatrics and Physiology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Wung CH, Wang CW, Lai KC, Chen CB, Chen WT, Hung SI, Chung WH. Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs. Front Pharmacol 2023; 14:1183491. [PMID: 37180708 PMCID: PMC10169607 DOI: 10.3389/fphar.2023.1183491] [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: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/16/2023] Open
Abstract
Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.
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Affiliation(s)
| | - Chuang-Wei Wang
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
| | - Kuo-Chu Lai
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City, Taiwan
| | - Chun-Bing Chen
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ti Chen
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shuen-Iu Hung
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wen-Hung Chung
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
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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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IL-15/IL-15Rα in SJS/TEN: Relevant Expression of IL15 and IL15RA in Affected Skin. Biomedicines 2022; 10:biomedicines10081868. [PMID: 36009415 PMCID: PMC9405300 DOI: 10.3390/biomedicines10081868] [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: 05/30/2022] [Revised: 07/14/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening hypersensitivity reaction to medications characterized by keratinocyte apoptosis and skin detachment. IL-15 serum levels have been associated with severity and prognosis of SJS/TEN. We have measured IL-15 concentrations in serum and blister fluid (BF) from patients with SJS/TEN by ELISA and used quantitative RT-PCR to analyze the expression of IL15 and IL15RA (encoding for IL-15 Receptor-α chain) genes in peripheral blood and BF cells, including isolated monocytes, and in affected skin. A positive correlation was found between IL-15 serum levels and a percent of detached skin. BF concentrations were higher, but no correlation was found. Higher IL15 and IL15RA gene expression levels were found in skin-infiltrating blister fluid cells compared to peripheral mononuclear cells. Moreover, IL15RA transcripts were barely detected in healthy skin, being the highest expression levels found in samples from two SJS/TEN patients who did not survive. The cutaneous expression of IL-15Rα in SJS/TEN may provide an explanation to the tissue-specific immune cytotoxic response in this clinical entity, and the results suggest that the effects of IL-15 in SJS/TEN patients may be dependent on the expression of its private receptor IL-15Rα in affected skin.
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Machoń N, Lewandowska J, Zdanowska N, Placek W, Owczarczyk-Saczonek A. Cutaneous Adverse Drug Reactions (CADRs)—Statistical Analysis of the Causal Relationship between the Drug, Comorbidities, Cofactors, and the Cutaneous Reaction—A Single-Centered Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19137982. [PMID: 35805639 PMCID: PMC9265797 DOI: 10.3390/ijerph19137982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/21/2022] [Accepted: 06/26/2022] [Indexed: 12/19/2022]
Abstract
Cutaneous adverse drug reactions (CADRs) are among the most common types of drug hypersensitivity reactions. The purpose of this study was to evaluate the clinical spectrum of CADRs and to determine the causal relationship between drugs, comorbidities, cofactors or concomitant symptoms, and cutaneous reactions. A retrospective hospital-based study was carried out over a period of 10 years at the Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology at the University of Warmia and Mazury in Olsztyn to record various CADRs, comorbidities, cofactors, and the suspected drug in hospitalized patients. The data were subjected to statistical analysis. CADRs were diagnosed in a total of 140 patients, 32.14% of whom were men and 67.86% of whom were women. The mean age was 66.33 years. The most commonly suspected drugs were Allopurinol 12.86%, Amoxicillin with clavulanic acid 10%, Amoxicillin 9.29%, Paracetamol 6.43%, Metronidazole 5%, and Carbamazepine 5%. Attention should be paid to the possibility of using a substitute for a suspected drug if CADRs arise, or discontinuing a drug that is unjustifiably overused. The results of the present study should also prompt research into a potential treatment that could be implemented concurrently with a drug that has a high predisposition to cause CADRs.
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Affiliation(s)
- Natalia Machoń
- Medical Faculty, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
- Correspondence:
| | - Julia Lewandowska
- Medical Faculty, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Natalia Zdanowska
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury in Olsztyn, 10-229 Olsztyn, Poland; (N.Z.); (W.P.); (A.O.-S.)
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury in Olsztyn, 10-229 Olsztyn, Poland; (N.Z.); (W.P.); (A.O.-S.)
| | - Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, University of Warmia and Mazury in Olsztyn, 10-229 Olsztyn, Poland; (N.Z.); (W.P.); (A.O.-S.)
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10
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Hernandez-Jaimes OA, Cazares-Olvera DV, Line J, Moreno-Eutimio MA, Gómez-Castro CZ, Naisbitt DJ, Castrejón-Flores JL. Advances in Our Understanding of the Interaction of Drugs with T-cells: Implications for the Discovery of Biomarkers in Severe Cutaneous Drug Reactions. Chem Res Toxicol 2022; 35:1162-1183. [PMID: 35704769 DOI: 10.1021/acs.chemrestox.1c00434] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Drugs can activate different cells of the immune system and initiate an immune response that can lead to life-threatening diseases collectively known as severe cutaneous adverse reactions (SCARs). Antibiotics, anticonvulsants, and antiretrovirals are involved in the development of SCARs by the activation of αβ naïve T-cells. However, other subsets of lymphocytes known as nonconventional T-cells with a limited T-cell receptor repertoire and innate and adaptative functions also recognize drugs and drug-like molecules, but their role in the pathogenesis of SCARs has only just begun to be explored. Despite 30 years of advances in our understanding of the mechanisms in which drugs interact with T-cells and the pathways for tissue injury seen during T-cell activation, at present, the development of useful clinical biomarkers for SCARs or predictive preclinical in vitro assays that could identify immunogenic moieties during drug discovery is an unmet goal. Therefore, the present review focuses on (i) advances in the understanding of the pathogenesis of SCARs reactions, (ii) a description of the interaction of drugs with conventional and nonconventional T-cells, and (iii) the current state of soluble blood circulating biomarker candidates for SCARs.
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Affiliation(s)
| | - Diana Valeria Cazares-Olvera
- Instituto Politécnico Nacional, Unidad Profesional Interdisciplinaria de Biotecnología, México City 07340, México
| | - James Line
- MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | | | | | - Dean J Naisbitt
- MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom
| | - José Luis Castrejón-Flores
- Instituto Politécnico Nacional, Unidad Profesional Interdisciplinaria de Biotecnología, México City 07340, México
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11
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Abstract
Delayed drug hypersensitivity continues to contribute to major clinical problems worldwide. The clinical presentations of delayed drug hypersensitivity are diverse, ranging from mild skin rashes to life-threatening systemic reactions. The pathomechanism of delayed drug hypersensitivity involves human leukocyte antigens (HLA) presentation of drugs/metabolites to T cell receptors (TCR), resulting in T-cell activation. The pathogenesis of delayed drug hypersensitivity also has reactivation of the virus, and activation of many immune mediators. In this review, we discuss the immune pathogenesis, molecular interactions of HLA/drugs/TCR, and downstream signaling of cytotoxic proteins/cytokines/chemokines, as well as disease prevention and management for delayed drug hypersensitivity.
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Tempark T, John S, Rerknimitr P, Satapornpong P, Sukasem C. Drug-Induced Severe Cutaneous Adverse Reactions: Insights Into Clinical Presentation, Immunopathogenesis, Diagnostic Methods, Treatment, and Pharmacogenomics. Front Pharmacol 2022; 13:832048. [PMID: 35517811 PMCID: PMC9065683 DOI: 10.3389/fphar.2022.832048] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/01/2022] [Indexed: 12/19/2022] Open
Abstract
SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different populations, and the successful implementation of pharmacogenomics in Thailand for the prevention of SCARs.
