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1.
Cell ; 162(4): 738-50, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26276630

RESUMEN

The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. VIDEO ABSTRACT.


Asunto(s)
Genoma Viral , Fiebre de Lassa/virología , Virus Lassa/genética , ARN Viral/genética , África Occidental/epidemiología , Animales , Evolución Biológica , Reservorios de Enfermedades , Ebolavirus/genética , Variación Genética , Glicoproteínas/genética , Fiebre Hemorrágica Ebola/virología , Humanos , Fiebre de Lassa/epidemiología , Fiebre de Lassa/transmisión , Virus Lassa/clasificación , Virus Lassa/fisiología , Murinae/genética , Mutación , Nigeria/epidemiología , Proteínas Virales/genética , Zoonosis/epidemiología , Zoonosis/virología
2.
N Engl J Med ; 371(22): 2092-100, 2014 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-25353969

RESUMEN

BACKGROUND: Limited clinical and laboratory data are available on patients with Ebola virus disease (EVD). The Kenema Government Hospital in Sierra Leone, which had an existing infrastructure for research regarding viral hemorrhagic fever, has received and cared for patients with EVD since the beginning of the outbreak in Sierra Leone in May 2014. METHODS: We reviewed available epidemiologic, clinical, and laboratory records of patients in whom EVD was diagnosed between May 25 and June 18, 2014. We used quantitative reverse-transcriptase-polymerase-chain-reaction assays to assess the load of Ebola virus (EBOV, Zaire species) in a subgroup of patients. RESULTS: Of 106 patients in whom EVD was diagnosed, 87 had a known outcome, and 44 had detailed clinical information available. The incubation period was estimated to be 6 to 12 days, and the case fatality rate was 74%. Common findings at presentation included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness (in 60%), diarrhea (in 51%), abdominal pain (in 40%), and vomiting (in 34%). Clinical and laboratory factors at presentation that were associated with a fatal outcome included fever, weakness, dizziness, diarrhea, and elevated levels of blood urea nitrogen, aspartate aminotransferase, and creatinine. Exploratory analyses indicated that patients under the age of 21 years had a lower case fatality rate than those over the age of 45 years (57% vs. 94%, P=0.03), and patients presenting with fewer than 100,000 EBOV copies per milliliter had a lower case fatality rate than those with 10 million EBOV copies per milliliter or more (33% vs. 94%, P=0.003). Bleeding occurred in only 1 patient. CONCLUSIONS: The incubation period and case fatality rate among patients with EVD in Sierra Leone are similar to those observed elsewhere in the 2014 outbreak and in previous outbreaks. Although bleeding was an infrequent finding, diarrhea and other gastrointestinal manifestations were common. (Funded by the National Institutes of Health and others.).


Asunto(s)
Ebolavirus/genética , Epidemias , Fiebre Hemorrágica Ebola/epidemiología , Dolor Abdominal , Adulto , Animales , Diarrea , Ebolavirus/aislamiento & purificación , Femenino , Fiebre , Fiebre Hemorrágica Ebola/complicaciones , Fiebre Hemorrágica Ebola/terapia , Fiebre Hemorrágica Ebola/virología , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sierra Leona/epidemiología , Carga Viral , Vómitos
3.
J Infect Dis ; 214(suppl 3): S203-S209, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27521365

RESUMEN

BACKGROUND: The 2013-2016 West African Ebola virus disease (EVD) epidemic is the largest recorded. Triage on the basis of clinical signs had limited success, and the time to diagnosis by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) could exceed 5 days. Here we describe the development and field validation of the ReEBOV Antigen Rapid Test (ReEBOV RDT) to aid triage of individuals with suspected EVD. METHODS: Samples from patients with suspected EVD were submitted to Kenema Government Hospital, Sierra Leone, for Lassa fever and EVD screening throughout 2014. Banked residual clinical samples were tested in November 2014 and January 2015 in a blinded field trial to estimate the clinical effectiveness of the ReEBOV RDT, compared with EBOV-specific qRT-PCR. RESULTS: Preliminary ReEBOV RDT performance demonstrated a positive percentage agreement (PPA) of 91.1% (195 of 214 results; 95% confidence interval [CI], 86.5%-94.6%) and a negative percentage agreement (NPA) of 90.2% (175 of 194; 95% CI, 85.1%-94.0%). The final estimates used by the Food and Drug Administration to determine whether to grant emergency use authorization for the test, which excluded a qRT-PCR reference method threshold cutoff, were a PPA of 62.1% (72 of 116 results; 95% CI, 52.6%-70.9%) and a NPA of 96.7% (58 of 60; 95% CI, 88.5%-99.6%), with a diagnostic likelihood of 18.6. A subsequent, independent evaluation by the World Health Organization generated results consistent with the preliminary performance estimates. CONCLUSIONS: The ReEBOV RDT demonstrated the potential to provide clinically effective rapid and accurate point-of-care test results and, thus, to be a powerful tool for increasing triage efficiency.


