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Wei BM, Fox LP, Kaffenberger BH, Korman AM, Micheletti RG, Mostaghimi A, Noe MH, Rosenbach M, Shinkai K, Kwah JH, Phillips EJ, Bolognia JL, Damsky W, Nelson CA. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Part I. Epidemiology, pathogenesis, clinicopathological features, and prognosis. J Am Acad Dermatol 2024; 90:885-908. [PMID: 37516359 DOI: 10.1016/j.jaad.2023.02.072] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 02/11/2023] [Accepted: 02/26/2023] [Indexed: 07/31/2023]
Abstract
Drug-induced hypersensitivity syndrome (DiHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe cutaneous adverse reaction (SCAR) characterized by an exanthem, fever, and hematologic and visceral organ involvement. Anticonvulsants, antibiotics, and allopurinol are the most common triggers. The pathogenesis involves a complex interplay between drugs, viruses, and the immune system primarily mediated by T-cells. DiHS/DRESS typically presents with a morbilliform eruption 2-6 weeks after drug exposure, and is associated with significant morbidity, mortality, and risk of relapse. Long-term sequelae primarily relate to organ dysfunction and autoimmune diseases. Part I of this continuing medical education activity on DiHS/DRESS provides an update on epidemiology, novel insights into pathogenesis, and a description of clinicopathological features and prognosis.
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Affiliation(s)
- Brian M Wei
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut
| | - Lindy P Fox
- Department of Dermatology, University of California, San Francisco, California
| | | | - Abraham M Korman
- Department of Dermatology, The Ohio State University, Columbus, Ohio
| | - Robert G Micheletti
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Arash Mostaghimi
- Department of Dermatology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Megan H Noe
- Department of Dermatology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Misha Rosenbach
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kanade Shinkai
- Department of Dermatology, University of California, San Francisco, California
| | - Jason H Kwah
- Department of Medicine, Section of Rheumatology, Allergy and Immunology, Yale School of Medicine, New Haven, Connecticut
| | - Elizabeth J Phillips
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jean L Bolognia
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut
| | - William Damsky
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut; Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Caroline A Nelson
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
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Zhu H, Ren V. Immunopathogenic Insights on Preferential Human Herpesvirus-6 Reactivation in Drug Rash With Eosinophilia and Systemic Symptoms: A Scoping Review. J Cutan Med Surg 2023; 27:388-398. [PMID: 37231539 PMCID: PMC10523827 DOI: 10.1177/12034754231177590] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 02/14/2023] [Accepted: 04/28/2023] [Indexed: 05/27/2023]
Abstract
INTRODUCTION Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic betaherpesvirus that can reactivate in drug rash with eosinophilia and systemic symptoms (DRESS). Despite recent publications advancing our understanding of HHV-6 in DRESS, the exact role of HHV-6 in disease pathogenesis remains unclear. METHODS A scoping review with the PubMed query "(HHV 6 AND (drug OR DRESS OR DIHS)) OR (HHV6 AND (drug OR DRESS OR DIHS))" was conducted in accordance with PRISMA guidelines. Articles containing original data on at least one DRESS patient with HHV-6 testing were included. RESULTS Our search returned a total of 373 publications, of which 89 met eligibility criteria. HHV-6 reactivation occurred in 63% of DRESS patients (n = 748), which was significantly more often than other herpesviruses. HHV-6 reactivation was associated with worse outcomes and greater severity in controlled studies. Case reports have demonstrated sometimes fatal HHV-6-related multi-organ involvement. Temporally, HHV-6 reactivation typically occurs 2 to 4 weeks after DRESS onset and has been linked to markers of immunologic signaling, such as OX40 (CD134), an HHV-6 entry receptor. Efficacy of antiviral or immunoglobulin treatment has only been demonstrated anecdotally, and steroid use may affect HHV-6 reactivation. CONCLUSION HHV-6 is implicated in DRESS more than in any other dermatologic condition. It is still unclear whether HHV-6 reactivation is cause or consequence of DRESS dysregulation. Similar pathogenic mechanisms precipitated by HHV-6 in other contexts may be relevant in DRESS. Future randomized controlled studies to assess effects of viral suppression on clinical outcomes is needed.
