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Athanasio BDS, Andrade AMDF, Costa VV, Castro JF, Garcia SLM, Teixeira MM, Souza DDG, Vidigal PVT, Lima CX. King's College criteria and the Clichy-Villejuif criteria require adjustments for assessing acute liver failure due to yellow fever. World J Transplant 2025; 15:100413. [DOI: 10.5500/wjt.v15.i1.100413] [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: 08/15/2024] [Revised: 10/03/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a severe condition characterized by rapid deterioration of liver function in individuals without preexisting liver disease. Liver transplantation (LT) is the most impactful treatment. Yellow fever (YF) is an infectious disease that primarily affects the liver and has a high mortality rate. However, LT can be a viable option for treating rare cases with extensive liver involvement. However, the criteria for assessing the severity of ALF and determining the indications for transplantation have not been specifically validated for cases caused by YF.
AIM To present necessary adjustments to established scoring systems for ALF secondary to YF.
METHODS This was an observational, retrospective, single-center study. Fourteen consecutive patients with confirmed ALF due to YF were monitored in the intensive care unit by a specialized liver transplant team during a three-month epidemic outbreak in Brazil. During hospitalization, general supportive therapeutic measures were implemented, and the patients were regularly assessed using the King's College criteria and the Clichy-Villejuif criteria to determine the severity of liver failure. LT is considered a viable measure for patients with signs of end-stage liver failure.
RESULTS Eight of 14 (57%) patients developed severe neurological alterations within the first 96 hours after hospital admission. Four patients underwent emergency LT, and despite a moderate viral infection of the graft after transplantation, the 5-year survival rate was 50%. Although the King's College criteria and the Clichy-Villejuif criteria are the main scoring systems for ALF, they are insufficient for predicting the risk of mortality in this context, primarily because of low serum bilirubin levels in the final stage of the disease and significant disparities between coagulation abnormalities and patient severity.
CONCLUSION To ensure good applicability in cases of YF-induced ALF, the authors suggest adaptations to the King's College and Clichy-Villejuif criteria.
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Affiliation(s)
- Bruno da Silva Athanasio
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | | | - Vivian Vasconcelos Costa
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
| | - Juliano Felix Castro
- Liver Transplantation Unit, Felicio Rocho Hospital, Belo Horizonte 30110-934, Minas Gerais, Brazil
| | | | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
| | - Daniele da Gloria Souza
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
| | | | - Cristiano Xavier Lima
- Department of Surgery, Federal University of Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
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2
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Ho YL, Nukui Y, Villaça PR, Okazaki E, Tatsui NH, Netto LC, Joelsons D, da Rocha TRF, de Mello Malta F, Pinho JRR, Segurado AAC, Rocha V. Intensive Therapeutic Plasma Exchange-New Approach to Treat and Rescue Patients with Severe Form of Yellow Fever. Trop Med Infect Dis 2025; 10:39. [PMID: 39998043 PMCID: PMC11860207 DOI: 10.3390/tropicalmed10020039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Severe yellow fever (YF) can result in acute liver failure (ALF) and high mortality. The role of therapeutic plasma exchange (TPE) in managing YF-ALF remains unclear. This study evaluated the impact of TPE strategies in severe YF. METHODS This observational case-series study evaluated three groups of patients classified according to treatment: G1 (standard intensive care support [ICS]), G2 (ICS + high-volume-TPE [HV-TPE]), and G3 (ICS + intensive TPE). HV-TPE was performed during 3 consecutive days with extra sessions of one plasma-volume, if necessary, whereas intensive TPE consisted of one plasma volume/session performed twice daily, with additional fresh frozen plasma infusion. Hemostatic agents, including tranexamic acid, platelets, and cryoprecipitate, were administered as needed. TPE was de-escalated based on clinical and laboratory parameters. The primary outcome was mortality. RESULTS Sixty-six patients were included (G1: 41, G2: 11, G3: 14). Groups had similar baseline characteristics. Mortality was significantly lower in G3 (14%) compared to G2 (82%) and G1 (85%) (p < 0.001). Additionally, G3 patients showed a higher frequency of undetectable YF viral load. CONCLUSIONS Intensive TPE is a feasible and effective intervention for severe YF, achieving an 84% reduction in mortality. The limitations of our results are the small sample size, observational and single-center study. Further studies are warranted to elucidate intensive TPE's role in YF management.
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Affiliation(s)
- Yeh-Li Ho
- Departamento de Infectologia e Medicina Tropical, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil (D.J.)
| | - Youko Nukui
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Paula Ribeiro Villaça
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Erica Okazaki
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Nelson Hidekazu Tatsui
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Lucas Chaves Netto
- Departamento de Infectologia e Medicina Tropical, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil (D.J.)
| | - Daniel Joelsons
- Departamento de Infectologia e Medicina Tropical, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil (D.J.)
| | - Tania Rubia Flores da Rocha
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Fernanda de Mello Malta
- LIM07, Departamento de Gastroenterologia, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - João Renato Rebello Pinho
- LIM07, Departamento de Gastroenterologia, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | - Aluisio Augusto Cotrim Segurado
- Departamento de Infectologia e Medicina Tropical, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil (D.J.)
| | - Vanderson Rocha
- Serviço de Hematologia, Hemoterapia e Terapia Celular, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
- Fundacao Pro-Sangue, Sao Paulo 05403-000, Brazil
- Churchill Hospital, Oxford University Hospitals, Oxford OX3 7LE, UK
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Gajurel K, Dhakal R, Deresinski S. Arbovirus in Solid Organ Transplants: A Narrative Review of the Literature. Viruses 2024; 16:1778. [PMID: 39599892 PMCID: PMC11599096 DOI: 10.3390/v16111778] [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: 09/29/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
The incidence of arbovirus infections has increased in recent decades. Other than dengue, chikungunya, and West Nile viruses, the data on arbovirus in solid organ transplant (SOT) are limited to case reports, and infections in renal transplant recipients account for most of the reported cases. Dengue and West Nile infections seem to be more severe with higher mortality in SOT patients than in the general population. Acute kidney injury is more frequent in patients with dengue and chikungunya although persistent arthralgia with the latter is less frequent. There is no clear relationship between arboviral infection and acute cellular rejection. Pre-transplant screening of donors should be implemented during increased arboviral activity but, despite donor screening and negative donor nucleic acid amplification test (NAT), donor derived infection can occur. NAT may be transiently positive. IgM tests lack specificity, and neutralizing antibody assays are more specific but not readily available. Other tests, such as immunohistochemistry, antigen tests, PCR, metagenomic assays, and viral culture, can also be performed. There are a few vaccines available against some arboviruses, but live vaccines should be avoided. Treatment is largely supportive. More data on arboviral infection in SOT are needed to understand its epidemiology and clinical course.
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Affiliation(s)
- Kiran Gajurel
- Division of Infectious Diseases, Carolinas Medical Center, Atrium Health, Charlotte, NC 28204, USA
| | | | - Stan Deresinski
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA;
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de Sousa FTG, Warnes CM, Manuli ER, Tjang LV, Carneiro PH, Maria de Oliveira Pinto L, Ng A, Bhat S, Zambrana JV, D'Elia Zanella LGFAB, Ho YL, Romano CM, Beatty PR, Biering SB, Kallas EG, Sabino EC, Harris E. Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1. EBioMedicine 2024; 109:105409. [PMID: 39454515 PMCID: PMC11539239 DOI: 10.1016/j.ebiom.2024.105409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/03/2024] [Accepted: 10/05/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Yellow fever virus (YFV) infections are a major global disease concern with high mortality in humans, and as such it is critical to identify clinical correlates of disease severity. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. METHODS Using serum samples from laboratory-confirmed YF patients with severe (n = 39) or non-severe (n = 18) disease in a well-defined hospital observational cohort in Brazil, plus samples from healthy uninfected controls (n = 11), we investigated factors associated with disease severity and endothelial dysfunction. FINDINGS We found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups, as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels, TEER values, and signs of disease severity. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. INTERPRETATION This study provides further evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans and suggests serum quantification of YFV NS1 and syndecan-1 as valuable tools for disease diagnosis and/or prognosis. FUNDING This work was supported by the US NIH and FAPESP.