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Affiliation(s)
- Therdpong Tempark
- Division of Dermatology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- The Pediatrics-Thai Severe Cutaneous Adverse Drug Reaction (Ped-Thai-SCAR) Research Group, Bangkok, Thailand
| | - Shobana John
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
| | - Pawinee Rerknimitr
- The Thai Severe Cutaneous Adverse Drug Reaction (Thai-SCAR) Research Group, Bangkok, Thailand
- Division of Dermatology, Department of Medicine, Faculty of Medicine, Skin, and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Patompong Satapornpong
- Division of General Pharmacy Practice, Department of Pharmaceutical Care, College of Pharmacy, Rangsit University, Pathum Thani, Thailand
- Excellence Pharmacogenomics and Precision Medicine Centre, College of Pharmacy, Rangsit University, Pathum Thani, Thailand
| | - Chonlaphat Sukasem
- The Pediatrics-Thai Severe Cutaneous Adverse Drug Reaction (Ped-Thai-SCAR) Research Group, Bangkok, Thailand
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand
- The Thai Severe Cutaneous Adverse Drug Reaction (Thai-SCAR) Research Group, Bangkok, Thailand
- Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check-up Services Center, Bumrungrad International Hospital, Bangkok, Thailand
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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13
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Lee JW, Lee SR, Kim MJ, Cho S, Youn SW, Yang MS, Kim SH, Kang HR, Kwon O. Skin manifestations and clinical features of drug reaction with eosinophilia and systemic symptoms (DRESS): A retrospective multicenter study of 125 patients. J Eur Acad Dermatol Venereol 2022; 36:1584-1592. [PMID: 35342995 DOI: 10.1111/jdv.18100] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction generally accompanied by skin manifestations as the first and most frequent symptoms. However, skin manifestations and associated clinical features of DRESS have not been fully explored and evaluated. OBJECTIVES This study aimed to describe the skin manifestations of DRESS in detail and analyze their association with demographic characteristics and extra-cutaneous clinical features. METHODS We conducted this retrospective study on patients with DRESS diagnosed between September 2009 and August 2021 at three medical institutes and validated using the RegiSCAR score. Data regarding demographics, skin manifestations, and clinical characteristics were retrieved through thorough chart reviews. RESULTS Among 182 potential cases of DRESS, the validated 125 cases were analyzed. A widespread rash extending over more than 50% of the body surface area was observed in 122 patients (97.6%) and typical facial edema was experienced by 67 patients (53.6%). Polymorphous maculopapules were the most common rash morphology (106, 84.8%): specifically, exfoliative (59, 47.2%), urticarial (57, 45.6%), and purpuric forms (39, 31.2%) were common. Mucosal involvement was observed in 41 patients (32.8%). Patients with carboxamide antiepileptics (carbamazepine and oxcarbazepine) experienced more edema (P = .014) and typical facial edema than those with allopurinol (P = .021). The RegiSCAR score was higher in patients with purpura (P < .01). CONCLUSIONS Skin manifestations of DRESS exhibit a wide range of skin lesions and can vary according to the culprit drugs. Early suspicion and prompt intervention are needed to improve prognosis.
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Affiliation(s)
- J W Lee
- Department of Dermatology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - S R Lee
- Department of Dermatology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea.,Department of Dermatology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, Republic of Korea
| | - M J Kim
- Department of Dermatology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - S Cho
- Department of Dermatology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, Republic of Korea
| | - S W Youn
- Department of Dermatology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - M S Yang
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, Republic of Korea
| | - S H Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - H R Kang
- Drug Safety Center, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea.,Department of Internal Medicine, Seoul National University College of Medicine.,Institute of Allergy and Clinical Immunology, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - O Kwon
- Department of Dermatology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea.,Laboratory of Cutaneous Aging and Hair Research, Clinical Research Institute, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea.,Institute of Human-Environment Interface Biology, Seoul National University, 101, Daehak-ro, Jongno-gu, Seoul, Republic of Korea
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14
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Morán-Mariños C, Alva-Diaz C, De la Cruz Ramirez W, Quincho-Lopez A, Mori N, Pacheco-Mendoza J, Romero-Sánchez R. Drug reaction with eosinophilia and systemic symptoms (DRESS) induced by phenytoin re-exposure: case report and systematic review. Acta Clin Belg 2022; 77:177-185. [PMID: 32469684 DOI: 10.1080/17843286.2020.1767459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse and severe skin reaction due to patients' susceptibility to medications, including phenytoin. The objective was to explore the characteristics of patients with DRESS secondary to phenytoin through a systematic review.Methods: We describe a case of DRESS syndrome secondary to phenytoin in a patient with previous exposure to this drug. A systematic literature review of cases of phenytoin-induced DRESS syndrome was conducted in PubMed/Medline, Scopus and Web of Science until May 2019.Results: 37 articles describing 40 cases of DRESS syndrome were selected. Mean age of onset was 33 years, without gender difference. Symptoms started between two and 90 days (mean ± 23 days). Liver and respiratory tract were most frequently involved, and eosinophilia was a common feature, it was presented with an average value of 9.7%. A discussion of the case and qualitative synthesis of the evidence reported in the literature were made.Conclusion: Patients and presentation characteristics will mostly be presented according to the criteria used by RegiSCAR. It is recommended to consider adequate monitoring of adverse reactions to antiepileptic drugs such as DRESS syndrome, given its severity and high lethality.
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Affiliation(s)
- Cristian Morán-Mariños
- Unidad de Investigación en Bibliometría, Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Perú
- Red de Eficacia Clínica y Sanitaria, REDECS, Lima, Perú
| | - Carlos Alva-Diaz
- Facultad de Ciencias de la Salud, Universidad Científica del Sur, Lima, Perú
| | - Walter De la Cruz Ramirez
- Departamento de investigación, docencia y atención especializada en epilepsia, Instituto Nacional de Ciencias Neurológicas, Lima, Perú
| | - Alvaro Quincho-Lopez
- Red de Eficacia Clínica y Sanitaria, REDECS, Lima, Perú
- Sociedad Científica de San Fernando, Universidad Nacional Mayor de San Marcos, Lima, Perú
| | - Nicanor Mori
- Servicio de Neurología, Departamento de Medicina y Oficina de Apoyo a la Docencia e Investigación (OADI), Hospital Daniel Alcides Carrión, Callao, Perú
| | - Josmel Pacheco-Mendoza
- Unidad de Investigación en Bibliometría, Vicerrectorado de Investigación, Universidad San Ignacio de Loyola, Lima, Perú
| | - Roberto Romero-Sánchez
- Servicio de Neurología, Departamento de Medicina y Oficina de Apoyo a la Docencia e Investigación (OADI), Hospital Daniel Alcides Carrión, Callao, Perú
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15
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Li A, Kazlouskaya V. Neutrophils in Fixed Drug Eruptions: Correction of a Mistaken Hypothesis. Am J Dermatopathol 2022; 44:106-110. [PMID: 35076426 DOI: 10.1097/dad.0000000000002038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT Classical histopathological findings of fixed drug eruption (FDE) include a lichenoid/interface dermatitis and perivascular infiltrate in the upper and deep dermis composed of lymphocytes and eosinophils accompanied by pigment incontinence. The presence of neutrophils is also an established finding but is less investigated. Sporadic cases of "neutrophilic FDE" have been reported and suggested as a separate entity, a rare variant, or an early stage of the condition. In this article, we report 16 cases of FDE with quantitative analysis showing that neutrophils are relatively common in FDE (68.8%) and that cases with abundant neutrophils had a significantly shorter onset-to-biopsy interval (3.7 vs. 16.9 days, P < 0.023). Our findings support that neutrophilic FDE more likely represents the early phase of FDE rather than a different entity. The presence of neutrophils expands the histopathological differential diagnosis of FDE to include neutrophilic dermatosis, signifying the value of clinical correlation.