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Affiliation(s)
- Harrison Zhu
- School of Medicine, Baylor College of Medicine, Houston, TX, USA
- HHV-6 Foundation, Santa Barbara, CA, USA
| | - Vicky Ren
- Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses. Microorganisms 2023; 11:microorganisms11020346. [PMID: 36838310 PMCID: PMC9966117 DOI: 10.3390/microorganisms11020346] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a heterogeneous, multiorgan and potentially life-threatening drug-hypersensitivity reaction (DHR) that occurs several days or weeks after drug initiation or discontinuation. DHRs constitute an emerging issue for public health, due to population aging, growing multi-organ morbidity, and subsequent enhanced drug prescriptions. DRESS has more consistently been associated with anticonvulsants, allopurinol and antibiotics, such as sulphonamides and vancomycin, although new drugs are increasingly reported as culprit agents. Reactivation of latent infectious agents such as viruses (especially Herpesviridae) plays a key role in prompting and sustaining aberrant T-cell and eosinophil responses to drugs and pathogens, ultimately causing organ damage. However, the boundaries of the impact of viral agents in the pathophysiology of DRESS are still ill-defined. Along with growing awareness of the multifaceted aspects of immune perturbation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing SARS-CoV-2-related disease (COVID-19) pandemic, novel interest has been sparked towards DRESS and the potential interactions among antiviral and anti-drug inflammatory responses. In this review, we summarised the most recent evidence on pathophysiological mechanisms, diagnostic approaches, and clinical management of DRESS with the aim of increasing awareness on this syndrome and possibly suggesting clues for future research in this field.
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Hu YQ, Lv CY, Cui A. Pulmonary sarcoidosis: A novel sequelae of drug reaction with eosinophilia and systemic symptoms: A case report. World J Clin Cases 2022; 10:13074-13080. [PMID: 36569008 PMCID: PMC9782944 DOI: 10.12998/wjcc.v10.i35.13074] [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: 09/14/2022] [Revised: 11/13/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon yet serious adverse drug hypersensitivity reaction with the presentations including rash, fever, lymphadenopathy, and internal organ involvement. Sarcoidosis is a systematic granulomatous disease with unknown etiology. We herein report a case of pulmonary sarcoidosis secondary to allopurinol-induced DRESS.
CASE SUMMARY A 37-year-old man with a history of hyperuricemia was treated with allopurinol for three weeks at a total dose of 7000 milligrams before developing symptoms including anorexia, fever, erythematous rash, and elevated transaminase. The patient was diagnosed with DRESS and was treated with prednisone for 6 mo until all the symptoms completely resolved. Three months later, the patient presented again because of a progressively worsening dry cough. His chest computed tomography images showed bilateral lung parenchyma involvement with lymph node enlargement, which was confirmed to be nonnecrotizing granuloma by pathological examination. Based on radiologic and pathological findings, he was diagnosed with sarcoidosis and was restarted on treatment with prednisone, which was continued for another 6 mo. Reexamination of chest imaging revealed complete resolution of parenchymal lung lesions and a significant reduction in the size of the mediastinal and hilar lymph nodes. Following a 6-month follow-up of completion of treatment, the patient's clinical condition remained stable with no clinical evidence of relapse.
CONCLUSION This is the first case in which pulmonary sarcoidosis developed as a late complication of allopurinol-induced DRESS. The case indicated that the autoimmune reaction of DRESS may play an important role in the pathogenesis of sarcoidosis.