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Affiliation(s)
- Francielle T G de Sousa
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA; Departamento de Doenças Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403000, Brazil; Laboratório de Investigação Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil.
| | - Colin M Warnes
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Erika R Manuli
- Departamento de Doenças Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403000, Brazil; Laboratório de Investigação Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil
| | - Laurentia V Tjang
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Pedro H Carneiro
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA.
| | - Luzia Maria de Oliveira Pinto
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA; Laboratório das Interações Vírus-Hospedeiros (LIVH), Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (IOC/Fiocruz), Rio de Janeiro 21040-360, Brazil.
| | - Arash Ng
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720-3200, USA.
| | - Samhita Bhat
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Jose Victor Zambrana
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Luiz G F A B D'Elia Zanella
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil
| | - Yeh-Li Ho
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil.
| | - Camila M Romano
- Departamento de Doenças Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403000, Brazil; Laboratório de Investigação Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil.
| | - P Robert Beatty
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA; Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720-3200, USA.
| | - Scott B Biering
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA
| | - Esper G Kallas
- Departamento de Doenças Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403000, Brazil; Laboratório de Investigação Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil; Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil.
| | - Ester C Sabino
- Departamento de Doenças Infecciosas e Parasitárias, Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403000, Brazil; Laboratório de Investigação Médica, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP 05403000, Brazil.
| | - Eva Harris
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA; Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720-3200, USA.
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THOMAS C, PICHARD C, ROUSSET D, DEMAR M, DJOSSOU F, SANNA A, DUDOGNON L, NACHER M, PUJO JM, MICHAUD C, GAILLET M, KALLEL H, EPELBOIN L. [Fatal case of co-infection with yellow fever virus and SARS-CoV2 during the 2020 Covid-19 pandemic in French Guiana]. MEDECINE TROPICALE ET SANTE INTERNATIONALE 2024; 4:mtsi.v4i3.2024.445. [PMID: 39931723 PMCID: PMC11809067 DOI: 10.48327/mtsi.v4i3.2024.445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 07/22/2024] [Indexed: 02/13/2025]
Abstract
The yellow fever virus (YFV), recently renamed Orthoflavivirus flavi, is an arbovirus of the Flaviviridae family and Orthoflavivirus genus endemic in South America and Tropical Africa. Brazil experienced an epidemic of unprecedented magnitude between 2016 and 2018. The resurgence of new cases in French Guiana in recent years has rekindled interest in the disease. In December 2019, the global pandemic of Covid-19 began and rapidly reached South America. The first cases were reported in French Guiana in March 2020. Many tropical diseases circulate in the region and the possibility of co-infections is therefore high. Here, we report the first case of YF virus-SARS-CoV2 co-infection in a 14-year-old French Amerindian boy who died within nine days. He had received a single dose of YF vaccine in childhood.
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Affiliation(s)
- Caroline THOMAS
- Laboratoire hospitalo-universitaire de parasitologie-mycologie, Centre hospitalier de Cayenne, Guyane. Service de réanimation polyvalente, Centre hospitalier universitaire (CHU) de Guadeloupe
- Unité des maladies infectieuses et tropicales, Centre hospitalier de Cayenne, Guyane
- Service de réanimation polyvalente du CHU de Guadeloupe, Les Abymes, Guadeloupe
| | - Clara PICHARD
- Équipe mobile de santé publique en communes (EMSPEC), Centre hospitalier de Cayenne, Guyane
| | - Dominique ROUSSET
- Laboratoire de virologie, Centre national de référence (CNR) arbovirus, Institut Pasteur de la Guyane, Cayenne, Guyane
| | - Magalie DEMAR
- Laboratoire hospitalo-universitaire de parasitologie-mycologie, Centre hospitalier de Cayenne, Guyane. Service de réanimation polyvalente, Centre hospitalier universitaire (CHU) de Guadeloupe
| | - Félix DJOSSOU
- Unité des maladies infectieuses et tropicales, Centre hospitalier de Cayenne, Guyane
| | - Alice SANNA
- Agence régionale de santé de Guyane, Cayenne, Guyane
- Centre d'investigation clinique, Inserm 1424, CH de Cayenne, Guyane
| | - Lise DUDOGNON
- Équipe mobile de santé publique en communes (EMSPEC), Centre hospitalier de Cayenne, Guyane
| | - Mathieu NACHER
- Centre d'investigation clinique, Inserm 1424, CH de Cayenne, Guyane
| | - Jean-Marc PUJO
- Service d'accueil des urgences et SAMU, CH de Cayenne, Guyane
| | - Céline MICHAUD
- Centres délocalisés de prévention et de soins, CH de Cayenne, Guyane
| | - Mélanie GAILLET
- Équipe mobile de santé publique en communes (EMSPEC), Centre hospitalier de Cayenne, Guyane
- Centres délocalisés de prévention et de soins, CH de Cayenne, Guyane
| | - Hatem KALLEL
- Service de médecine intensive réanimation, CH de Cayenne, Guyane
| | - Loïc EPELBOIN
- Unité des maladies infectieuses et tropicales, Centre hospitalier de Cayenne, Guyane
- Centre d'investigation clinique, Inserm 1424, CH de Cayenne, Guyane
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McSteen BW, Ying XH, Lucero C, Jesudian AB. Viral etiologies of acute liver failure. World J Virol 2024; 13:97973. [PMID: 39323454 PMCID: PMC11401000 DOI: 10.5501/wjv.v13.i3.97973] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/07/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024] Open
Abstract
Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with an estimated annual global incidence of more than one million cases. While drug-induced liver injury, including acetaminophen toxicity, is the leading cause of ALF in the Western world, viral infections remain a significant cause of ALF and the most common cause in many developing nations. Given the high mortality rates associated with ALF, healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis, rapid treatment initiation when possible, and optimal management, which may include liver transplantation. This review aims to provide a summary of viral causes of ALF, diagnostic approaches, treatment options, and expected outcomes.
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Affiliation(s)
- Brian W McSteen
- Department of Medicine, New York-Presbyterian/Weill Cornell Campus, New York, NY 10021, United States
| | - Xiao-Han Ying
- Department of Medicine, New York-Presbyterian/Weill Cornell Campus, New York, NY 10021, United States
| | - Catherine Lucero
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, United States
| | - Arun B Jesudian
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10021, United States
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Gadali KE, Rafya M, El Mansouri AE, Maatallah M, Vanderlee A, Mehdi A, Neyts J, Jochmans D, De Jonghe S, Benkhalti F, Sanghvi YS, Taourirte M, Lazrek HB. Design, synthesis, and molecular modeling studies of novel 2-quinolone-1,2,3-triazole-α-aminophosphonates hybrids as dual antiviral and antibacterial agents. Eur J Med Chem 2024; 268:116235. [PMID: 38377828 DOI: 10.1016/j.ejmech.2024.116235] [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: 12/21/2023] [Revised: 02/01/2024] [Accepted: 02/12/2024] [Indexed: 02/22/2024]
Abstract
With the aim to identify new antiviral agents with antibacterial properties, a series of 2-quinolone-1,2,3-triazole derivatives bearing α-aminophosphonates was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, single crystal XRD and HRMS analyses. These compounds were examined against five RNA viruses (YFV, ZIKV, CHIKV, EV71 and HRV) from three distinct families (Picornaviridae, Togaviridae and Flaviviridae) and four bacterial strains (S. aureus, E. feacalis, E. coli and P. aeruginosa). The α-aminophosphonates 4f, 4i, 4j, 4k, 4p and 4q recorded low IC50 values of 6.8-10.91 μM, along with elevated selectivity indices ranging from 2 to more than 3, particularly against YFV, CHIKV and HRV-B14. Besides, the synthesized compounds were generally more sensitive toward Gram-positive bacteria, with the majority of them displaying significant potency against E. feacalis. Specifically, an excellent anti-enterococcus activity was obtained by compound 4q with MIC and MBC values of 0.03 μmol/mL, which were 8.7 and 10 times greater than those of the reference drugs ampicillin and rifampicin, respectively. Also, compounds 4f, 4p and 4q showed potent anti-staphylococcal activity with MIC values varying between 0.11 and 0.13 μmol/mL, compared to 0.27 μmol/mL for ampicillin. The results from DFT and molecular docking simulations were in agreement with the biological assays, proving the binding capability of hybrids 4f, 4i, 4j, 4k, 4p and 4q with viral and bacterial target enzymes through hydrogen bonds and other non-covalent interactions. The in silico ADME/Tox prediction revealed that these molecules possess moderate to good drug-likeness and pharmacokinetic properties, with a minimal chance of causing liver toxicity or carcinogenic effects.