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16
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Bakir M, Almeshal H, Alturki R, Obaid S, Almazroo A. Toxic Epidermal Necrolysis Post COVID-19 Vaccination - First Reported Case. Cureus 2021; 13:e17215. [PMID: 34540442 PMCID: PMC8442571 DOI: 10.7759/cureus.17215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2021] [Indexed: 01/26/2023] Open
Abstract
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a spectrum of acute, delayed-type hypersensitivity reactions that affect the skin and the mucous membranes. Medications are the culprit cause of these disorders in addition to infections and in very rare instances vaccinations. We report a case of TEN in a 49-year-old woman with no previous medical history. The disorder developed one week after receiving the first dose of COVID-19 vaccine with no other identifiable causes. The patient received two doses of tumor necrosis factor-alpha inhibitor (etanercept) and she stopped developing new lesions after two days of the initial dose; complete healing was observed after 22 days and no side effects were observed in our patient. This case demonstrates an extremely rare complication to the COVID-19 vaccine. The benefits of receiving the COVID-19 outweigh the potential risk.
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Affiliation(s)
- Mohamad Bakir
- Department of Medicine and Surgery, College of Medicine, Alfaisal University, Riyadh, SAU
| | - Hanan Almeshal
- Department of Dermatology, Prince Mohammed Bin Abdulaziz Hospital, Riyadh, SAU
| | - Rifah Alturki
- Department of Dermatology, Prince Mohammed Bin Abdulaziz Hospital, Riyadh, SAU
| | - Sulaiman Obaid
- Department of Dermatology, Prince Mohammed Bin Abdulaziz Hospital, Riyadh, SAU
| | - Areej Almazroo
- Department of Dermatology, Prince Mohammed Bin Abdulaziz Hospital, Riyadh, SAU
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17
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Portney DA, Baker HP, Boyle MM, Barbosa VH, Luu HH. Drug Reaction with Eosinophilia and Systemic Syndrome in Revision Arthroplasty for a Prosthetic Knee Infection: A Case Report. JBJS Case Connect 2021; 11:e20.00805. [PMID: 34038391 DOI: 10.2106/jbjs.cc.20.00805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
CASE A 51-year-old woman underwent stage I of a 2-stage revision for a prosthetic knee infection with a vancomycin-impregnated articulating cement spacer followed by IV vancomycin and ceftriaxone. Four weeks later, she developed fevers, a diffuse cutaneous eruption, lymphadenopathy, transaminitis, and acute renal tubular necrosis before being diagnosed with drug reaction with eosinophilia and systemic syndrome (DRESS). CONCLUSION DRESS is a rare, potentially life-threatening adverse drug reaction with cutaneous manifestations and multiorgan involvement. Although rare, its incidence in orthopaedic patients is likely to increase with the aging population. It must be recognized early to minimize end-stage organ dysfunction and mortality.
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Affiliation(s)
- Daniel A Portney
- Department of Orthopaedic Surgery, University of Chicago, Chicago, Illinois
| | - Hayden P Baker
- Department of Orthopaedic Surgery, University of Chicago, Chicago, Illinois
| | - Margaret M Boyle
- Department of Dermatology, University of Chicago, Chicago, Illinois
| | | | - Hue H Luu
- Department of Orthopaedic Surgery, University of Chicago, Chicago, Illinois
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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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Brandt C, McGuire L, Uetrecht J. Severe cutaneous adverse reaction associated with antiseizure medications: Diagnosis, management, and prevention. Epilepsy Behav 2021; 117:107844. [PMID: 33639435 DOI: 10.1016/j.yebeh.2021.107844] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/06/2023]
Abstract
Severe cutaneous adverse reactions (SCARs) are potentially life-threatening, with considerable morbidity and mortality. They are nonimmediate hypersensitivity reactions that occur in specifically predisposed patients with delayed T-cell-mediated hypersensitivity reaction. Antiseizure medications (ASMs) are among the drugs that can induce SCAR. Increased awareness of SCAR among clinicians treating patients with ASMs is critically important for early recognition of symptoms, prompt identification and removal of the causal drug, and early intervention to reduce SCAR-related acute and long-term morbidity and mortality. The diagnosis, management, and prevention of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are reviewed, along with the current understanding of the pathomechanisms and role of genetics in SCAR development. Supportive care and immunomodulating treatments for SCAR are discussed.
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Affiliation(s)
- Christian Brandt
- Department of General Epileptology, Bethel Epilepsy Centre, Mara Hospital, Bielefeld, Germany.
| | - Lynanne McGuire
- MedVal Scientific Information Services, LLC, Princeton, NJ, USA
| | - Jack Uetrecht
- Department of Pharmacology & Toxicology, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
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20
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Lalosevic MS, Lalosevic J, Stjepanovic M, Stojanovic M, Stojkovic M. Drug Induced Cutaneous Manifestations due to Treatment of Gastrointestinal Disorders. Curr Drug Metab 2021; 22:99-107. [PMID: 33198613 DOI: 10.2174/1389200221999201116143109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 08/03/2020] [Accepted: 09/01/2020] [Indexed: 01/19/2023]
Abstract
Cutaneous manifestations due to drugs used in the treatment of gastrointestinal disorders are multiple and common. Adequate diagnosis is of great importance, bearing in mind that the therapeutic regimen depends on its diagnosis. In this review, we provided an overview of the most common drug-induced skin lesions with a detailed explanation of the disease course, presentation and treatment, having in mind that in recent years, novel therapeutic modalities have been introduced in the treatment of various gastrointestinal disorders, and that incidence of cutaneous adverse reactions has been on the rise.
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Affiliation(s)
- Milica S Lalosevic
- Clinic of Gastroenterology and Hepatology, Clinical Center of Serbia, Belgrade, Serbia
| | - Jovan Lalosevic
- Clinic of Dermatovenereology, Clinical Center of Serbia, Belgrade, Serbia
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21
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Marxer CA, Frey N, Bodmer M, Bircher AJ, Jick SS, Meier CR, Spoendlin J. Survival after Stevens‒Johnson Syndrome or Toxic Epidermal Necrolysis: A United Kingdom‒Based Cohort Study. J Invest Dermatol 2020; 141:1349-1351.e1. [PMID: 33221338 DOI: 10.1016/j.jid.2020.09.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 11/15/2022]
Affiliation(s)
- Carole A Marxer
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland
| | - Noel Frey
- Insel Data Coordination Lab, Inselspital Bern, Bern, Switzerland
| | - Michael Bodmer
- Internal Medicine, Zuger Kantonsspital, Baar, Switzerland
| | | | - Susan S Jick
- Boston Collaborative Drug Surveillance Program, Lexington, Massachusetts, USA; Boston University, School of Public Health, Boston, Massachusetts, USA
| | - Christoph R Meier
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland; Boston Collaborative Drug Surveillance Program, Lexington, Massachusetts, USA.
| | - Julia Spoendlin
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland
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22
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A Nationwide Study of Severe Cutaneous Adverse Reactions Based on the Multicenter Registry in Korea. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 9:929-936.e7. [PMID: 32961314 DOI: 10.1016/j.jaip.2020.09.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.