Asunto(s)
Antígenos Virales/sangre , Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/diagnóstico , Inmunoensayo/métodos , Sistemas de Atención de Punto , Ebolavirus/genética , Ebolavirus/aislamiento & purificación , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/virología , Hospitales , Humanos , ARN Viral/sangre , Juego de Reactivos para Diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sierra Leona
4.
J Infect Dis ; 214(suppl 3): S110-S121, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27402779

RESUMEN

BACKGROUND: Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013-2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. METHODS: Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities. RESULTS: Augustine Goba, director of the KGH Lassa laboratory, diagnosed the first documented case of EVD in Sierra Leone, on 25 May 2014. Thereafter, KGH received and cared for numbers of patients with EVD that quickly overwhelmed the capacity for safe management. Numerous healthcare workers contracted and lost their lives to EVD. The vast majority of subsequent EVD cases in West Africa can be traced back to a single transmission chain that includes this first diagnosed case. CONCLUSIONS: Responding to the challenges of confronting 2 hemorrhagic fever viruses will require continued investments in the development of countermeasures (vaccines, therapeutic agents, and diagnostic assays), infrastructure, and human resources.


Asunto(s)
Brotes de Enfermedades , Ebolavirus/aislamiento & purificación , Genoma Viral/genética , Fiebre Hemorrágica Ebola/epidemiología , Fiebre de Lassa/epidemiología , Virus Lassa/aislamiento & purificación , Adolescente , Adulto , África Occidental/epidemiología , Niño , Preescolar , Ebolavirus/genética , Monitoreo Epidemiológico , Femenino , Genómica , Guinea/epidemiología , Fiebre Hemorrágica Ebola/diagnóstico , Fiebre Hemorrágica Ebola/transmisión , Fiebre Hemorrágica Ebola/virología , Humanos , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/transmisión , Fiebre de Lassa/virología , Virus Lassa/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Sierra Leona/epidemiología , Adulto Joven
5.
Virol J ; 8: 314, 2011 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-21689444

RESUMEN

Lassa fever is a neglected tropical disease with a significant impact on the health care system of endemic West African nations. To date, case reports of Lassa fever have focused on laboratory characterisation of serological, biochemical and molecular aspects of the disease imported by infected individuals from Western Africa to the United States, Canada, Europe, Japan and Israel. Our report presents the first comprehensive real time diagnosis and characterization of a severe, hemorrhagic Lassa fever case in a Sierra Leonean individual admitted to the Kenema Government Hospital Lassa Fever Ward. Fever, malaise, unresponsiveness to anti-malarial and antibiotic drugs, followed by worsening symptoms and onset of haemorrhaging prompted medical officials to suspect Lassa fever. A recombinant Lassa virus protein based diagnostic was employed in diagnosing Lassa fever upon admission. This patient experienced a severe case of Lassa hemorrhagic fever with dysregulation of overall homeostasis, significant liver and renal system involvement, the interplay of pro- and anti-inflammatory cytokines during the course of hospitalization and an eventual successful outcome. These studies provide new insights into the pathophysiology and management of this viral illness and outline the improved infrastructure, research and real-time diagnostic capabilities within LASV endemic areas.


Asunto(s)
Fiebre de Lassa/diagnóstico , Fiebre de Lassa/patología , Virus Lassa/aislamiento & purificación , Adulto , Anciano , Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , Creación de Capacidad , Niño , Técnicas de Laboratorio Clínico/métodos , Trazado de Contacto , Femenino , Humanos , Inmunoensayo/métodos , Masculino , Embarazo , Sierra Leona , Resultado del Tratamiento , Adulto Joven
6.
Virol J ; 8: 404, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21843352

RESUMEN

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion.