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Affiliation(s)
- Khadija El Gadali
- Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco; Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco
| | - Meriem Rafya
- Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco
| | - Az-Eddine El Mansouri
- University of the Free State Faculty of Natural and Agricultural Sciences Chemistry Department 205 Nelson Mandela, Bloemfontein, 9301, South Africa
| | - Mohamed Maatallah
- Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco
| | - Arie Vanderlee
- Institut Européen des Membranes, IEM, UMR 5635, Univ. Montpellier, CNRS, ENSCM, 34095 Montpellier, France
| | - Ahmad Mehdi
- ICGM, UMR5253 1919, Route de Mende 34293 Montpellier cedex 5, France
| | - Johan Neyts
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, B-3000 Leuven, Belgium
| | - Dirk Jochmans
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, B-3000 Leuven, Belgium
| | - Steven De Jonghe
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, B-3000 Leuven, Belgium
| | - Fatiha Benkhalti
- Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco
| | - Yogesh S Sanghvi
- Rasayan Inc, 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA
| | - Moha Taourirte
- Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco.
| | - Hassan B Lazrek
- Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco.
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8
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Giugni FR, Aiello VD, Faria CS, Pour SZ, Cunha MDP, Giugni MV, Pinesi HT, Ledesma FL, Morais CE, Ho YL, Sztajnbok J, de Morais Fernezlian S, Ferraz da Silva LF, Mauad T, Ferreira Alves VA, Hilário do Nascimento Saldiva P, Antonangelo L, Dolhnikoff M, Duarte-Neto AN. Understanding yellow fever-associated myocardial injury: an autopsy study. EBioMedicine 2023; 96:104810. [PMID: 37757571 PMCID: PMC10550587 DOI: 10.1016/j.ebiom.2023.104810] [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: 04/16/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF. METHODS This retrospective autopsy study included cases from the São Paulo (Brazil) epidemic of 2017-2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers. FINDINGS Seventy-three confirmed YF cases with a median age of 48 (34-60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p = 0.01) and cardiovascular controls (p < 0.001) in Dunn test. INTERPRETATION Myocardial injury is frequent in severe YF, due to multifactorial mechanisms, including direct YFV-mediated damage, endothelial cell injury, and inflammatory response, with a possible prominent role for IP-10. FUNDING This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo, Bill and Melinda Gates Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.
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Affiliation(s)
- Fernando Rabioglio Giugni
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil; Instituto do Coração InCor, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Vera Demarchi Aiello
- Instituto do Coração InCor, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Caroline Silverio Faria
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Shahab Zaki Pour
- Laboratório de Evolução Molecular e Bioinformática, Instituto de Ciências Biomédicas, Universidade de São Paulo, SP, Brazil
| | - Marielton Dos Passos Cunha
- Laboratório de Evolução Molecular e Bioinformática, Instituto de Ciências Biomédicas, Universidade de São Paulo, SP, Brazil
| | - Melina Valdo Giugni
- Instituto do Coração InCor, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Henrique Trombini Pinesi
- Instituto do Coração InCor, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Felipe Lourenço Ledesma
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Carolina Esteves Morais
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Yeh-Li Ho
- Departamento de Moléstias Infecciosas e Parasitárias, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | | | - Luiz Fernando Ferraz da Silva
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil; Serviço de Verificação de Óbitos da Capital (SVOC), Universidade de São Paulo, São Paulo, SP, Brazil
| | - Thais Mauad
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | | | - Leila Antonangelo
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Marisa Dolhnikoff
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Amaro Nunes Duarte-Neto
- Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
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9
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Ribeiro YP, Falcão LFM, Smith VC, de Sousa JR, Pagliari C, Franco ECS, Cruz ACR, Chiang JO, Martins LC, Nunes JAL, Vilacoert FSDS, Santos LCD, Furlaneto MP, Fuzii HT, Bertonsin Filho MV, da Costa LD, Duarte MIS, Furlaneto IP, Martins Filho AJ, Aarão TLDS, Vasconcelos PFDC, Quaresma JAS. Comparative Analysis of Human Hepatic Lesions in Dengue, Yellow Fever, and Chikungunya: Revisiting Histopathological Changes in the Light of Modern Knowledge of Cell Pathology. Pathogens 2023; 12:pathogens12050680. [PMID: 37242350 DOI: 10.3390/pathogens12050680] [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: 01/12/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Arboviruses, such as yellow fever virus (YFV), dengue virus (DENV), and chikungunya virus (CHIKV), present wide global dissemination and a pathogenic profile developed in infected individuals, from non-specific clinical conditions to severe forms, characterised by the promotion of significant lesions in different organs of the harbourer, culminating in multiple organ dysfunction. An analytical cross-sectional study was carried out via the histopathological analysis of 70 samples of liver patients, collected between 2000 and 2017, with confirmed laboratory diagnoses, who died due to infection and complications due to yellow fever (YF), dengue fever (DF), and chikungunya fever (CF), to characterise, quantify, and compare the patterns of histopathological alterations in the liver between the samples. Of the histopathological findings in the human liver samples, there was a significant difference between the control and infection groups, with a predominance of alterations in the midzonal area of the three cases analysed. Hepatic involvement in cases of YF showed a greater intensity of histopathological changes. Among the alterations evaluated, cell swelling, microvesicular steatosis, and apoptosis were classified according to the degree of tissue damage from severe to very severe. Pathological abnormalities associated with YFV, DENV, and CHIKV infections showed a predominance of changes in the midzonal area. We also noted that, among the arboviruses studied, liver involvement in cases of YFV infection was more intense.