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23
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Do MD, Mai TP, Do AD, Nguyen QD, Le NH, Le LGH, Hoang VA, Le AN, Le HQ, Richette P, Resche-Rigon M, Bardin T. Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study. Arthritis Res Ther 2020; 22:182. [PMID: 32746911 PMCID: PMC7397637 DOI: 10.1186/s13075-020-02273-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 07/20/2020] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. METHODS All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8-40.1], P < 0.0001), female sex (OR 333 [40-43,453], P < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120-125,847], P < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101-122], P < 0.0001), diuretics intake (OR 304 [35-40,018], P < 0.0001), eGFR < 60 ml/min/1.73 m2 (OR 100 [32-353], P < 0.0001), history of allopurinol-induced skin reaction (OR 78 [6-10,808], P = 0.004), and HLA-B*58:01 carriage (OR 147 [45-746], P < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs (n = 74), risk factors were eGFR < 60 ml/min/1.73 m2 (OR 4.9 [1.61-14.6], P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2-3777], P = 0.01), and asymptomatic hyperuricemia (OR 27 [2-3777], P = 0.01). CONCLUSION This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.
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Affiliation(s)
- Minh Duc Do
- Center for Molecular Biomedicine, University of Medicine and Pharmacy, at Ho Chi Minh City, Vietnam
| | - Thao Phuong Mai
- Department of Physiology, Pathophysiology and Immunology, Faculty of Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Anh Duy Do
- Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam
| | - Quang Dinh Nguyen
- French Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Centre, Ho Chi Minh City, Vietnam
| | - Nghia Hieu Le
- French Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Centre, Ho Chi Minh City, Vietnam
| | - Linh Gia Hoang Le
- Center for Molecular Biomedicine, University of Medicine and Pharmacy, at Ho Chi Minh City, Vietnam
| | - Vu Anh Hoang
- Center for Molecular Biomedicine, University of Medicine and Pharmacy, at Ho Chi Minh City, Vietnam
| | - Anh Ngoc Le
- Department of Scientific Research, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Hung Quoc Le
- Department of Tropical Disease, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Pascal Richette
- Université de Paris, U1132, INSERM, 75010, Paris, France.,Department of Rheumatology, AP-HP, Lariboisière hospital, 2 rue A. Paré, 75010, Paris, France
| | - Matthieu Resche-Rigon
- Université de Paris, ECSTRRA Team U1153, INSERM, 75010, Paris, France.,Department of Biostatistics, AP-HP, Saint-Louis hospital, 75010, Paris, France
| | - Thomas Bardin
- French Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Centre, Ho Chi Minh City, Vietnam. .,Université de Paris, U1132, INSERM, 75010, Paris, France. .,Department of Rheumatology, AP-HP, Lariboisière hospital, 2 rue A. Paré, 75010, Paris, France.
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24
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Avancées dans la compréhension de la physiopathologie de la nécrolyse épidermique (syndrome de Stevens-Johnson et nécrolyse épidermique toxique). Ann Dermatol Venereol 2020; 147:475-481. [DOI: 10.1016/j.annder.2020.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/30/2020] [Accepted: 02/12/2020] [Indexed: 12/17/2022]
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25
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Abstract
Cutaneous adverse drug reactions are unpredictable and include various different skin conditions of varying degrees of severity. The most concerning are usually referred to as severe cutaneous adverse reactions (SCARs) and include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS) or hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). All are delayed type IV hypersensitivity reactions in which a T-cell-mediated drug-specific immune response is responsible for causing the disease. Nonetheless, specific T-cell subpopulations develop in response to certain environmental conditions and produce cytokines that orchestrate the various phenotypes. Cytotoxic T lymphocytes (CTLs), T-helper type 1 (Th1), Th2, Th17, and regulatory T cells (Treg), among other T-cell subpopulations, participate in the development of SCAR phenotypes. Cell subpopulations belonging to the innate immune system, comprising natural killer cells, innate lymphoid cells, monocytes, macrophages and dendritic cells, can also participate in shaping specific immune responses in various clinical conditions. Additionally, tissue-resident cells, including keratinocytes, can contribute to epidermal damage by secreting chemokines that attract pro-inflammatory immunocytes. The final phenotypes in each clinical entity result from the complex interactions between a variety of cell lineages, their products, soluble mediators and genetic and environmental factors. Although the pathophysiology of these reactions is not fully understood, intensive research in recent years has led to major progress in our understanding of the contribution of certain cell types and soluble mediators to the variability of SCAR phenotypes.
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Affiliation(s)
- Teresa Bellón
- La Paz Hospital Health Research Institute-IdiPAZ, Pº Castellana 261, 28046, Madrid, Spain.
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26
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Zhao J, Hu L, Zhang L, Zhou M, Gao L, Cheng L. Causative drugs for drug-induced cutaneous reactions in central China: a 608-case analysis. An Bras Dermatol 2019; 94:664-670. [PMID: 31789251 PMCID: PMC6939179 DOI: 10.1016/j.abd.2019.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 01/07/2019] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Reports regarding the causative drugs of drug-induced cutaneous adverse reactions in China are indistinct, such that different regions have reported the spectrum of drugs differs substantially in different clinical conditions. OBJECTIVE To explore the causative drugs that led to cutaneous reactions. METHODS Adverse drug reaction reports from central China were collected and divided into cutaneous adverse reactions and severe cutaneous adverse reactions groups. Cases were reviewed retrospectively for causative drugs. RESULTS The male:female ratio was equal in both cutaneous adverse reactions and severe cutaneous adverse reactions. In cutaneous adverse reactions (n=482), the highest incidence happened between 51 and 60 years of age and the top three causative drugs were antibiotics (48%), Chinese medicine (16%), and allopurinol (9%). In severe cutaneous adverse reactions (n=126), the highest incidence happened between 41 and 50 years of age and the top three causative drugs were sedative-hypnotics and antiepileptics (39%), antibiotics (22%), and allopurinol (15%). Carbamazepine was the most frequently used single-drug (16/18) in sedative-hypnotics and antiepileptics. β-lactams were the most frequently used antibiotics that induced both cutaneous adverse reactions and severe cutaneous adverse reactions. STUDY LIMITATIONS The small sample size, retrospective design, collection of cutaneous adverse reactions and severe cutaneous adverse reactions at different time frames and locations, and exclusion of patients taking more than five medications are limitations of the study. CONCLUSIONS Gender does not affect cutaneous adverse reactions and severe cutaneous adverse reactions. The top three drugs to induce cutaneous adverse reactions are antibiotics, Chinese medicine, and allopurinol, while those that triggered severe cutaneous adverse reactions are sedative-hypnotics and antiepileptics, antibiotics, and allopurinol. Carbamazepine is the most frequent single drug that induces severe cutaneous adverse reactions. β-lactams are the most frequently used antibiotics that induce both cutaneous adverse reactions and severe cutaneous adverse reactions.
