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Henriques P, Caldeira-Araújo H, Brazão MDL, Abreu AM, Vigário AM, Rosa A. Primary Dengue and Long-Term Health Status in Madeira Island, Portugal: A Retrospective Questionnaire-Based Study. Am J Trop Med Hyg 2024; 111:403-411. [PMID: 38955194 PMCID: PMC11310610 DOI: 10.4269/ajtmh.23-0502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 03/18/2024] [Indexed: 07/04/2024] Open
Abstract
Dengue is among the most important mosquito-borne viral diseases worldwide. Although its acute manifestations are well known, little is known about the long-term impact of dengue on the population's health status. Madeira Island experienced a single outbreak of autochthonous dengue from September 2012 to March 2013. To extend our knowledge about the clinical impact of the outbreak on this naive population, we applied an online questionnaire to 168 adults diagnosed with dengue at the time to characterize retrospectively their symptoms during the infection and to identify long-term manifestations, possibly triggered by dengue. The most frequent symptoms during the clinical period, reported by more than three-quarters of our participants, were fever, myalgia, extreme tiredness, and headaches, whereas vomiting, pruritus, nausea, retro-orbital pain, and arthralgia occurred in 35% to 50% of participants. In the 8 years after dengue, 61.5% of participants reported at least one recurrent previously nonexistent symptom, the most frequent being headaches, abundant hair loss, extreme tiredness, arthralgia, and myalgia, experienced by 25% to 35% of participants. Nearly 20% of the participants with persistent symptoms reported the onset of chronic illness in the 4 years after dengue, most frequently ophthalmological and autoimmune diseases (5.6% each), versus only 2.2% of chronic disease onset in participants without persistent symptoms. Our results suggest that the occurrence of persistent symptoms after primary dengue might be more frequent than anticipated and may persist for several years, having an impact on the health status and well-being of a considerable proportion of the infected population.
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Affiliation(s)
- Paulo Henriques
- Projeto Medicina, Faculdade de Ciências da Vida, Universidade da Madeira, Funchal, Portugal
| | - Helena Caldeira-Araújo
- Projeto Medicina, Faculdade de Ciências da Vida, Universidade da Madeira, Funchal, Portugal
- CQM-Centro de Química da Madeira, Universidade da Madeira, Funchal, Portugal
| | - Maria da Luz Brazão
- Projeto Medicina, Faculdade de Ciências da Vida, Universidade da Madeira, Funchal, Portugal
- Serviço de Medicina Interna, Hospital Central do Funchal, SESARAM-EPERAM, Funchal, Portugal
| | - Ana Maria Abreu
- Departamento de Matemática, Faculdade de Ciências Exatas e da Engenharia, Universidade da Madeira, Funchal, Portugal
- Centro de Investigação em Matemática e Aplicações, Universidade de Évora, Évora, Portugal
| | - Ana Margarida Vigário
- Projeto Medicina, Faculdade de Ciências da Vida, Universidade da Madeira, Funchal, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Alexandra Rosa
- Projeto Medicina, Faculdade de Ciências da Vida, Universidade da Madeira, Funchal, Portugal
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Juneja D, Jain R, Nasa P. Dengue induced acute liver failure: A meta summary of case reports. World J Virol 2024; 13:91457. [PMID: 38616857 PMCID: PMC11008400 DOI: 10.5501/wjv.v13.i1.91457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/19/2024] [Accepted: 02/20/2024] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Dengue fever is the most common cause of viral hemorrhagic fever, with more than 400 million cases being reported annually, worldwide. Even though hepatic involvement is common, acute liver failure (ALF) is a rare complication of dengue fever. AIM To analyze the demographic profile, symptomology, hospital course and outcomes of patients presenting with ALF secondary to dengue infection by reviewing the published case reports. METHODS A systematic search was performed from multiple databases including PubMed, Reference