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Affiliation(s)
- Yasmin Pacheco Ribeiro
- Center for Biological and Health Sciences, State University of Pará, Belém 66087-662, PA, Brazil
| | - Luiz Fabio Magno Falcão
- Center for Biological and Health Sciences, State University of Pará, Belém 66087-662, PA, Brazil
| | - Vanessa Cavaleiro Smith
- Section of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | - Jorge Rodrigues de Sousa
- Center for Biological and Health Sciences, State University of Pará, Belém 66087-662, PA, Brazil
| | - Carla Pagliari
- School of Medicine, São Paulo University, São Paulo 01246-903, SP, Brazil
| | | | - Ana Cecília Ribeiro Cruz
- Section of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | - Janniffer Oliveira Chiang
- Section of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | - Livia Carício Martins
- Section of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | - Juliana Abreu Lima Nunes
- Section of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | | | - Lais Carneiro Dos Santos
- Section of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | | | - Hellen Thais Fuzii
- Tropical Medicine Center, Federal University of Pará, Belém 66055-240, PA, Brazil
| | | | - Luccas Delgado da Costa
- Section of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua 67030-000, PA, Brazil
| | | | - Ismari Perini Furlaneto
- Center for Biological and Health Sciences, State University of Pará, Belém 66087-662, PA, Brazil
| | | | | | | | - Juarez Antônio Simões Quaresma
- Center for Biological and Health Sciences, State University of Pará, Belém 66087-662, PA, Brazil
- School of Medicine, São Paulo University, São Paulo 01246-903, SP, Brazil
- Tropical Medicine Center, Federal University of Pará, Belém 66055-240, PA, Brazil
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10
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Ricciardi MJ, Rust LN, Pedreño-Lopez N, Yusova S, Biswas S, Webb GM, Gonzalez-Nieto L, Voigt TB, Louw JJ, Laurino FD, DiBello JR, Raué HP, Barber-Axthelm AM, Chun K, Uttke S, Raphael LMS, Yrizarry-Medina A, Rosen BC, Agnor R, Gao L, Labriola C, Axthelm M, Smedley J, Julander JG, Bonaldo MC, Walker LM, Messaoudi I, Slifka MK, Burton DR, Kallas EG, Sacha JB, Watkins DI, Burwitz BJ. Therapeutic neutralizing monoclonal antibody administration protects against lethal yellow fever virus infection. Sci Transl Med 2023; 15:eade5795. [PMID: 36989376 PMCID: PMC10617428 DOI: 10.1126/scitranslmed.ade5795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 03/10/2023] [Indexed: 03/31/2023]
Abstract
Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a single administration of either of these two potently neutralizing antibodies during acute infection fully controlled viremia and prevented severe disease and death in treated animals. Given the potential severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing YFV cases during outbreaks.
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Affiliation(s)
- Michael J. Ricciardi
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- George Washington University, 2121 I St. NW, Washington, DC 20052, USA
| | - Lauren N. Rust
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Nuria Pedreño-Lopez
- George Washington University, 2121 I St. NW, Washington, DC 20052, USA
- IrsiCaixa AIDS Research Institute, Ctra. del Canyet SN, Badalona 08916, Barcelona, Spain
| | - Sofiya Yusova
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Sreya Biswas
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Gabriela M. Webb
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
| | | | - Thomas B. Voigt
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- George Washington University, 2121 I St. NW, Washington, DC 20052, USA
| | - Johan J. Louw
- George Washington University, 2121 I St. NW, Washington, DC 20052, USA
| | | | - John R. DiBello
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
| | - Hans-Peter Raué
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Aaron M. Barber-Axthelm
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Kimberly Chun
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Samantha Uttke
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Lidiane M. S. Raphael
- Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Brandon C. Rosen
- Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Rebecca Agnor
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Lina Gao
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Caralyn Labriola
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Michael Axthelm
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Jeremy Smedley
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Justin G. Julander
- Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA
| | - Myrna C. Bonaldo
- Laboratório de Biologia Molecular de Flavivírus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Ilhem Messaoudi
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA
| | - Mark K. Slifka
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - Dennis R. Burton
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA 92037, USA
| | - Esper G. Kallas
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- Department of Infectious and Parasitic Diseases, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Jonah B. Sacha
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - David I. Watkins
- Mabloc LLC, 725 21st St. NW, Suite 301, Washington, DC 20052, USA
- George Washington University, 2121 I St. NW, Washington, DC 20052, USA
| | - Benjamin J. Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
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11
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Fernandes EG, Gomes Porto VB, de Oliveira PMN, Duarte-Neto AN, de Sousa Maia MDL, Lignani LK, Nogueira JS, Teixeira GV, Iglezias SD, Blanco RM, Sato HK. Yellow Fever Vaccine-Associated Viscerotropic Disease among Siblings, São Paulo State, Brazil. Emerg Infect Dis 2023; 29:493-500. [PMID: 36823036 PMCID: PMC9973707 DOI: 10.3201/eid2903.220989] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
We describe 5 cases of yellow fever vaccine-associated viscerotropic disease (YEL-AVD) in 2 familial clusters during the 2017-2018 yellow fever (YF) vaccination campaign in São Paulo state, Brazil. The first case was that of a 40-year-old white man who died of icterohemorrhagic syndrome, which was confirmed to be YEL-AVD by using real-time reverse transcription PCR to detect 17DD YF vaccine in the liver. Ten years previously, his brother died of a clinically similar disease without a confirmed diagnosis 9 days after YF vaccination. The second cluster included 3 of 9 siblings in whom hepatitis developed in the first week after receiving fractionated doses of YF vaccine. Two of them died of hemorrhagic diathesis and renal and respiratory failure, and 17DD-YF vaccine was detected in serum samples from all patients and in the liver in 1 case. Genetic factors might play a substantial role in the incidence of YEL-AVD.
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12
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Frassetto FP, Rosemberg S. Neuropathology of yellow fever autopsy cases. Trop Dis Travel Med Vaccines 2023; 9:1. [PMID: 36707912 PMCID: PMC9883951 DOI: 10.1186/s40794-022-00187-1] [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: 06/25/2022] [Accepted: 12/14/2022] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Yellow fever is a viral hemorrhagic fever caused by yellow fever virus, a mosquito-borne flavivirus. Despite an effective vaccine, major outbreaks continue to occur around the world. Even though it is not a proven neurotropic virus, neurological symptoms in more severe clinical forms are frequent. The understanding of this apparent paradox is still rarely addressed in literature. METHODS The brains of thirty-eight patients with yellow fever confirmed by RT-PCR, who underwent autopsy, were analyzed morphologically to identify and characterize neuropathological changes. The data were compared with brains collected from individuals without the disease, as a control group. Both cases and controls were subdivided according to the presence or absence of co-concurrent septic shock, to exclude changes of the sepsis associated encephalopathy. To verify possible morphological differences between the yellow fever cases groups, between the control groups, and between the cases and the controls, we applied the statistical tests Fisher's exact test and chi-square, with p values < 0.05 considered statistically significant. RESULTS All cases and controls presented, at least focally, neuropathological changes, which included edema, meningeal and parenchymal inflammatory infiltrate and hemorrhages, and perivascular inflammatory infiltrate. We did not find an unequivocal aspect of encephalitis. The only parameter that, after statistical analysis, can be attributed to yellow fever was the perivascular inflammatory infiltrate. CONCLUSIONS The neuropathological findings are sufficient to justify the multiple clinical neurologic disturbances detected in the YF cases. Since most of the parameters evaluated did not show statistically significant difference between cases and controls, an explanation for most of the neuropathological findings may be the vascular changes, consequent to shock induced endotheliopathy, associated with stimulation of the immune system inherent to systemic infectious processes. The statistical difference obtained in yellow fever cases regarding perivascular infiltrate can be can be explained by the immune activation inherent to the condition.