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Affiliation(s)
- Jun Zhao
- School of Ophthalmology & Optometry Affiliated to Shenzhen University, Shenzhen, China; Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen Eye Institute, Shenzhen, China
| | - Lei Hu
- Department of Pharmacy, Peking University People's Hospital, Beijing, China
| | - Lihua Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Maosong Zhou
- Department of Dermatology, Changsha Eighth People's Hospital, Changsha, China
| | - Lichen Gao
- Department of Pharmacy, Department of Oncology, Cancer Institute, Changsha Central Hospital, Changsha, China
| | - Lin Cheng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Shenzhen Eyeis Visual Science Research Institute, Shenzhen, China; School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
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27
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Zhang L, Qian M, Hong L, Wu Q. First case report of acute generalized exanthematous pustulosis (AGEP) caused by mifepristone. Contact Dermatitis 2019; 82:177-179. [PMID: 31626328 DOI: 10.1111/cod.13424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/11/2019] [Accepted: 10/17/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Li Zhang
- Department of Obstetrics and Gynecology, Ningbo Women and Children's Hospital, Ningbo, China
| | - Miaohong Qian
- Department of Obstetrics and Gynecology, Ningbo Women and Children's Hospital, Ningbo, China
| | - Ling Hong
- Department of Obstetrics and Gynecology, Ningbo Women and Children's Hospital, Ningbo, China
| | - Qunxiong Wu
- Department of Obstetrics and Gynecology, Ningbo Women and Children's Hospital, Ningbo, China
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28
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Blanca-Lopez N, Soriano V, Garcia-Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. J Asthma Allergy 2019; 12:217-233. [PMID: 31496752 PMCID: PMC6690438 DOI: 10.2147/jaa.s164806] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 02/03/2019] [Indexed: 12/20/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.
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Affiliation(s)
| | - Victor Soriano
- General University Hospital of Alicante-ISABIAL
, Alicante, Madrid, Spain
| | - Elena Garcia-Martin
- Medical and Surgery Therapy Department, University of Extremadura, Caceres, Spain
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29
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Zhang C, Van DN, Hieu C, Craig T. Drug-induced severe cutaneous adverse reactions: Determine the cause and prevention. Ann Allergy Asthma Immunol 2019; 123:483-487. [PMID: 31400461 DOI: 10.1016/j.anai.2019.08.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 07/24/2019] [Accepted: 08/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Approximately 45% of all adverse drug reactions are manifested in the skin. Although most are mild, severe cutaneous adverse reactions (SCARs) are potentially lethal. OBJECTIVE To review the etiology and clinical manifestations of severe cutaneous adverse reactions (SCARs) and the demographic characteristics of patients with SCARs. METHODS This study is a retrospective review of electronic medical records for patients who developed drug-induced cutaneous reactions and were treated for initial or ongoing care at a university medical center from June 4, 2008, to August 10, 2018. Search terms included Stevens-Johnson syndrome(SJS) , drug rash with eosinophilia and systemic symptoms(DRESS), acute generalized exanthematous pustulosis(AGEP), toxic epidermal necrolysis (TEN), and TEN/SJS overlap. RESULTS Of 596 cases of drug-induced rash, 35 cases (5.9%) of SCARs were encountered (male-to-female ratio, 1.06:1.0; mean age, 48.5 years). Of those 35 cases, 32 were in white patients (91.4%). The most common manifestations were DRESS (19 [54.3%]), SJS (8 [22.8%]), AGEP (6 [17.1%]), TEN (1 [2.9%]), and overlap (1 [2.9%]). Multiple causative drugs were implicated in 14 cases, whereas a single drug was responsible in 21 cases. The most common drugs implicated were antibiotics (88.1%). The most common causative antibiotics were cephalosporins (23.7%). Most of the patients with SCARs were given triamcinolone cream and prednisone alone (18 [51.4%]), methylprednisolone alone (1 [2.9%]), methylprednisolone and prednisone combined (4 [11.4%]), methylprednisolone and prednisolone (1 [2.9%]) or prednisone and prednisolone (1 [2.9%]). CONCLUSION The most common SCARs were, in order, DRESS, SJS, AGEP, TEN, and overlap. The most common causative drugs were, in order, cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and fluoroquinolones.
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Affiliation(s)
- Cindy Zhang
- Department of Medicine and Pediatrics, Allergy and Immunology, Program, Penn State University, Hershey, Pennsylvania
| | | | - Chu Hieu
- Bach Mai Hospital, Hanoi, Vietnam
| | - Timothy Craig
- Department of Medicine and Pediatrics, Allergy and Immunology, Program, Penn State University, Hershey, Pennsylvania.
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30
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Gonçalo M. HLA-B*58:01 is not the only risk factor associated with allopurinol-induced severe cutaneous adverse drug reactions. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:S7. [PMID: 30613583 DOI: 10.21037/atm.2018.08.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Margarida Gonçalo
- Clinic of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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31
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Tanaka R, Yonemori K, Hirakawa A, Kinoshita F, Kobayashi Y, Yamazaki N, Fujimoto M, Tamura K, Fujiwara Y. Anticancer Agent-Induced Life-Threatening Skin Toxicities: A Database Study of Spontaneous Reporting Data. Oncologist 2018; 24:266-272. [PMID: 30254188 DOI: 10.1634/theoncologist.2017-0511] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 04/12/2018] [Indexed: 02/04/2023] Open
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening cutaneous and mucosal adverse reactions to drugs. Nevertheless, the connection to anticancer agents remains unclear. To provide insight into the association of such adverse reactions with anticancer agents, we analyzed the profile of anticancer agent-induced SJS and TEN in the Japanese population. Of the 9,738 SJS/TEN events recorded in a database of spontaneous reporting data, 485 (5%, further categorized as SJS, 384 events, 79%; TEN, 101 events, 21%) were identified as anticancer agent-induced, and 53 of these (11%) were fatal. Multivariate logistic regression analyses indicated that, compared with patients using other drugs, those using anticancer drugs had lower incident risk of death (hazard ratio [HR], 0.592; p = .0006), longer median time to onset of SJS/TEN (18 vs. 11 days; p < .0001; multivariate Cox regression: HR, 0.66; p < .0001), and a higher likelihood of developing SJS/TEN later than 70 days after initiation of the suspected causal agent (15% vs. 7%; p < .0001), highlighting the need for vigilance and continuous monitoring for SJS/TEN in patients treated with anticancer agents. IMPLICATIONS FOR PRACTICE: Life-threatening skin toxicities induced by anti-cancer agents indicated significantly lower incident risk of death and longer time to onset of symptoms than for those induced by other drugs.
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Affiliation(s)
- Ryota Tanaka
- Divisions of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
- Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Dermatology, University of Tsukuba, Tsukuba, Japan
| | - Kan Yonemori
- Divisions of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Akihiro Hirakawa
- Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Fumie Kinoshita
- Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Yumiko Kobayashi
- Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Naoya Yamazaki
- Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Manabu Fujimoto
- Department of Dermatology, University of Tsukuba, Tsukuba, Japan
| | - Kenji Tamura
- Divisions of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuhiro Fujiwara
- Divisions of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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32
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Wang F, Ye Y, Luo ZY, Gao Q, Luo DQ, Zhang X. Diverse expression of TNF-α and CCL27 in serum and blister of Stevens-Johnson syndrome/toxic epidermal necrolysis. Clin Transl Allergy 2018; 8:12. [PMID: 29713456 PMCID: PMC5909236 DOI: 10.1186/s13601-018-0199-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 03/14/2018] [Indexed: 01/13/2023] Open
Abstract
Background The pathogenesis of Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is not fully understood. Our previous study reported that chemokine CCL27 was overexpressed in serum of SJS/TEN patients. The objective of this study was to investigate the levels of CCL27 and TNF-α in serum and blister fluid from patients with SJS/TEN during the acute stage or resolution phase. Methods A total of 27 patients with SJS/TEN and 39 healthy donors were recruited to the study. Serum and vesicular levels of CCL27 and TNF-α were determined by enzyme-linked immunosorbent assays. Results Serum levels of CCL27 and TNF-α were significantly elevated in patients with SJS/TEN during the acute stage as compared to the resolution phase and also compared with levels observed in normal controls (P = 0.001/< 0.001; P = 0.012/< 0.001). Serum TNF-α levels were significantly higher in patients with SJS/TEN during the resolution phase compared with normal controls (P < 0.001). Serum CCL27 levels were positively correlated with TNF-α levels during the acute stage (rs = 0.660; P < 0.001). Blister fluid exhibited much lower CCL27 levels than serum did during the acute stage (P = 0.008). TNF-α levels were much higher in vesicles in contrast to serum from acute stage (P = 0.040) as well as serum from resolution phase (P = 0.029). Conclusions Our study demonstrated roles of CCL27 and TNF-α in promoting the course of SJS/TEN. CCL27 may act early in the course of disease, via the circulation, whereas TNF-α acts throughout the course of disease, in skin lesions.