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Affiliation(s)
- Yu-Qi Hu
- Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Chen-Yang Lv
- Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
- Department of Pulmonary and Critical Care Medicine, The First Hospital of Fangshan District, Beijing 102499, China
| | - Ai Cui
- Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
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Chemokines in Severe Cutaneous Adverse Reactions (SCARs). Biomolecules 2021; 11:biom11060847. [PMID: 34204146 PMCID: PMC8228887 DOI: 10.3390/biom11060847] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 12/19/2022] Open
Abstract
Although the incidence of severe cutaneous adverse reactions (SCARs) to medications is very low, SCARs can result in disability or even death if they are not diagnosed and treated properly. As the rapid recognition of SCARs is essential, it is necessary to develop diagnostic markers for them that can also be used to assess severity and predict outcomes in the early phase. In addition, it is important to identify novel therapeutic targets for SCARs. Chemokines are chemotactic cytokines that control the migratory patterns and locations of immune cells and usually exhibit markedly specific associations with certain human diseases. In Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), the Th1-associated chemokines chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 predominate, while in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS), the levels of the Th2-associated chemokines chemokine (C-C motif) ligand 17 (CCL17) and CCL22 are markedly elevated. We suggest that the distinct chemokine profiles of SJS/TEN and DIHS/DRESS can be used to aid their differential diagnosis. CXCL10 has also been reported to be associated with the development of long-term sequelae in DIHS/DRESS. This review focuses on the chemokines involved in the pathogenesis and adjuvant diagnosis of SCARs, particularly SJS/TEN and DIHS/DRESS, but also provides a brief overview of SCARs and the chemokine superfamily. As it is being increasingly recognized that an association exists between human herpesvirus 6 (HHV-6) and DIHS/DRESS, the possible roles of the chemokine/chemokine receptor homologs encoded by HHV-6 in the pathogenesis of DIHS/DRESS are also discussed.
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Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS). Int J Mol Sci 2021; 22:ijms22042147. [PMID: 33670052 PMCID: PMC7927043 DOI: 10.3390/ijms22042147] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/16/2021] [Accepted: 02/19/2021] [Indexed: 12/14/2022] Open
Abstract
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe type of adverse drug eruption associated with multiorgan involvement and the reactivation of human herpesvirus 6, which arises after prolonged exposure to certain drugs. Typically, two waves of disease activity occur during the course of DIHS/DRESS; however, some patients experience multiple waves of exacerbation and remission of the disease. Severe complications, some of which are related to cytomegalovirus reactivation, can be fatal. DIHS/DRESS is distinct from other drug reactions, as it involves herpes virus reactivation and can lead to the subsequent development of autoimmune diseases. The association between herpesviruses and DIHS/DRESS is now well established, and DIHS/DRESS is considered to arise as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be mediated by distinct types of immune cells. It appears that both CD4 and CD8 T cells are involved in the pathogenesis of DIHS/DRESS but play distinct roles. CD4 T cells mainly initiate drug allergies in response to drug antigens, and then herpesvirus-specific CD8 T cells that target virus-infected cells emerge, resulting in tissue damage. Regulatory T-cell dynamics are also suggested to contribute to the diverse symptoms of DIHS/DRESS. However, the pathomechanisms of this complex disease remain largely unknown. In particular, how viral infections contribute to the pathogenesis of DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. This review describes the clinical features of DIHS/DRESS, including the associated complications and sequelae, and discusses recent advances in our understanding of the immunopathogenic mechanisms of DIHS/DRESS.
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Domínguez-Mozo MI, Nieto-Guerrero A, Pérez-Pérez S, García-Martínez MÁ, Arroyo R, Álvarez-Lafuente R. MicroRNAs of Human Herpesvirus 6A and 6B in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients. Front Immunol 2020; 11:2142. [PMID: 33072077 PMCID: PMC7531184 DOI: 10.3389/fimmu.2020.02142] [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: 04/21/2020] [Accepted: 08/06/2020] [Indexed: 12/19/2022] Open
Abstract
Human herpesvirus-6A (HHV-6A) and −6B (HHV-6B) might be involved in the etiopathogenesis of multiple sclerosis (MS), especially the HHV-6A. We aim at assessing, for the first time in the scientific literature, the HHV-6A/B microRNAs in MS patients. We analyzed the miRNAs of HHV-6A: miR-U86, and −6B: hhv6b-miR-Ro6-1, −2, −3-3p, −3-5p, and −4 in paired samples of serum and CSF of 42 untreated MS patients and 23 patients with other neurological diseases (OND), using Taqman MicroRNA Assays. Intrathecal HHV-6A/B antibody production and anti-HHV-6A/B IgG/IgM levels in serum were measured. MS clinical data were available. We detected the following miRNAs: hhv6b-miR-Ro6-2 (serum: MS:97.7%, OND:95.7%; CSF: MS:81%, OND:86.4%), 3-3p (serum: MS:4.8%, OND:0%; CSF: MS:2.4%, OND:4.5%), −3-5p (serum: MS:95.2%, OND:91.3%; CSF: MS:50%, OND:54.5%), and miR-U86 (serum: MS:54.8%, OND:47.8%; CSF: MS:11.9%, OND:9.1%). In the serum of the whole population (MS and OND patients) we found a significant correlation between the levels of hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.839, pcorr = 3E-13), −2 and miR-U86 (Spearman r = 0.578, pcorr = 0.001) and −3-5p and miR-U86 (Spearman r = 0.698, pcorr = 1.34E-5); also in the CSF, between hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.626, pcorr = 8.52E-4). These correlations remained statistically significant when both populations were considered separately. The anti-HHV-6A/B IgG levels in CSF and the intrathecal antibody production in positive MS patients for hhv6b-miR-Ro6-3-5p were statistically significant higher than in the negative ones (pcorr = 0.006 and pcorr = 0.036). The prevalence of miR-U86 (30.8%) in the CSF of individuals without gadolinium-enhancing lesions was higher (p = 0.035) than in the ones with these lesions (0%); however, the difference did not withstand Bonferroni correction (pcorr = 0.105). We propose a role of HHV-6A/B miRNAs in the maintenance of the viral latency state. Further investigations are warranted to validate these results and clarify the function of these viral miRNAs.