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Affiliation(s)
- Fernando Pereira Frassetto
- grid.11899.380000 0004 1937 0722Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, SP Brazil ,grid.261331.40000 0001 2285 7943Present Address: Department of Radiation Oncology, Ohio State University, OH Columbus, United States of America
| | - Sergio Rosemberg
- grid.11899.380000 0004 1937 0722Department of Pathology, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, SP Brazil
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13
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New Insights into the Mechanism of Immune-Mediated Tissue Injury in Yellow Fever: The Role of Immunopathological and Endothelial Alterations in the Human Lung Parenchyma. Viruses 2022; 14:v14112379. [PMID: 36366477 PMCID: PMC9698388 DOI: 10.3390/v14112379] [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: 08/10/2022] [Revised: 09/28/2022] [Accepted: 10/19/2022] [Indexed: 01/31/2023] Open
Abstract
Yellow fever (YF) may cause lesions in different organs. There are no studies regarding the in situ immune response in the human lung and investigating immunopathological aspects in fatal cases can help to better understand the evolution of the infection. Lung tissue samples were collected from 10 fatal cases of human yellow fever and three flavivirus-negative controls who died of other causes and whose lung parenchymal architecture was preserved. In YFV-positive fatal cases, the main histopathological changes included the massive presence of diffuse alveolar inflammatory infiltrate, in addition to congestion and severe hemorrhage. The immunohistochemical analysis of tissues in the lung parenchyma showed significantly higher expression of E-selectin, P-selectin, ICAM-1, VCAM-1 in addition to cytokines such as IL-4, IL-10, IL-13, TNF- α, IFN-γ and TGF-β compared to the negative control. The increase in immunoglobulins ICAM-1 and VCAM-1 results in strengthening of tissue transmigration signaling. E-selectin and P-selectin actively participate in this process of cell migration and formation of the inflammatory infiltrate. IFN-γ and TNF-α participate in the process of cell injury and viral clearance. The cytokines IL-4 and TGF-β, acting in synergism, participate in the process of tissue regeneration and breakdown. The anti-inflammatory cytokines IL-4, IL-10 and IL-13 also act in the reduction of inflammation and tissue repair. Our study indicates that the activation of the endothelium aggravates the inflammatory response by inducing the expression of adhesion molecules and cytokines that contribute to the rolling, recruitment, migration and eliciting of the inflammatory process in the lung parenchyma, contributing to the fatal outcome of the disease.
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14
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de Albuquerque BHDR, de Oliveira MTFC, Aderaldo JF, de Medeiros Garcia Torres M, Lanza DCF. Human seminal virome: a panel based on recent literature. Basic Clin Androl 2022; 32:16. [PMID: 36064315 PMCID: PMC9444275 DOI: 10.1186/s12610-022-00165-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
Background The seminal virome and its implications for fertility remain poorly understood. To date, there are no defined panels for the detection of viruses of clinical interest in seminal samples. Results In this study, we characterized the human seminal virome based on more than 1,000 studies published over the last five years. Conclusions The number of studies investigating viruses that occur in human semen has increased, and to date, these studies have been mostly prospective or related to specific clinical findings. Through the joint analysis of all these studies, we have listed the viruses related to the worsening of seminal parameters and propose a new panel with the main viruses already described that possibly affect male fertility and health. This panel can assist in evaluating semen quality and serve as a tool for investigation in cases of infertility.
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15
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Nastri AC, Duarte-Neto AN, Casadio LVB, Souza WMD, Claro IM, Manuli ER, Selegatto G, Salomão MC, Fialkovitz G, Taborda M, Almeida BLD, Magri MC, Guedes AR, Perdigão Neto LV, Sataki FM, Guimarães T, Mendes-Correa MC, Tozetto-Mendoza TR, Fumagalli MJ, Ho YL, Maia da Silva CA, Coletti TM, Goes de Jesus J, Romano CM, Hill SC, Pybus O, Rebello Pinho JR, Ledesma FL, Casal YR, Kanamura CT, Tadeu de Araújo LJ, Ferreira CSDS, Guerra JM, Figueiredo LTM, Dolhnikoff M, Faria NR, Sabino EC, Alves VAF, Levin AS. Understanding Sabiá virus infections (Brazilian mammarenavirus). Travel Med Infect Dis 2022; 48:102351. [PMID: 35537676 DOI: 10.1016/j.tmaid.2022.102351] [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: 03/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 02/09/2023]
Abstract
BACKGROUND Only two naturally occurring human Sabiá virus (SABV) infections have been reported, and those occurred over 20 years ago. METHODS We diagnosed two new cases of SABV infection using metagenomics in patients thought to have severe yellow fever and described new features of histopathological findings. RESULTS We characterized clinical manifestations, histopathology and analyzed possible nosocomial transmission. Patients presented with hepatitis, bleeding, neurological alterations and died. We traced twenty-nine hospital contacts and evaluated them clinically and by RT-PCR and neutralizing antibodies. Autopsies uncovered unique features on electron microscopy, such as hepatocyte "pinewood knot" lesions. Although previous reports with similar New-World arenavirus had nosocomial transmission, our data did not find any case in contact tracing. CONCLUSIONS Although an apparent by rare, Brazilian mammarenavirus infection is an etiology for acute hemorrhagic fever syndrome. The two fatal cases had peculiar histopathological findings not previously described. The virological diagnosis was possible only by contemporary techniques such as metagenomic assays. We found no subsequent infections when we used serological and molecular tests to evaluate close contacts.
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Affiliation(s)
- Ana Catharina Nastri
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Amaro Nunes Duarte-Neto
- Department of Pathology, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Núcleo de Anatomia Patológica, Instituto Adolfo Lutz, Sao Paulo, Brazil.
| | - Luciana Vilas Boas Casadio
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - William Marciel de Souza
- World Reference Center for Emerging Viruses and Arboviruses and Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
| | - Ingra M Claro
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Erika R Manuli
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Gloria Selegatto
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Matias C Salomão
- Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Gabriel Fialkovitz
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Mariane Taborda
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Bianca Leal de Almeida
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Marcello C Magri
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Ana Rúbia Guedes
- Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Lauro Vieira Perdigão Neto
- Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Fatima Mitie Sataki
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Thais Guimarães
- Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Maria Cassia Mendes-Correa
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | | | - Marcilio Jorge Fumagalli
- Centro de Pesquisa em Virologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
| | - Yeh-Li Ho
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Camila Alves Maia da Silva
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Thaís M Coletti
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Jaqueline Goes de Jesus
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Camila M Romano
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Sarah C Hill
- Department of Zoology, University of Oxford, United Kingdom Department of Pathobiology and Population Sciences, The Royal Veterinary College, United Kingdom; Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom.
| | - Oliver Pybus
- Department of Zoology, University of Oxford, United Kingdom.
| | - João Renato Rebello Pinho
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
| | | | - Yuri R Casal
- Department of Pathology, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | | | | | | | | | - Luiz Tadeu Moraes Figueiredo
- Centro de Pesquisa em Virologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
| | - Marisa Dolhnikoff
- Department of Pathology, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | - Nuno R Faria
- Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Department of Zoology, University of Oxford, United Kingdom; MRC Centre for Global Infectious Disease Analysis, J-IDEA, Imperial College London, London, United Kingdom.
| | - Ester C Sabino
- Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
| | | | - Anna S Levin
- Division of Infectious Diseases, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Department of Infectious Diseases, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Infection Control Department, Hospital das Clínicas, Faculdade de Medicina, Universidade de Sao Paulo, Brazil.
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16
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Arantes MF, Seabra VF, Lins PRG, Rodrigues CE, Reichert BV, Silveira MAD, Li HY, Malbouisson LM, Andrade L. Risk Factors for Acute Kidney Injury and Death in Patients Infected With the Yellow Fever Virus During the 2018 Outbreak in São Paulo, Brazil. Kidney Int Rep 2021; 7:601-609. [PMID: 35257072 PMCID: PMC8897308 DOI: 10.1016/j.ekir.2021.12.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/23/2021] [Accepted: 12/13/2021] [Indexed: 01/10/2023] Open
Abstract
Introduction Methods Results Conclusion
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Affiliation(s)
- Márcia Fernanda Arantes
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Victor Faria Seabra
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Ricardo Gessolo Lins
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Camila Eleuterio Rodrigues
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Bernardo Vergara Reichert
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Ho Yeh Li
- Intensive Care Unit, Department of Infectious and Parasitic Diseases, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz Marcelo Malbouisson
- Division of Anesthesiology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Lúcia Andrade
- Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
- Correspondence: Lúcia Andrade, Division of Nephrology, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 3 andar, sala 3310, São Paulo, SP 01246-903, Brazil.