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Affiliation(s)
- Fang Wang
- 1Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080 China
| | - Yanting Ye
- 1Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080 China
| | - Ze-Yu Luo
- 1Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080 China
| | - Qian Gao
- 1Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080 China
| | - Di-Qing Luo
- 2Department of Dermatology, Eastern Hospital of First Affiliated Hospital, Sun Yat-sen University, 183 Huangpu Rd. E, Guangzhou, 510700 China
| | - Xingqi Zhang
- 1Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080 China
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33
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Kim H, Chadwick L, Alzaidi Y, Picker J, Poduri A, Manzi S. HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion. Pediatrics 2018; 141:S434-S438. [PMID: 29610167 DOI: 10.1542/peds.2017-1361] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2017] [Indexed: 11/24/2022] Open
Abstract
Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The Food and Drug Administration-approved label for oxcarbazepine currently presents information regarding a pharmacogenomic association with the HLA antigen allele HLA-B*15:02 and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the presence of this allele is not routinely recommended before administration of oxcarbazepine. In practice, even with carbamazepine, HLA antigen testing is not always performed before initiating treatment because of lack of physician awareness of the recommendations and because of the desire to initiate treatment without delay. We present the clinical course of a pediatric patient with focal epilepsy refractory to several AEDs who developed drug reaction with eosinophilia and systemic symptoms after oxcarbazepine administration. The pharmacogenomic testing for various HLA antigen alleles was performed post hoc, and results were evaluated for structural similarities between AEDs and their molecular associations with HLA antigen proteins. In addition, we review the population-wide prevalence of various hypersensitivity reactions to AEDs and associated HLA antigen alleles. Finally, we discuss the potential utility of preemptive pharmacogenomic screening of patients before pharmacological treatment of epilepsy to assess the risk of developing hypersensitivity reactions.
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Affiliation(s)
- Hyun Kim
- Clinical Pharmacogenomics Service.,Departments of Pharmacy and.,School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences University, Boston, Massachusetts; and
| | - Laura Chadwick
- Clinical Pharmacogenomics Service.,Departments of Pharmacy and
| | - Yasir Alzaidi
- School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences University, Boston, Massachusetts; and
| | - Jonathan Picker
- Clinical Pharmacogenomics Service.,Division of Genetics and Genomics, and.,Departments of Pediatrics and
| | - Annapurna Poduri
- Neurology, Boston Children's Hospital, Boston, Massachusetts.,Neurology, Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Shannon Manzi
- Clinical Pharmacogenomics Service, .,Departments of Pharmacy and
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34
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An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity. J Immunol Res 2018; 2018:6431694. [PMID: 29651444 PMCID: PMC5830968 DOI: 10.1155/2018/6431694] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/09/2017] [Indexed: 02/07/2023] Open
Abstract
Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.
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35
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Adler NR, Aung AK, Ergen EN, Trubiano J, Goh MSY, Phillips EJ. Recent advances in the understanding of severe cutaneous adverse reactions. Br J Dermatol 2017; 177:1234-1247. [PMID: 28256714 DOI: 10.1111/bjd.15423] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2017] [Indexed: 12/17/2022]
Abstract
Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross-reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients.
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Affiliation(s)
- N R Adler
- School of Public Health & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.,Alfred Hospital, Melbourne, Victoria, Australia
| | - A K Aung
- School of Public Health & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.,Alfred Hospital, Melbourne, Victoria, Australia
| | - E N Ergen
- Department of Dermatology, University of Alabama, Birmingham, AL, U.S.A
| | - J Trubiano
- Austin Health, Melbourne, Victoria, Australia.,The University of Melbourne, Melbourne, Victoria, Australia
| | - M S Y Goh
- Alfred Hospital, Melbourne, Victoria, Australia
| | - E J Phillips
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.,Department of Medicine, Vanderbilt University Medical Centre, Nashville, TN, U.S.A
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Abstract
Drug hypersensitivity reactions affect over 7% of the population and are problematic both for patients and doctors. They frequently occur in the form of exanthematous drug eruptions. The clinical manifestation of delayed hypersensitivity reactions is very variable ranging from localized fixed drug eruptions to life-threatening, severe bullous mucocutaneous eruptions or systemic drug hypersensitivity syndromes. In the case of suspicion of an exanthematous drug eruption, the causality should initially be assessed according to the proposed algorithm. If both the chronology and the clinical symptoms are indicative of a delayed drug hypersensitivity reaction, the suspected drug should be avoided. Only in cases of urgent therapeutic indications and if alternative drugs are not available, the options of "treating through" and temporary tolerance induction by "desensitization" should be considered after an individual risk-benefit analysis.
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37
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38
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Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, Phillips EJ. Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2017; 5:547-563. [PMID: 28483310 PMCID: PMC5424615 DOI: 10.1016/j.jaip.2017.01.025] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 01/11/2017] [Accepted: 01/18/2017] [Indexed: 12/17/2022]
Abstract
Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell-mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.