Citation Analysis, Science Direct, and Google Scholar. The search terms used were "dengue" OR "severe dengue" OR "dengue shock syndrome" OR "dengue haemorrhagic syndrome" OR "dengue fever" AND "acute liver failure" OR "hepatic failure" OR "liver injury". The inclusion criteria were: (1) Case reports or case series with individual patient details; (2) Reported acute liver failure secondary to dengue infection; and (3) Published in English language and on adult humans. The data were extracted for patient demographics, clinical symptomatology, clinical interventions, hospital and intensive care unit course, need for organ support and clinical outcomes. RESULTS Data from 19 case reports fulfilling the predefined inclusion criteria were included. The median age of patients was 38 years (inter quartile range: Q3-Q1 26.5 years) with a female preponderance (52.6%). The median days from diagnosis of dengue to development of ALF was 4.5 d. The increase in aspartate aminotransferase was higher than that in alanine aminotransferase (median 4625 U/L vs 3100 U/L). All the patients had one or more organ failure, with neurological failure present in 73.7% cases. 42.1% patients required vasopressor support and hepatic encephalopathy was the most reported complication in 13 (68.4%) cases. Most of the patients were managed conservatively and 2 patients were taken up for liver transplantation. Only 1 death was reported (5.3%). CONCLUSION Dengue infection may rarely lead to ALF. These patients may frequently require intensive care and organ support. Even though most of these patients may improve with supportive care, liver transplantation may be a therapeutic option in refractory cases.
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Affiliation(s)
- Deven Juneja
- Department of Critical Care Medicine, Max Super Speciality Hospital, New Delhi 110017, India
| | - Ravi Jain
- Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, Rajasthan, India
| | - Prashant Nasa
- Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
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Rivera JA, Rengifo AC, Rosales-Munar A, Díaz-Herrera TH, Ciro JU, Parra E, Alvarez-Díaz DA, Laiton-Donato K, Caldas ML. Genotyping of dengue virus from infected tissue samples embedded in paraffin. Virol J 2023; 20:100. [PMID: 37231481 DOI: 10.1186/s12985-023-02072-5] [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: 02/06/2023] [Accepted: 05/14/2023] [Indexed: 05/27/2023] Open
Abstract
Dengue has become one of the vector-borne diseases that affect humans worldwide. In Latin American countries, Colombia is historically one of the most affected by epidemics of this flavivirus. The underreporting of signs and symptoms of probable cases of dengue, the lack of characterization of the serotypes of the infection, and the few detailed studies of postmortem necropsies of patients are among other conditions that have delayed progress in the knowledge of the pathogenesis of the disease. This study presents the results of fragment sequencing assays on paraffin-embedded tissue samples from fatal DENV cases during the 2010 epidemic in Colombia. We found that the predominant serotype was DENV-2, with the Asian/American genotype of lineages 1 and 2. This work is one of the few reports of the circulating genotypes of dengue during the 2010 epidemic in Colombia, one of the most lethal dates in the country's history.
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Grants
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
- contract 757 project 2013 Instituto Nacional de Salud (INS), Dirección de Investigación en Salud Pública (DISP), and the Colombian Department of Science, Technology, and Innovation (Minciencias)
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Affiliation(s)
- Jorge Alonso Rivera
- Dirección de investigación en Salud Pública, Grupo de Morfología Celular, Instituto Nacional de Salud, Avenue 26 No. 51-20 - Zone 6 CAN, Bogotá, Colombia
| | - Aura Caterine Rengifo
- Dirección de investigación en Salud Pública, Grupo de Morfología Celular, Instituto Nacional de Salud, Avenue 26 No. 51-20 - Zone 6 CAN, Bogotá, Colombia.