Asunto(s)
Inmunoensayo , Fiebre de Lassa , Virus Lassa/genética , Complicaciones Infecciosas del Embarazo/virología , Ribavirina/administración & dosificación , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/inmunología , Antígenos Virales/análisis , Antígenos Virales/inmunología , Estudios de Casos y Controles , Citocinas/análisis , Citocinas/biosíntesis , Femenino , Muerte Fetal , Variación Genética , Humanos , Inyecciones Intravenosas , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/tratamiento farmacológico , Fiebre de Lassa/epidemiología , Fiebre de Lassa/inmunología , Fiebre de Lassa/virología , Virus Lassa/inmunología , Virus Lassa/aislamiento & purificación , Reacción en Cadena de la Polimerasa , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/mortalidad , Tercer Trimestre del Embarazo , Salud Pública , ARN Viral/análisis , Ribavirina/uso terapéutico , Sierra Leona/epidemiología , Adulto Joven
7.
Sci Rep ; 8(1): 5939, 2018 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-29651117

RESUMEN

Lassa fever, a hemorrhagic fever caused by Lassa virus (LASV), is endemic in West Africa. It is difficult to distinguish febrile illnesses that are common in West Africa from Lassa fever based solely on a patient's clinical presentation. The field performance of recombinant antigen-based Lassa fever immunoassays was compared to that of quantitative polymerase chain assays (qPCRs) using samples from subjects meeting the case definition of Lassa fever presenting to Kenema Government Hospital in Sierra Leone. The recombinant Lassa virus (ReLASV) enzyme-linked immunosorbant assay (ELISA) for detection of viral antigen in blood performed with 95% sensitivity and 97% specificity using a diagnostic standard that combined results of the immunoassays and qPCR. The ReLASV rapid diagnostic test (RDT), a lateral flow immunoassay based on paired monoclonal antibodies to the Josiah strain of LASV (lineage IV), performed with 90% sensitivity and 100% specificity. ReLASV immunoassays performed better than the most robust qPCR currently available, which had 82% sensitivity and 95% specificity. The performance characteristics of recombinant antigen-based Lassa virus immunoassays indicate that they can aid in the diagnosis of LASV Infection and inform the clinical management of Lassa fever patients.


Asunto(s)
Anticuerpos Antivirales/inmunología , Antígenos Virales/aislamiento & purificación , Fiebre de Lassa/diagnóstico , Virus Lassa/aislamiento & purificación , África Occidental , Anticuerpos Antivirales/genética , Antígenos Virales/genética , Humanos , Inmunoensayo/métodos , Inmunoglobulina M/inmunología , Fiebre de Lassa/inmunología , Fiebre de Lassa/virología , Virus Lassa/inmunología , Virus Lassa/patogenicidad , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Sierra Leona , Estudios de Validación como Asunto
8.
Science ; 345(6202): 1369-72, 2014 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-25214632

RESUMEN

In its largest outbreak, Ebola virus disease is spreading through Guinea, Liberia, Sierra Leone, and Nigeria. We sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone to ~2000× coverage. We observed a rapid accumulation of interhost and intrahost genetic variation, allowing us to characterize patterns of viral transmission over the initial weeks of the epidemic. This West African variant likely diverged from central African lineages around 2004, crossed from Guinea to Sierra Leone in May 2014, and has exhibited sustained human-to-human transmission subsequently, with no evidence of additional zoonotic sources. Because many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines, and therapies critical to outbreak response.


Asunto(s)
Brotes de Enfermedades , Ebolavirus/genética , Monitoreo Epidemiológico , Fiebre Hemorrágica Ebola/transmisión , Fiebre Hemorrágica Ebola/virología , Secuencia de Bases , Ebolavirus/aislamiento & purificación , Variación Genética , Genoma Viral/genética , Genómica/métodos , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Mutación , Análisis de Secuencia de ADN , Sierra Leona/epidemiología
9.
PLoS Negl Trop Dis ; 8(3): e2748, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24651047

RESUMEN

BACKGROUND: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. CONCLUSIONS/SIGNIFICANCE: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF.


Asunto(s)
Fiebre de Lassa/epidemiología , Virus Lassa/aislamiento & purificación , Adolescente , Adulto , Factores de Edad , Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , Niño , Preescolar , Femenino , Humanos , Inmunoensayo , Incidencia , Lactante , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/tratamiento farmacológico , Fiebre de Lassa/mortalidad , Masculino , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Ribavirina/uso terapéutico , Estaciones del Año , Sierra Leona/epidemiología , Análisis de Supervivencia , Adulto Joven
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