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Affiliation(s)
- Jonathan Grant Peter
- Division of Allergology and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Rannakoe Lehloenya
- Division of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Sipho Dlamini
- Division of Infectious Diseases, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Kimberly Risma
- Division of Allergy, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Katie D White
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
| | - Katherine C Konvinse
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn
| | - Elizabeth J Phillips
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn; Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
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39
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Wang F, Zhao YK, Li M, Zhu Z, Zhang X. Trends in culprit drugs and clinical entities in cutaneous adverse drug reactions: a retrospective study. Cutan Ocul Toxicol 2017; 36:370-376. [PMID: 28423957 DOI: 10.1080/15569527.2017.1301947] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Fang Wang
- Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China,
| | - Yu-Kun Zhao
- Department of Dermatology, Eastern Hospital of First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, and
| | - Minyi Li
- Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China,
| | - Zhe Zhu
- Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Xingqi Zhang
- Department of Dermatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China,
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40
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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: 18] [Impact Index Per Article: 2.0] [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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Frey N, Bircher A, Bodmer M, Jick SS, Meier CR, Spoendlin J. Validation of Stevens-Johnson syndrome or toxic epidermal necrolysis diagnoses in the Clinical Practice Research Datalink. Pharmacoepidemiol Drug Saf 2016; 26:429-436. [DOI: 10.1002/pds.4124] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 10/05/2016] [Accepted: 10/13/2016] [Indexed: 11/09/2022]
Affiliation(s)
- Noel Frey
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences; University of Basel; Basel Switzerland
- Hospital Pharmacy; University Hospital Basel; Basel Switzerland
| | | | | | - Susan S. Jick
- Boston Collaborative Drug Surveillance Program; Boston University School of Public Health; Lexington MA USA
| | - Christoph R. Meier
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences; University of Basel; Basel Switzerland
- Hospital Pharmacy; University Hospital Basel; Basel Switzerland
- Boston Collaborative Drug Surveillance Program; Boston University School of Public Health; Lexington MA USA
| | - Julia Spoendlin
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences; University of Basel; Basel Switzerland
- Hospital Pharmacy; University Hospital Basel; Basel Switzerland
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Incidence of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Nationwide Population-Based Study Using National Health Insurance Database in Korea. PLoS One 2016; 11:e0165933. [PMID: 27835661 PMCID: PMC5106005 DOI: 10.1371/journal.pone.0165933] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 10/20/2016] [Indexed: 01/26/2023] Open
Abstract
Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases; however, it is hard to estimate their incidence due to the rarity of these diseases. We evaluated the incidence of SJS and TEN using a nationwide administrative database. Methods We used a national medical insurance review system (Health Insurance Review and Assessment) database which contained the claim data of the entire nation from 2009 to 2013 to estimate the accurate incidence of SJS and TEN in Korea. The diagnostic codes of L511 (SJS) or L512 (TEN) from the International Classification of Diseases-10th revision were used to define the target study population. We also retrospectively followed up a 2011 SJS and TEN cohort for 24 months in order to assess the in-hospital mortality, related complications and total claims cost due to SJS and TEN. Results A total of 1,167 (938 SJS and 229 TEN) cases were newly diagnosed from 2010 to 2013. The age- and sex-standardized annual incidences estimated in this study were 3.96 to 5.03 in SJS and 0.94 to 1.45 in TEN per million. There was no significant change in annual incidence throughout the study periods. When analyzed by 10-year age groups, the annual incidence was the lowest in group 20–29 years and the highest in group 70 for both SJS and TEN. Based on the 2011 cohort analysis, the in-hospital mortality were 5.7 and 15.1% for SJS and TEN, respectively. The mortality increased with age, particularly, after 40 years of age. Among the complications related with SJS or TEN, ocular sequelae was the most common (43.1 and 43.4% of SJS and TEN patients, respectively) followed by urethral sequelae (5.7 and 9.4% of SJS and TEN patients, respectively). Conclusion Overall, our data suggest that SJS, and TEN are infrequent but constantly arise throughout the years.
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Li YY, Jin YM, He LP, Bai JS, Liu J, Yu M, Chen JH, Wen J, Kuang YQ. Clinical analysis of HIV/AIDS patients with drug eruption in Yunnan, China. Sci Rep 2016; 6:35938. [PMID: 27796328 PMCID: PMC5086857 DOI: 10.1038/srep35938] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/07/2016] [Indexed: 01/11/2023] Open
Abstract
Drug eruption is the most common clinical presentation in patients with HIV/AIDS. The systemic clinical and risk factors associated with drug eruption remain unknown. A retrospective analysis in HIV/AIDS patients with drug eruption was carried out with demographic data, epidemiological data, clinical characteristics, laboratory data and follow-up data. The risk factors correlated with prognosis were assessed by case control analysis. A total of 134 out of 1817 HIV/AIDS patients (7.4%) presented drug eruptions. The major class of sensitizing drug was HAART drugs (47.7%), followed by antibiotics (47.0%). Nevirapine (39.6%) was the most common sensitizing drug in the HAART regimens. The patients received HAART or had allergic history were prone to develop drug eruption. The alanine aminotransferase, albumin, globulin, creatinine, blood urea nitrogen (BUN), lymphocytes, red blood cells (RBC) and eosinophils of the drug eruption patients were significantly different the control patients. The allergic history, opportunistic infection, viral load, CD4 cell count, high globulin and low albumin were the risk factors correlated with death in HIV/AIDS patients with drug eruption. It is proposed that patients with higher viral loads, higher globulin levels and lower white blood cells (WBC) should be given special attention for the prevention of complications and death.
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Affiliation(s)
- Yu-Ye Li
- Department of Dermatology and Venerology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, P. R. China
| | - Yong-Mei Jin
- Department of Dermatology and Venerology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, P. R. China.,Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Li-Ping He
- School of Public Health, Kunming Medical University, Kunming 650500, P. R. China
| | - Jin-Song Bai
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jun Liu
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Min Yu
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jian-Hua Chen
- Department of HIV/AIDS, The Third People's Hospital of Kunming, Kunming 650041, P. R. China
| | - Jing Wen
- Center for Translational Medicine, Huaihe Clinical College, Henan University, Kaifeng 475000, P. R. China.,Pharmaceutical College, Henan University, Kaifeng 475001, P. R. China
| | - Yi-Qun Kuang
- Center for Translational Medicine, Huaihe Clinical College, Henan University, Kaifeng 475000, P. R. China
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Pinho A, Coutinho I, Gameiro A, Gouveia M, Gonçalo M. Patch testing - a valuable tool for investigating non-immediate cutaneous adverse drug reactions to antibiotics. J Eur Acad Dermatol Venereol 2016; 31:280-287. [PMID: 27477905 DOI: 10.1111/jdv.13796] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 05/06/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND Antibiotics are among the most frequent causes of cutaneous adverse drug reactions (CADR); patch testing may be an important tool in their evaluation and management. We assessed the role of patch testing as a diagnostic tool in non-immediate CADR to antibiotics, and evaluated cross-reactivity among them. METHODS We reviewed data from all patients with non-immediate CADR attributed to antibiotics, which were patch tested between 2000 and 2014 at our dermatology department. RESULTS Patch tests were performed in 260 patients, and showed overall reactivity to antibiotics of 21.5%, especially in the context of drug reactions with eosinophilia and systemic symptoms (DRESS) (31.6%), maculopapular exanthema (MPE) (21.8%), Stevens-Johnson syndrome/toxic epidermal necrolysis (20%) and acute generalized exanthematous pustulosis (AGEP) (18.1%). Patch test reactivity was higher for amoxicillin, mainly in DRESS (44.4%) and MPE (25.6%), and dicloxacillin (50% in AGEP and 37.5% in MPE). Reactivity to clindamycin occurred, especially in the setting of MPE (23.2%). In AGEP and DRESS, patch tests were useful in detecting reactivity to quinolones (50-100%). Overall reactivity was lower for vancomycin (9.1%), co-trimoxazole (8.6%), macrolides (4.8%) and cephalosporins (4.4%). Positive patch tests for more than one antibiotic occurred in 29/56 cases (51.8%), mostly explained by cross-reactions. Twenty of 24 cases reacted to both amoxicillin and ampicillin. All five cases reacting to ciprofloxacin cross-reacted with other quinolones. CONCLUSION Although oral rechallenge is considered the gold standard for confirming drug imputability in CADR, patch testing could be suggested as a first choice in the study of non-immediate reactions, since it is a safe and valuable procedure.