| | - Alicia Rosales-Munar
- Dirección de investigación en Salud Pública, Grupo de Morfología Celular, Instituto Nacional de Salud, Avenue 26 No. 51-20 - Zone 6 CAN, Bogotá, Colombia
| | - Taylor H Díaz-Herrera
- Dirección de investigación en Salud Pública, Grupo de Morfología Celular, Instituto Nacional de Salud, Avenue 26 No. 51-20 - Zone 6 CAN, Bogotá, Colombia
| | - José Usme Ciro
- CIST-Centro de Investigaciones en Salud Para el Trópico, Facultad de Medicina, Universidad Cooperativa de Colombia, Santa Marta, 47003, Colombia
| | - Edgar Parra
- Dirección de Redes en Salud Pública, Grupo de Patología, Instituto Nacional de Salud, Bogotá, Colombia
| | - Diego A Alvarez-Díaz
- Dirección de investigación en Salud Pública, Grupo de Genómica de Microorganismos Emergentes, Instituto Nacional de Salud, Bogotá, Colombia
| | - Katherine Laiton-Donato
- Dirección de investigación en Salud Pública, Grupo de Genómica de Microorganismos Emergentes, Instituto Nacional de Salud, Bogotá, Colombia
| | - María Leonor Caldas
- Dirección de investigación en Salud Pública, Grupo de Morfología Celular, Instituto Nacional de Salud, Avenue 26 No. 51-20 - Zone 6 CAN, Bogotá, Colombia
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Mrzljak A, Tabain I, Premac H, Bogdanic M, Barbic L, Savic V, Stevanovic V, Jelic A, Mikulic D, Vilibic-Cavlek T. The Role of Emerging and Neglected Viruses in the Etiology of Hepatitis. Curr Infect Dis Rep 2019; 21:51. [PMID: 31754812 DOI: 10.1007/s11908-019-0709-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW In this review, we present the overview of emerging and neglected viruses associated with liver involvement. RECENT FINDINGS Hepatitis E virus (HEV) emerged in the last two decades, causing hepatitis in many parts of the world. Moreover, liver involvement was also described in some emerging arboviral infections. Many reports showed dengue-associated liver injury; however, chikungunya, West Nile, tick-borne encephalitis, and Zika virus are rarely associated with clinically manifest liver disease. In addition, some neglected highly prevalent viruses such as adenoviruses and parvovirus B19 are capable of causing hepatitis in specific population groups. Anelloviruses (torque teno virus/torque teno mini virus/torque teno midi virus, SEN virus), human bocavirus, pegiviruses, and lymphocytic choriomeningitis virus have shown a little potential for causing hepatitis, but their role in the etiology of liver disease remains to be determined. In addition to the well-known hepatotropic viruses, many emerging and neglected viruses have been associated with liver diseases. The number of emerging zoonotic viruses has been increasingly recognized. While zoonotic potential of HEV is well documented, the recent identification of new hepatitis-related animal viruses such as HEV strains from rabbits and camels, non-primate hepaciviruses in domestic dogs and horses, as well as equine and porcine pegivirus highlights the possible zoonotic transmission in the context of "One Health." However, zoonotic potential and hepatotropism of animal hepatitis viruses remain to be determined.
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Affiliation(s)
- Anna Mrzljak
- Department of Medicine, Merkur University Hospital, Salata 3b, 10000, Zagreb, Croatia.
- School of Medicine, University of Zagreb, Zagreb, Croatia.