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17
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Yellow Fever in Transplantation. Curr Infect Dis Rep 2021. [DOI: 10.1007/s11908-021-00761-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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18
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Duarte-Neto AN, Teixeira TA, Caldini EG, Kanamura CT, Gomes-Gouvêa MS, Dos Santos ABG, Monteiro RAA, Pinho JRR, Mauad T, da Silva LFF, Saldiva PHN, Dolhnikoff M, Leite KRM, Hallak J. Testicular pathology in fatal COVID-19: A descriptive autopsy study. Andrology 2021; 10:13-23. [PMID: 34196475 PMCID: PMC8444746 DOI: 10.1111/andr.13073] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Multi-organ damage is a common feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, going beyond the initially observed severe pneumonia. Evidence that the testis is also compromised is growing. OBJECTIVE To describe the pathological findings in testes from fatal cases of COVID-19, including the detection of viral particles and antigens, and inflammatory cell subsets. MATERIALS AND METHODS Postmortem testicular samples were obtained by percutaneous puncture from 11 deceased men and examined by reverse-transcription polymerase chain reaction (RT-PCR) for RNA detection and by light and electron microscopy (EM) for SARS-CoV-2. Immunohistochemistry (IHC) for the SARS-CoV-2 N-protein and lymphocytic and histiocytic markers was also performed. RESULTS Eight patients had mild interstitial orchitis, composed mainly of CD68+ and TCD8+ cells. Fibrin thrombi were detected in five cases. All cases presented congestion, interstitial edema, thickening of the tubular basal membrane, decreased Leydig and Sertoli cells with reduced spermatogenesis, and strong expression of vascular cell adhesion molecule (VCAM) in vessels. IHC detected SARS-Cov-2 antigen in Leydig cells, Sertoli cells, spermatogonia, and fibroblasts in all cases. EM detected viral particles in the cytoplasm of fibroblasts, endothelium, Sertoli and Leydig cells, spermatids, and epithelial cells of the rete testis in four cases, while RT-PCR detected SARS-CoV-2 RNA in three cases. DISCUSSION AND CONCLUSION The COVID-19-associated testicular lesion revealed a combination of orchitis, vascular changes, basal membrane thickening, Leydig and Sertoli cell scarcity, and reduced spermatogenesis associated with SARS-CoV-2 local infection that may impair hormonal function and fertility in men.
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Affiliation(s)
- Amaro N Duarte-Neto
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Instituto Adolfo Lutz, São Paulo, Brazil
| | - Thiago A Teixeira
- Departamento de Cirurgia, Disciplina de Urologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Elia G Caldini
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - Michele S Gomes-Gouvêa
- Departamento de Gastroenterologia (LIM-07), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Angela B G Dos Santos
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Renata A A Monteiro
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - João R R Pinho
- Departamento de Gastroenterologia (LIM-07), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Thais Mauad
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Luiz F F da Silva
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Serviço de Verificação de Óbitos da Capital, Universidade de São Paulo, São Paulo, Brazil
| | - Paulo H N Saldiva
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marisa Dolhnikoff
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Katia R M Leite
- Departamento de Cirurgia, Disciplina de Urologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Jorge Hallak
- Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Departamento de Cirurgia, Disciplina de Urologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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19
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Neves YCS, de Castro-Lima VAC, Solla DJF, Ogata VSDM, Pereira FL, Araujo JM, Nastri ACS, Ho YL, Chammas MC. Staging liver fibrosis after severe yellow fever with ultrasound elastography in Brazil: A six-month follow-up study. PLoS Negl Trop Dis 2021; 15:e0009594. [PMID: 34283826 PMCID: PMC8323872 DOI: 10.1371/journal.pntd.0009594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 07/30/2021] [Accepted: 06/24/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Yellow fever (YF) is a hemorrhagic disease caused by an arbovirus endemic in South America, with recent outbreaks in the last years. Severe cases exhibit fulminant hepatitis, but there are no studies regarding its late-term effects on liver parenchyma. Thus, the aim of this study was to determine the frequency and grade of liver fibrosis in patients who recovered from severe YF and to point out potential predictors of this outcome. METHODOLOGY/PRINCIPAL FINDINGS We followed-up 18 patients who survived severe YF during a recent outbreak (January-April 2018) in Brazil using ultrasound (US) with shear-wave elastography (SWE) at 6 months after symptoms onset. No patient had previous history of liver disease. Median liver stiffness (LS) was 5.3 (4.6-6.4) kPa. 2 (11.1%) patients were classified as Metavir F2, 1 (8.3%) as F3 and 1 (8.3%) as F4; these two last patients had features of cardiogenic liver congestion on Doppler analysis. Age and cardiac failure were associated with increased LS (p = 0.036 and p = 0.024, respectively). SAPS-3 at ICU admission showed a tendency of association with significant fibrosis (≥ F2; p = 0.053). 7 patients used sofosbuvir in a research protocol, of which none showed liver fibrosis (p = 0.119). CONCLUSIONS/SIGNIFICANCE We found a low frequency of liver fibrosis in severe YF survivors. US with SWE may have a role in the follow up of patients of age and / or with comorbidities after hospital discharge in severe YF, a rare but reemergent disease.
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Affiliation(s)
- Yuri Costa Sarno Neves
- Radiology Institute, Department of Radiology and Oncology, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | | | - Davi Jorge Fontoura Solla
- Department of Neurology, Division of Neurosurgery, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Vivian Simone de Medeiros Ogata
- Radiology Institute, Department of Radiology and Oncology, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Fernando Linhares Pereira
- Radiology Institute, Department of Radiology and Oncology, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Jordana Machado Araujo
- Department and Division of Infectious and Parasitic Diseases, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Ana Catharina Seixas Nastri
- Department and Division of Infectious and Parasitic Diseases, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Yeh-Li Ho
- Department and Division of Infectious and Parasitic Diseases, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
| | - Maria Cristina Chammas
- Radiology Institute, Department of Radiology and Oncology, Hospital das Clinicas HCFMUSP, University of Sao Paulo, São Paulo, Brazil
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20
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Fernandes NCCDA, Cunha MS, Guerra JM, Diaz-Delgado J, Ressio RA, Cirqueira CS, Kanamura CT, Fuentes-Castillo D, Catão-Dias JL. Yellow Fever as Cause of Death of Titi Monkeys ( Callicebus Spp.). Vet Pathol 2021; 58:730-735. [PMID: 33955292 DOI: 10.1177/03009858211009781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
From 2016 to 2018, an epidemic wave of yellow fever (YF) occurred in Brazil, affecting a large number of Platyrrhini monkeys. Titi monkeys (Callicebus spp.) were severely affected yet pathological characterizations are lacking. This study characterized epizootic YF in 43 titi monkeys (Callicebus spp.) with respect to the microscopic lesions in liver, kidney, spleen, heart, brain, and lung, as well as the distribution of immunolabeling for YF virus antigen, and the flaviviral load in the liver. Of 43 titi monkeys examined, 18 (42%) were positive for yellow fever virus (YFV) by immunohistochemistry or reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Affected livers had consistent marked panlobular necrotizing hepatitis, lipidosis, and mild inflammation, with intense immunolabeling for YFV mainly in centrilobular hepatocytes (zone 1; P = .05). In the spleen, consistent findings were variable lymphoid depletion (10/11), lymphoid necrosis (lymphocytolysis; 4/11), and immunolabeling for YFV in histiocytic cells (3/16). The main finding in the kidney was multifocal acute necrosis of tubular epithelium (5/7) that was occasionally associated with intracytoplasmic immunolabeling for YFV (6/15). These data indicate that titi monkeys are susceptible to YFV infection, developing severe hepatic lesions and high viral loads, comparable to humans and Alouatta spp. Thus, Callicebus spp. may be reliable sentinels for YF surveillance.