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Affiliation(s)
- María I Domínguez-Mozo
- Environmental Factors in Degenerative Diseases Research Group, Instituto Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Alejandro Nieto-Guerrero
- Environmental Factors in Degenerative Diseases Research Group, Instituto Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Silvia Pérez-Pérez
- Environmental Factors in Degenerative Diseases Research Group, Instituto Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - María Á García-Martínez
- Environmental Factors in Degenerative Diseases Research Group, Instituto Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
| | - Rafael Arroyo
- Neurology Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
| | - Roberto Álvarez-Lafuente
- Environmental Factors in Degenerative Diseases Research Group, Instituto Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain
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Takahashi K, Sato Y, Sekizuka T, Kuroda M, Suzuki T, Hasegawa H, Katano H. High expression of JC polyomavirus-encoded microRNAs in progressive multifocal leukoencephalopathy tissues and its repressive role in virus replication. PLoS Pathog 2020; 16:e1008523. [PMID: 32324824 PMCID: PMC7200015 DOI: 10.1371/journal.ppat.1008523] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 05/05/2020] [Accepted: 04/07/2020] [Indexed: 12/18/2022] Open
Abstract
JC polyomavirus (JCPyV, JCV) causes progressive multifocal leukoencephalopathy (PML) in immunocompromised hosts. JCPyV replicates in oligodendrocytes within the brain tissue of patients with PML. The JCPyV genome encodes a microRNA (miRNA) in the region encoding the large T antigen. JCPyV-encoded miRNA (miR-J1) has been detected in the tissue and cerebrospinal fluid samples of patients with PML; however, there are no reports describing the localization of polyomavirus-encoded miRNA in histological samples of patients with virus-associated diseases. In the present study, we detected high miR-J1 expression in the nuclei of JCPyV-infected cells in PML tissue samples via in situ hybridization. Additionally, in situ hybridization also revealed the expression of BK polyomavirus (BKPyV, BKV)-encoded miRNA in lesions of BKPyV-associated nephropathy. In situ hybridization for miR-J1-5p and -3p showed positive signals in 24/25 (96%) of PML tissues that were positive for JCPyV by immunohistochemistry. Higher copy numbers of miR-J1 were detected in PML tissues than in non-PML tissues by real-time reverse transcription PCR. Next generation sequencing showed that miR-J1-5p, a mature miRNA of primary miRNA, was predominant in the lesions compared with miR-J1-3p, another mature miRNA. Deletion or mutation of miR-J1 in recombinant JCPyV promoted the production of JCPyV-encoded proteins in cells transfected with JCPyV DNA, suggesting that polyomavirus-encoded miRNA may have a repressive role in viral replication in PML tissues. In situ hybridization for viral miRNA may be a useful diagnostic tool for PML.
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Affiliation(s)
- Kenta Takahashi
- Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Yuko Sato
- Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Tsuyoshi Sekizuka
- Pathogen Genomics Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Makoto Kuroda
- Pathogen Genomics Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Tadaki Suzuki
- Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Hideki Hasegawa
- Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
| | - Harutaka Katano
- Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan
- * E-mail:
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