| | - Irena Tabain
- Department of Virology, Croatian Institute of Public Health, Zagreb, Croatia
| | - Hrvoje Premac
- Department of Medicine, Varazdin General Hospital, Varazdin, Croatia
| | - Maja Bogdanic
- Department of Virology, Croatian Institute of Public Health, Zagreb, Croatia
| | - Ljubo Barbic
- Department of Microbiology and Infectious Diseases with Clinic, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
| | - Vladimir Savic
- Poultry Center, Laboratory for Virology and Serology, Croatian Veterinary Institute, Zagreb, Croatia
| | - Vladimir Stevanovic
- Department of Microbiology and Infectious Diseases with Clinic, Faculty of Veterinary Medicine, University of Zagreb, Zagreb, Croatia
| | - Ana Jelic
- Department of Medicine, Merkur University Hospital, Salata 3b, 10000, Zagreb, Croatia
| | - Danko Mikulic
- Department of Surgery, Merkur University Hospital, Zagreb, Croatia
| | - Tatjana Vilibic-Cavlek
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Virology, Croatian Institute of Public Health, Zagreb, Croatia
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Dissanayake HA, Seneviratne SL. Liver involvement in dengue viral infections. Rev Med Virol 2018; 28. [PMID: 29465794 DOI: 10.1002/rmv.1971] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/03/2018] [Accepted: 01/08/2018] [Indexed: 12/17/2022]
Affiliation(s)
| | - Suranjith L. Seneviratne
- Institute of Immunity and Transplantation; Royal Free Hospital and University College London; London UK
- Department of Surgery, Faculty of Medicine; University of Colombo; Colombo Sri Lanka
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Bächler P, Baladron MJ, Menias C, Beddings I, Loch R, Zalaquett E, Vargas M, Connolly S, Bhalla S, Huete Á. Multimodality Imaging of Liver Infections: Differential Diagnosis and Potential Pitfalls. Radiographics 2016; 36:1001-23. [PMID: 27232504 DOI: 10.1148/rg.2016150196] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Imaging plays an important role in the diagnosis, characterization, and management of infectious liver disease. In clinical practice, the main contributions of imaging are in detecting early disease, excluding other entities with a similar presentation, establishing a definitive diagnosis when classic findings are present, and guiding appropriate antimicrobial, interventional, or surgical treatment. The most common imaging features of bacterial, viral, parasitic, and fungal hepatic infections are described, and key imaging and clinical manifestations are reviewed that may be useful to narrow the differential diagnosis and avoid pitfalls in image interpretation. Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging allow accurate detection of most hepatic infections and, in some circumstances, may provide specific signs to identify the underlying pathogen and exclude other entities with similar imaging features. In bacterial and parasitic infections, specific imaging features may be enough to exclude a neoplasm and, occasionally, to identify the underlying infectious agent. US and CT are important means to guide percutaneous aspiration or drainage when needed. In viral infections, imaging is critical to exclude entities that may manifest with similar clinical and laboratory findings. Disseminated fungal infections require early detection at imaging because they can be fatal if not promptly treated. Familiarity with the epidemiology, pathogenesis, clinical manifestations, imaging features, and treatment of hepatic infections can aid in radiologic diagnosis and guide appropriate patient care. (©)RSNA, 2016.
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Affiliation(s)
- Pablo Bächler
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - María José Baladron
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Christine Menias
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Ignacio Beddings
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Ron Loch
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Eugenio Zalaquett
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Matías Vargas
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Sarah Connolly
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Sanjeev Bhalla
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
| | - Álvaro Huete
- From the Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 367, 2nd Floor, Santiago 8330024, Chile (P.B., M.J.B., I.B., E.Z., M.V., A.H.); Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.L., S.C., S.B.)
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Kularatne SAM, Imbulpitiya IVB, Abeysekera RA, Waduge RN, Rajapakse RPVJ, Weerakoon KGAD. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infect Dis 2014; 14:141. [PMID: 24628767 PMCID: PMC4008311 DOI: 10.1186/1471-2334-14-141] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 03/10/2014] [Indexed: 12/31/2022] Open
Abstract
Background Dengue infection carries a potential risk of death despite stringent management of plasma leak and haemorrhage. It appears that the extent of liver dysfunction determines the outcome. Methods We present a postmortem study of five patients, died of dengue shock syndrome who had markedly elevated liver enzymes and irreparable circulatory failure. Results All were females with a median age of 46 years (range 20–50 years). All had positive NS1 and IgM. Clinically, one patient developed severe degree of hepatic encephalopathy whilst three patients developed uncontrollable bleeding manifestations. Dengue virus was detected in three liver specimens by reverse transcription PCR. Histology of the liver revealed massive necrosis with haemorrhages in these patients with evidence of micro and macrovesicular steatosis with significant periportal inflammatory infiltrate. No significant ischaemic changes or necrosis was observed in the other organs. Conclusions Severe haemorrhagic necrosis of the liver was the cause of death in these patients probably due to direct viral infection. Predilection for severe liver disease remains unknown. Therefore, it is prudent to think beyond plasma leak as the main pathology of dengue infection and attempts should be made to develop other treatment modalities to prevent and manage unforeseen fatal complications of dengue infection.