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Affiliation(s)
| | | | | | - Josué Diaz-Delgado
- 117328Texas A&M Veterinary Medical Diagnostic Laboratory, College Station, TX, USA
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21
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Ultrasound Findings and Laboratory Predictors of Early Mortality in Patients With Severe Yellow Fever. AJR Am J Roentgenol 2021; 216:1392-1399. [PMID: 33703928 DOI: 10.2214/ajr.20.23455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE. Yellow fever is a hemorrhagic disease caused by an arbovirus endemic in South America; outbreaks have occurred in recent years. The purpose of this study was to describe abdominal ultrasound findings in patients with severe yellow fever and correlate them with clinical and laboratory data. MATERIALS AND METHODS. A retrospective cohort study was performed between January and April 2018. The subjects were patients admitted to an ICU with polymerase chain reaction-confirmed yellow fever. Bedside sonography was performed within 48 hours of admission. Images were independently analyzed by two board-certified radiologists. Laboratory test samples were collected within 12 hours of image acquisition. Multivariable logistic regression analysis was performed to identify 30-day mortality predictors; p < .05 was considered statistically significant. RESULTS. Forty-six patients (40 [87%] men, six [13%] women; mean age, 47.5 ± 15.2 years) were evaluated with bedside sonography. Laboratory tests showed high serum levels of aspartate aminotransferase (5319 U/L), total bilirubin (6.2 mg/dL), and creati-nine (4.3 mg/dL). Twenty-six (56.5%) patients died within 30 days of admission (median time to death, 5 days [interquartile range, 2-9 days]). The most frequent ultrasound findings were gallbladder wall thickening (80.4%), increased renal cortex echogenicity (71.7%), increased liver parenchyma echogenicity (65.2%), perirenal fluid (52.2%), and ascites (30.4%). Increased renal echogenicity was associated with 30-day mortality (84.6% versus 55.0%; p = .046) and was an independent predictor of this outcome after multivariate analysis (odds ratio, 10.89; p = .048). CONCLUSION. Reproducible abdominal ultrasound findings in patients with severe yellow fever may be associated with severity of disease and prognosis among patients treated in the ICU.
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22
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Zhou D, Yang F, Lin L, Tang L, Li L, Yang Y, Liu D, Zhang C, Wu T, Wei H, Zhang X, Zhang L. The sirtuin 1 activator SRT1720 alleviated endotoxin-induced fulminant hepatitis in mice. Exp Anim 2021; 70:302-310. [PMID: 33678756 PMCID: PMC8390304 DOI: 10.1538/expanim.20-0014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The metabolic sensor sirtuin 1 (SIRT1) also functions as a checkpoint in inflammation, and SRT1720 is a highly active and selective SIRT1 activator shown to
alleviate inflammatory injury in several recent experimental studies. In the present study, the potential effects and underlying mechanisms of SRT1720 on
lipopolysaccharide (LPS)-induced fulminant hepatitis in D-galactosamine (D-Gal)-sensitized mice were investigated. The results indicated that treatment with
SRT1720 inhibited LPS/D-Gal-induced elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated the histological abnormalities,
suppressed the induction of tumor necrosis factor alpha (TNF-α) and IL-6, mitigated the phosphorylation of c-Jun N-terminal kinase (JNK), downregulated the
activities of caspase 8, caspase 9 and caspase 3, decreased the level of cleaved caspase 3, reduced the TUNEL-positive cells, and improved the survival rate of
the LPS/D-Gal-exposed mice. These data indicated that treatment with the SIRT1 activator SRT1720 alleviated LPS/D-Gal-induced fulminant hepatitis, which might
be attributed to the suppressive effects of SRT1720 on TNF-α production and the subsequent activation of the apoptosis cascade.
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Affiliation(s)
- Dan Zhou
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Feng Yang
- Department of Gynaecology and Obstetrics, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Ling Lin
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Li Tang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Longjiang Li
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Yongqiang Yang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
| | - Dingrong Liu
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Chong Zhang
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Tong Wu
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Huijie Wei
- Department of Pathology, Fuling Central Hospital, 2 Gaosuntang Road, Chongqing 408099, P.R. China
| | - Xiaoming Zhang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, 188 Tanhualin Road, Wuhan 430061, P.R. China.,Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, 188 Tanhualin Road, Wuhan 430061, P.R. China
| | - Li Zhang
- Department of Pathophysiology, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China.,Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, 1 Yixueyuan Road, Chongqing 400016, P.R. China
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23
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Santos DOD, de Oliveira AR, de Lucena FP, de Mattos SA, de Carvalho TP, Costa FB, Moreira LGA, Paixão TAD, Santos RL. Histopathologic Patterns and Susceptibility of Neotropical Primates Naturally Infected With Yellow Fever Virus. Vet Pathol 2020; 57:681-686. [PMID: 32783517 DOI: 10.1177/0300985820941271] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Yellow fever is an important zoonotic viral disease that can be fatal for both human and nonhuman primates. We evaluated histopathologic changes in free-ranging neotropical primates naturally infected with yellow fever virus (YFV) compared with uninfected cohorts. The most frequent lesions in primates infected with YFV were hepatic changes characterized by midzonal necrosis with lipidosis and mild inflammation including lymphocytes, macrophages, plasma cells, and infrequently neutrophils. Importantly, severe necrotizing hepatic lesions were often observed in Alouatta sp. (howler monkeys), whereas Callithrix sp. (common marmosets) had nearly no hepatic changes. Moderate to severe hepatic necrosis was present in 21/23 (91%) of the YFV-positive Alouatta sp. compared with 10/29 (34%) of the YFV-positive Callithrix sp. (P < .0001; odds ratio = 20). Similarly, hepatitis was more intense in Alouatta sp. compared with Callithrix sp. Furthermore, the frequency of YFV infection was significantly higher in Alouatta sp. compared with Callithrix sp. or Sapajus sp. (capuchin monkeys). Therefore, these data support the notion that Alouatta sp. is highly susceptible to infection and YFV-induced lesions, whereas Callithrix sp. is susceptible to infection but has a lower frequency of YFV-induced lesions.
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24
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Lemos FDO, França A, Lima Filho ACM, Florentino RM, Santos ML, Missiaggia DG, Rodrigues GOL, Dias FF, Souza Passos IB, Teixeira MM, Andrade AMDF, Lima CX, Vidigal PVT, Costa VV, Fonseca MC, Nathanson MH, Leite MF. Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection. Hepatol Commun 2020; 4:657-669. [PMID: 32363317 PMCID: PMC7193135 DOI: 10.1002/hep4.1504] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/18/2022] Open
Abstract
Yellow fever (YF) is a viral hemorrhagic fever that typically involves the liver. Brazil recently experienced its largest recorded YF outbreak, and the disease was fatal in more than a third of affected individuals, mostly because of acute liver failure. Affected individuals are generally treated only supportively, but during the recent Brazilian outbreak, selected patients were treated with liver transplant. We took advantage of this clinical experience to better characterize the clinical and pathological features of YF-induced liver failure and to examine the mechanism of hepatocellular injury in YF, to identify targets that would be amenable to therapeutic intervention in preventing progression to liver failure and death. Patients with YF liver failure rapidly developed massive transaminase elevations, with jaundice, coagulopathy, thrombocytopenia, and usually hepatic encephalopathy, along with pathological findings that included microvesicular steatosis and lytic necrosis. Hepatocytes began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium (Ca2+) channel that is not normally expressed in hepatocytes. Experiments in an animal model, isolated hepatocytes, and liver-derived cell lines showed that this new expression of ITPR3 was associated with increased nuclear Ca2+ signaling and hepatocyte proliferation, and reduced steatosis and cell death induced by the YF virus. Conclusion: Yellow fever often induces liver failure characterized by massive hepatocellular damage plus steatosis. New expression of ITPR3 also occurs in YF-infected hepatocytes, which may represent an endogenous protective mechanism that could suggest approaches to treat affected individuals before they progress to liver failure, thereby decreasing the mortality of this disease in a way that does not rely on the costly and limited resource of liver transplantation.
