Journal Article > LetterFull Text
Nature. 2015 June 17; Volume 524 (Issue 7563); 97-101.; DOI:10.1038/nature14594
Carroll MW, Matthews DA, Hiscox JA, Elmore MJ, Pollakis G, et al.
Nature. 2015 June 17; Volume 524 (Issue 7563); 97-101.; DOI:10.1038/nature14594
West Africa is currently witnessing the most extensive Ebola virus (EBOV) outbreak so far recorded. Until now, there have been 27,013 reported cases and 11,134 deaths. The origin of the virus is thought to have been a zoonotic transmission from a bat to a twoyear-old boy in December 2013 (ref. 2). From this index case the virus was spread by human-to-human contact throughout Guinea, Sierra Leone and Liberia. However, the origin of the particular virus in each country and time of transmission is not known and currently relies on epidemiological analysis, which may be unreliable owing to the difficulties of obtaining patient information. Here we trace the genetic evolution of EBOV in the current outbreak that has resulted in multiple lineages. Deep sequencing of 179 patient samples processed by the European Mobile Laboratory, the first diagnostics unit to be deployed to the epicentre of the outbreak in Guinea, reveals an epidemiological and evolutionary history of the epidemic from March 2014 to January 2015. Analysis of EBOV genome evolution has also benefited from a similar sequencing effort of patient samples from Sierra Leone. Our results confirm that the EBOV from Guinea moved into Sierra Leone, most likely in April or early May. The viruses of the Guinea/Sierra Leone lineage mixed around June/July 2014. Viral sequences covering August, September and October 2014 indicate that this lineage evolved independently within Guinea. These data can be used in conjunction with epidemiological information to test retrospectively the effectiveness of control measures, and provides an unprecedented window into the evolution of an ongoing viral haemorrhagic fever outbreak.
Journal Article > ResearchFull Text
N Engl J Med. 2016 January 7; Volume 374 (Issue 1); 33-42.; DOI:10.1056/NEJMoa1511812
van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, et al.
N Engl J Med. 2016 January 7; Volume 374 (Issue 1); 33-42.; DOI:10.1056/NEJMoa1511812
BACKGROUND
In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea.
METHODS
In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group.
RESULTS
A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.
CONCLUSIONS
The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).
In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea.
METHODS
In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group.
RESULTS
A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.
CONCLUSIONS
The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).
Journal Article > LetterFull Text
N Engl J Med. 2022 June 30; Volume 386 (Issue 26); 2528-2530.; DOI:10.1056/NEJMc2120183
Koundouno FR, Kafetzopoulou LE, Faye M, Renevey A, Soropogui B, et al.
N Engl J Med. 2022 June 30; Volume 386 (Issue 26); 2528-2530.; DOI:10.1056/NEJMc2120183
Journal Article > ResearchFull Text
mSphere. 2017 August 30; Volume 2 (Issue 4); DOI:10.1128/mSphereDirect.00325-17
Carroll MW, Haldenby S, Rickett NY, Palyi B, Garcia-Dorival I, et al.
mSphere. 2017 August 30; Volume 2 (Issue 4); DOI:10.1128/mSphereDirect.00325-17
In this study, samples from the 2013-2016 West African Ebola virus outbreak from patients in Guinea with Ebola virus disease (EVD) were analyzed to discover and classify what other pathogens were present. Throat swabs were taken from deceased EVD patients, and peripheral blood samples were analyzed that had been taken from patients when they presented at the treatment center with acute illness. High-throughput RNA sequencing (RNA-seq) and bioinformatics were used to identify the potential microorganisms. This approach confirmed Ebola virus (EBOV) in all samples from patients diagnosed as acute positive for the virus by quantitative reverse transcription-PCR in deployed field laboratories. Nucleic acid mapping to Plasmodium was also used on the patient samples, confirming results obtained with an antigen-based rapid diagnostic test (RDT) conducted in the field laboratories. The data suggested that a high Plasmodium load, as determined by sequence read depth, was associated with mortality and influenced the host response, whereas a lower parasite load did not appear to affect outcome. The identifications of selected bacteria from throat swabs via RNA-seq were confirmed by culture. The data indicated that the potential pathogens identified in the blood samples were associated with translocation from the gut, suggesting the presence of bacteremia, which transcriptome data suggested may induce or aggravate the acute-phase response observed during EVD. Transcripts mapping to different viruses were also identified, including those indicative of lytic infections. The development of high-resolution analysis of samples from patients with EVD will help inform care pathways and the most appropriate general antimicrobial therapy to be used in a resource-poor setting.
IMPORTANCE
Our results highlight the identification of an array of pathogens in the blood of patients with Ebola virus disease (EVD). This has not been done before, and the data have important implications for the treatment of patients with EVD, particularly considering antibiotic stewardship. We show that EVD patients who were also infected with Plasmodium, particularly at higher loads, had more adverse outcomes than patients with lower levels of Plasmodium. However, the presence of Plasmodium did not influence the innate immune response, and it is likely that the presence of EBOV dominated this response. Several viruses other than EBOV were identified, and bacteria associated with sepsis were also identified. These findings were indicative of bacterial translocation across the gut during the acute phase of EVD.
IMPORTANCE
Our results highlight the identification of an array of pathogens in the blood of patients with Ebola virus disease (EVD). This has not been done before, and the data have important implications for the treatment of patients with EVD, particularly considering antibiotic stewardship. We show that EVD patients who were also infected with Plasmodium, particularly at higher loads, had more adverse outcomes than patients with lower levels of Plasmodium. However, the presence of Plasmodium did not influence the innate immune response, and it is likely that the presence of EBOV dominated this response. Several viruses other than EBOV were identified, and bacteria associated with sepsis were also identified. These findings were indicative of bacterial translocation across the gut during the acute phase of EVD.
Journal Article > ResearchFull Text
Nature. 2016 May 4; Volume 533 (Issue 7601); 100-104.; DOI:10.1038/nature17949
Ruibal P, Oestereich L, Ludtke A, Becker-Ziaja B, Wozniak DM, et al.
Nature. 2016 May 4; Volume 533 (Issue 7601); 100-104.; DOI:10.1038/nature17949
Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.
Journal Article > ResearchFull Text
N Engl J Med. 2014 November 5; Volume 372 (Issue 1); DOI:10.1056/NEJMoa1411249
Brah E, Lamah MC, Fletcher TE, Jacob S, Brett-Major D, et al.
N Engl J Med. 2014 November 5; Volume 372 (Issue 1); DOI:10.1056/NEJMoa1411249
Background In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. Methods From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. Results Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). Conclusions Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.
Journal Article > Short ReportFull Text
N Engl J Med. 2014 October 9; Volume 371 (Issue 15); 1418-1425.; DOI:10.1056/NEJMoa1404505
Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, et al.
N Engl J Med. 2014 October 9; Volume 371 (Issue 15); 1418-1425.; DOI:10.1056/NEJMoa1404505
In March 2014, the World Health Organization was notified of an outbreak of a communicable disease characterized by fever, severe diarrhea, vomiting, and a high fatality rate in Guinea. Virologic investigation identified Zaire ebolavirus (EBOV) as the causative agent. Full-length genome sequencing and phylogenetic analysis showed that EBOV from Guinea forms a separate clade in relationship to the known EBOV strains from the Democratic Republic of Congo and Gabon. Epidemiologic investigation linked the laboratory-confirmed cases with the presumed first fatality of the outbreak in December 2013. This study demonstrates the emergence of a new EBOV strain in Guinea.