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Gonçalves D, de Queiroz Prado R, Almeida Xavier E, Cristina de Oliveira N, da Matta Guedes PM, da Silva JS, Moraes Figueiredo LT, Aquino VH. Immunocompetent mice model for dengue virus infection [corrected]. ScientificWorldJournal 2012; 2012:525947. [PMID: 22666132 PMCID: PMC3362018 DOI: 10.1100/2012/525947] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 02/19/2012] [Indexed: 11/23/2022] Open
Abstract
Dengue fever is a noncontagious infectious disease caused by dengue virus (DENV). DENV belongs to the family Flaviviridae, genus Flavivirus, and is classified into four antigenically distinct serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. The number of nations and people affected has increased steadily and today is considered the most widely spread arbovirus (arthropod-borne viral disease) in the world. The absence of an appropriate animal model for studying the disease has hindered the understanding of dengue pathogenesis. In our study, we have found that immunocompetent C57BL/6 mice infected intraperitoneally with DENV-1 presented some signs of dengue disease such as thrombocytopenia, spleen hemorrhage, liver damage, and increase in production of IFNγ and TNFα cytokines. Moreover, the animals became viremic and the virus was detected in several organs by real-time RT-PCR. Thus, this animal model could be used to study mechanism of dengue virus infection, to test antiviral drugs, as well as to evaluate candidate vaccines.
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Affiliation(s)
- Denise Gonçalves
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Monte Alegre, 14049-900 Ribeirao Preto, SP, Brazil.
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Abstract
Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.
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Affiliation(s)
- Henryk Dancygier
- Chair, Department of Medicine II, Klinikum Offenbach, Goethe University Frankfurt/Main, Starkenburgring 66, Offenbach, 63069 Germany
- Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY USA
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Lin CF, Wan SW, Chen MC, Lin SC, Cheng CC, Chiu SC, Hsiao YL, Lei HY, Liu HS, Yeh TM, Lin YS. Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. J Transl Med 2008; 88:1079-89. [PMID: 18679379 DOI: 10.1038/labinvest.2008.70] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease.
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Affiliation(s)
- Chiou-Feng Lin
- Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan
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Ling LM, Wilder-Smith A, Leo YS. Fulminant hepatitis in dengue haemorrhagic fever. J Clin Virol 2007; 38:265-8. [PMID: 17306619 DOI: 10.1016/j.jcv.2006.12.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2006] [Revised: 12/05/2006] [Accepted: 12/13/2006] [Indexed: 12/31/2022]
Abstract
Dengue virus is estimated to cause over 100 million infections throughout the world annually. While dengue infections can have a wide range of infections, atypical manifestations have been described. These involve the central nervous system, cardiac alterations and hepatitis. Here, we highlight a case of dengue haemorrhagic fever (DHF) with fulminant hepatitis. A 55-year-old male was admitted for 16 days, developing severe thrombocytopenia as low as 6x10(9)/L, haematocrit of 48% with transaminitis: ALT: 3,515 U/L, AST: 12,541 U/L, GGT: 1,094 U/L. Subsequent investigations excluded any occult liver lesions, hepatitis A, B and C, Wilson's disease, Epstein-Barr virus and Cytomegalo virus as possible causes. His dengue PCR was positive. His condition subsequently improved with supportive treatment. Liver injury from dengue virus is mediated by its direct infection of hepatocytes and kupffer cells. While mild to moderate elevations of serum aminotransferases (ALT and AST<5X normal) are common in dengue virus infection, liver failure rarely dominate the clinical picture. Liver dysfunction was commoner in DHF, with case reports indicating that severe hepatic dysfunction (ALT and AST>10X normal) was seen with DHF associated with spontaneous bleeding tendencies. Overall prognosis depends on age and other concomitant co-morbidities. We seek to review the literature on dengue infections with hepatitis and discuss issues pertaining to pathophysiology of liver impairment in dengue, the frequency of transaminitis associated with DHF and the overall prognosis.
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Affiliation(s)
- L M Ling
- Department of Infectious Diseases, Communicable Disease Centre, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
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