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Affiliation(s)
| | - Andressa França
- Department of Physiology and BiophysicsUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | | | - Rodrigo M. Florentino
- Department of Physiology and BiophysicsUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | - Marcone Loiola Santos
- Department of Physiology and BiophysicsUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | - Dabny G. Missiaggia
- Department of Physiology and BiophysicsUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | | | - Felipe Ferraz Dias
- Center of MicroscopyUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | | | - Mauro M. Teixeira
- Department of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | | | - Cristiano Xavier Lima
- Hepatic Transplant ServiceHospital Felício RochoBelo HorizonteBrazil
- SurgeryUniversidade Federal de Minas GeraisBelo HorizonteBrazil
| | | | | | - Matheus Castro Fonseca
- Brazilian Biosciences National Laboratory (LNBio)Brazilian Center for Research in Energy and MaterialsRua Giuseppe Máximo ScolfaroCampinasBrazil
| | - Michael H. Nathanson
- Section of Digestive DiseasesDepartment of Internal MedicineYale University School of MedicineNew HavenCT
| | - M. Fatima Leite
- Department of Physiology and BiophysicsUniversidade Federal de Minas GeraisBelo HorizonteBrazil
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25
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Sorgi S, Bonezi V, Dominguez MR, Gimenez AM, Dobrescu I, Boscardin S, Nakaya HI, Bargieri DY, Soares IS, Silveira ELV. São Paulo School of Advanced Sciences on Vaccines: an overview. J Venom Anim Toxins Incl Trop Dis 2020; 26:e20190061. [PMID: 32362926 PMCID: PMC7187638 DOI: 10.1590/1678-9199-jvatitd-2019-0061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 02/21/2020] [Indexed: 01/08/2023] Open
Abstract
Two years ago, we held an exciting event entitled the São Paulo School of Advanced Sciences on Vaccines (SPSASV). Sixty-eight Ph.D. students, postdoctoral fellows and independent researchers from 37 different countries met at the Mendes Plaza Hotel located in the city of Santos, SP - Brazil to discuss the challenges and the new frontiers of vaccinology. The SPSASV provided a critical and comprehensive view of vaccine research from basics to the current state-of-the-art techniques performed worldwide. For 10 days, we discussed all the aspects of vaccine development in 36 lectures, 53 oral presentations and 2 poster sessions. At the end of the course, participants were further encouraged to present a model of a grant proposal related to vaccine development against individual pathogens. Among the targeted pathogens were viruses (Chikungunya, HIV, RSV, and Influenza), bacteria (Mycobacterium tuberculosis and Streptococcus pyogenes), parasites (Plasmodium falciparum or Plasmodium vivax), and the worm Strongyloides stercoralis. This report highlights some of the knowledge shared at the SPSASV.
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Affiliation(s)
- Sara Sorgi
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
- Dipartimento di Biotecnologie Mediche, Universita’ degli Studi di Siena, Siena, Italia
| | - Vivian Bonezi
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Mariana R. Dominguez
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Alba Marina Gimenez
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Irina Dobrescu
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Silvia Boscardin
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Helder I. Nakaya
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Daniel Y. Bargieri
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Irene S. Soares
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Eduardo L. V. Silveira
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
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26
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Avelino-Silva VI, Figueiredo-Mello C, Casadio LVB, Nastri ACSS, Marcilio I, Ribeiro AF, Levin AS, Sabino EC. Confronting the Multidimensional Challenges of Research in the Context of Emerging Infectious Diseases in Brazil: The Example of Yellow Fever. Am J Trop Med Hyg 2020; 103:38-40. [PMID: 32228776 DOI: 10.4269/ajtmh.19-0559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
In the most recent Brazilian yellow fever (YF) outbreak, a group of clinicians and researchers initiated in mid-January 2018 a considerable effort to develop a multicenter randomized controlled clinical trial to evaluate the effect of sofosbuvir on YF viremia and clinical outcomes (Brazilian Clinical Trials Registry: RBR-93dp9n). The approval of this protocol had urgency given the seasonal/short-lived pattern of YF transmission, large number of human cases, and epidemic transmission at the outskirts of a large urban center. However, many intricacies in the research regulatory and ethical submission systems in Brazil were indomitable even under such pressing conditions. By April 2018, we had enrolled 29 patients for a target sample size of 90 participants. Had enrollment been initiated 3 weeks earlier, an additional 31 patients could have been enrolled, reaching the prespecified sample size for the interim analysis. This recent experience highlights the urgent need to improve local preparedness for research in the setting of explosive outbreaks, as has been seen in the last few years in different countries.
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Affiliation(s)
| | - Claudia Figueiredo-Mello
- Instituto de Infectologia Emílio Ribas, Faculdade de Medicina da Universidade de Sao Paulo, São Paulo, Brazil
| | | | - Ana C S S Nastri
- Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Izabel Marcilio
- Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ana F Ribeiro
- Instituto de Infectologia Emílio Ribas, São Paulo, Brazil
| | - Anna S Levin
- Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ester C Sabino
- Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
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Disease Resurgence, Production Capability Issues and Safety Concerns in the Context of an Aging Population: Is There a Need for a New Yellow Fever Vaccine? Vaccines (Basel) 2019; 7:vaccines7040179. [PMID: 31717289 PMCID: PMC6963298 DOI: 10.3390/vaccines7040179] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/28/2019] [Accepted: 11/05/2019] [Indexed: 12/19/2022] Open
Abstract
Yellow fever is a potentially fatal, mosquito-borne viral disease that appears to be experiencing a resurgence in endemic areas in Africa and South America and spreading to non-endemic areas despite an effective vaccine. This trend has increased the level of concern about the disease and the potential for importation to areas in Asia with ecological conditions that can sustain yellow fever virus transmission. In this article, we provide a broad overview of yellow fever burden of disease, natural history, treatment, vaccine, prevention and control initiatives, and vaccine and therapeutic agent development efforts.
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Sekhawat V, Lucas SB. Re-emergent yellow fever: new faces of an old killer. Histopathology 2019; 75:636-637. [PMID: 31643117 DOI: 10.1111/his.13939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 06/10/2019] [Indexed: 12/23/2022]
Affiliation(s)
- Vivek Sekhawat
- St Barts and The Royal London Hospital, Bartshealth Trust London, London, UK
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Duarte-Neto AN. Pathology of infectious diseases: new agents, opportunistic, neglectable, emergent, reemergent diseases and why not super resistant nosocomial bacteria? AUTOPSY AND CASE REPORTS 2019; 9:e2019126. [PMID: 31641650 PMCID: PMC6768261 DOI: 10.4322/acr.2019.126] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Indexed: 01/05/2023] Open
Affiliation(s)
- Amaro Nunes Duarte-Neto
- Universidade de São Paulo (USP), Faculty of Medicine, Hospital das Clínicas. São Paulo, SP, Brazil
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30
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Kallas EG, Wilder-Smith A. Managing severe yellow fever in the intensive care: lessons learnt from Brazil. J Travel Med 2019; 26:5513107. [PMID: 31180486 PMCID: PMC6621914 DOI: 10.1093/jtm/taz043] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 11/13/2022]
Affiliation(s)
- E G Kallas
- Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paolo, Brazil
| | - A Wilder-Smith
- Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.,Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, Germany
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