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Affiliation(s)
- A Pinho
- Department of Dermatology, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - I Coutinho
- Department of Dermatology, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - A Gameiro
- Department of Dermatology, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - M Gouveia
- Department of Dermatology, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - M Gonçalo
- Department of Dermatology, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Clinic of Dermatology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Graudins LV, Ly J, Trubiano J, Aung AK. More than skin deep. Ten year follow-up of delayed cutaneous adverse drug reactions (CADR). Br J Clin Pharmacol 2016; 82:1040-7. [PMID: 27265387 DOI: 10.1111/bcp.13030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/09/2016] [Accepted: 06/02/2016] [Indexed: 12/17/2022] Open
Abstract
AIMS To determine the gaps in practice regarding appropriate ADR documentation and risk communication for patients diagnosed with severe cutaneous adverse drug reactions (CADR). METHODS This was a retrospective observational cohort study conducted using hospital coding and databases to identify inpatients diagnosed with CADR from January 2004 to August 2014. Hospital discharge summaries, ADR reports and pharmacy dispensing records were reviewed for ADR documentation. Patients still living in Australia and who did not opt out of being contacted were invited to be surveyed by telephone to determine their understanding of recommendations, re-exposure rates and long-term effects. RESULTS Of 85 patients identified, median age was 59 (IQR 44-72) years and 47.1% were male. The most common diagnosis was TENS (49.4%). Ten patients (11.8%) died as inpatients. Of the 81 patients with a drug-related causality, 47 (58%) had appropriate documentation in all three required medical record platforms. Of the 56 eligible patients, 38 (67.9%) were surveyed; 13% had no information provided upon discharge and 26.3% patients had a mismatch in knowledge of implicated medications. No surveyed patient had a relapse of CADR, but 23.7% had a subsequent unrelated allergic reaction. Thirteen patients (34.2%) reported long-term effects. CONCLUSIONS We found gaps in the accuracy of ADR documentation and communication of risk at discharge, which indicated risks to patient safety. Electronic systems are being developed to improve documentation. Written information about CADR is being provided at discharge to improve patient understanding and knowledge.
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Affiliation(s)
- Linda Velta Graudins
- Pharmacy Department, Alfred Health, 55 Commercial Road, Melbourne, 3004, Victoria, Australia.
| | - Jenny Ly
- Pharmacy Department, Alfred Health, 55 Commercial Road, Melbourne, 3004, Victoria, Australia
| | - Jason Trubiano
- Department of Infectious Diseases, Alfred Health, 55 Commercial Road, Melbourne, 3004, Victoria, Australia.,Department of Infectious Diseases, Peter MacCallum Cancer Centre, Victoria, Australia.,Department of Infectious Diseases, Austin Health, 145 Studley Road, Heidelberg, 3184, Victoria, Australia.,Department of Medicine, University of Melbourne, Victoria, Australia
| | - Ar Kar Aung
- Department of Infectious Diseases, Alfred Health, 55 Commercial Road, Melbourne, 3004, Victoria, Australia.,Department of General Medicine, Alfred Health and Monash University, Victoria, Australia
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Abstract
PURPOSE OF REVIEW Population ageing is a worldwide phenomenon. The presence of multiple comorbidities, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, as well as skin changes in the elderly contribute to a unique diagnostic and management problem. This article reviews the epidemiology of cutaneous adverse drug reactions in the elderly and elaborates on a few specific types of reactions which are more relevant to the elderly. RECENT FINDINGS Chronic dermatoses, for example, eczema, have been reported to be associated with the use of long-term medications such as calcium channel blockers and hydrochlorothiazide. Elderly patients receiving treatment for cancers may develop chemotherapy-related cutaneous side effects, including those associated with newer 'targeted' molecular therapies. Elderly patients who develop severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have worse prognosis in terms of mortality. SUMMARY Persons of advanced age often have multiple comorbidities and are on multiple medications. This can result in higher probability of an elderly person developing drug eruptions. It is important for the clinician to be aware of the range of drug-related eruptions and their implications.
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Abstract
Life-threatening and benign drug reactions occur frequently in the skin, affecting 8 % of the general population and 2-3 % of all hospitalized patients, emphasizing the need for physicians to effectively recognize and manage patients with drug-induced eruptions. Neurologic medications represent a vast array of drug classes with cutaneous side effects. Approximately 7 % of the United States (US) adult population is affected by adult-onset neurological disorders, reflecting a large number of patients on neurologic drug therapies. This review elucidates the cutaneous reactions associated with medications approved by the US Food and Drug Administration (FDA) to treat the following neurologic pathologies: Alzheimer disease, amyotrophic lateral sclerosis, epilepsy, Huntington disease, migraine, multiple sclerosis, Parkinson disease, and pseudobulbar affect. A search of the literature was performed using the specific FDA-approved drug or drug classes in combination with the terms 'dermatologic,' 'cutaneous,' 'skin,' or 'rash.' Both PubMed and the Cochrane Database of Systematic Reviews were utilized, with side effects ranging from those cited in randomized controlled trials to case reports. It behooves neurologists, dermatologists, and primary care physicians to be aware of the recorded cutaneous adverse reactions and their severity for proper management and potential need to withdraw the offending medication.
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Affiliation(s)
| | | | - Sylvia Hsu
- Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph S Kass
- Department of Neurology, Baylor College of Medicine, 7200 Cambridge St., 9th Floor, Houston, TX, 77030, USA.
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Park HJ, Kim YJ, Kim DH, Kim J, Park KH, Park JW, Lee JH. HLA Allele Frequencies in 5802 Koreans: Varied Allele Types Associated with SJS/TEN According to Culprit Drugs. Yonsei Med J 2016; 57:118-26. [PMID: 26632391 PMCID: PMC4696942 DOI: 10.3349/ymj.2016.57.1.118] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 06/30/2015] [Accepted: 07/02/2015] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea. MATERIALS AND METHODS We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01. RESULTS HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03. CONCLUSION HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.
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Affiliation(s)
- Hye Jung Park
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Young Joo Kim
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Hyun Kim
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Junho Kim
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Hee Park
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Won Park
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hyun Lee
- Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea.
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Yang F, Gu B, Zhang L, Xuan J, Luo H, Zhou P, Zhu Q, Yan S, Chen SA, Cao Z, Xu J, Xing Q, Luo X. HLA-B*13:01 is associated with salazosulfapyridine-induced drug rash with eosinophilia and systemic symptoms in Chinese Han population. Pharmacogenomics 2015; 15:1461-9. [PMID: 25303297 DOI: 10.2217/pgs.14.69] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Salazosulfapyridine (SASP) frequently causes several adverse reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). This study aims to assess whether there is an association between SASP-induced DRESS and HLA-A, -B and -C alleles in the Chinese Han population. SUBJECTS & METHODS We performed an association study of six subjects with SASP-induced DRESS, 30 SASP-tolerant patients and 283 general subjects from the human MHC database, all of whom are Han Chinese. RESULTS The frequency of the SASP-induced DRESS patients carrying the HLA-B*13:01 allele is 66.67% (4/6). It is significantly higher compared with the general Chinese Han population (15.19%, 43/283; odds ratio: 11.16; p = 0.007) or with the SASP-tolerant patients (13.33%, 4/30; odds ratio: 13.00; p = 0.004). CONCLUSION These findings show for the first time that in the Chinese Han population, HLA-B*13:01 is associated with SASP-induced DRESS. HLA-B*13:01 might serve as a potential genetic marker for reducing the prevalence of SASP-induced DRESS.
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Affiliation(s)
- Fanping Yang
- Huashan Hospital, Fudan University, Shanghai, China
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Didona D, Paolino G, Garcovich S, Caposiena Caro RD, Didona B. Successful use of etanercept in a case of toxic epidermal necrolysis induced by rituximab. J Eur Acad Dermatol Venereol 2015; 30:e83-e84. [PMID: 26428058 DOI: 10.1111/jdv.13330] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- D Didona
- Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
| | - G Paolino
- Department of Dermatology, La Sapienza University of Rome, Rome, Italy
| | - S Garcovich
- Unit of Dermatology, Catholic University, Policlinico "A. Gemelli" University Hospital, Rome, Italy
| | - R D Caposiena Caro
- Department of Dermatology, University of Rome "Tor Vergata", Rome, Italy
| | - B Didona
- Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
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