今日の臨床サポート

エボラウイルス病・エボラ出血熱

著者: 古宮伸洋 日本赤十字社和歌山医療センター

監修: 大曲貴夫 国立国際医療研究センター

著者校正/監修レビュー済:2022/08/17
参考ガイドライン:
  1. 世界保健機関(World Health Organization:WHO):Clinical management of patients with viral haemorrhagic fever: A pocket guide for front-line health workers
  1. 米国疾病管理予防センター(Centers for Disease Control and Prevention:CDC):(Ebola virus disease)
  1. 厚生労働省:ウイルス性出血熱 診療の手引き 2017改訂新版
患者向け説明資料

概要・推奨   

  1. エボラ出血熱(Ebola hemorrhagic fever)またはエボラウイルス病(Ebola virus disease)とは、フィロウイルス科エボラウイルス属のRNAウイルスによる急性ウイルス感染症である。
  1. 発熱、頭痛などの非特異的な急性ウイルス感染症状で発症し、重症化した場合には多臓器不全や出血症状を来たす事のある致死率の高い疾患である。
  1. 脱水、ショック、低酸素、電解質異常などに対する支持療法を行う(推奨度1 OJG)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
古宮伸洋 : 特に申告事項無し[2022年]
監修:大曲貴夫 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 主に以下の点について加筆した。
  1. エボラウイルスとしてこれまで5つが知られていたが、西アフリカのコウモリから6つ目となるボンバリウイルスが発見された。
  1. 近年では西アフリカのギニアで2021年2月に小規模な流行が発生した。コンゴ民主共和国では2020年6月から2年間にわたり流行が続き3,470例の確定例が報告された。同国ではそれ以外にも間欠的に小規模な流行が散発し続けている。
  1. 特異的な抗ウイルス治療として2種類の抗体薬(REGN-EB3、mAb114)が有効性を示した。
  1. ワクチンとしてまず2019年にrVSVΔG-ZEBOV-GP(Ervebo®)がWHOの事前承認を受けて流行地での対応に使用された。2021年にはAd26.ZEBOV(Zabdeno®)と MVA-BN-Filo(Mvabea®)も事前承認を受けた。

病態・疫学・診察

疾患のポイント  
  1. エボラ出血熱(Ebola hemorrhagic fever)またはエボラウイルス病(Ebola virus disease)とは、フィロウイルス科エボラウイルス属のRNAウイルスによる急性ウイルス感染症である。
  1. 発熱、頭痛などの非特異的な急性ウイルス感染症状で発症し、重症化した場合には多臓器不全や出血症状を来たす事のある致死率の高い疾患である。消化管などから出血症状を来すことがありエボラ出血熱と呼ばれてきたが、出血症状を示さないケースも多いことから現在、国際的にはエボラウイルス病と呼ばれる。
  1. 主には血液、便、吐物などの患者体液に直接接触することでヒト-ヒト感染を起こす。飛沫感染や空気感染の可能性については議論がある。空気感染の可能性は非常に低いと想定されているが、エアロゾルが産生されるような状況では空気感染対策まで行うことが推奨される。
  1. 補液などの支持療法が治療の中心である。特異的な抗ウイルス治療として2種類の抗体薬(REGN-EB3、mAb114)が有効である。
  1. ワクチンが有効であり、EVD患者診療に当たる医療者など曝露リスクの高い職種への曝露前予防、また患者家族などへの曝露後予防に使用されている。
  1. 現感染症法では、一類感染症に指定されており、患者が発生した場合は直ちに届けが必要である。特定感染症指定医療機関及び第一種感染症指定医療機関でのみ受け入れ可能となっている。また、病原体は特定一種病原体に指定されている。現在のところ、我が国での感染例は認めていない。
 
 
  1. 疾患について:
フィロウイルス科エボラウイルス属には、以下の6つのウイルスが属している。このうちレストンエボラウイルスはヒトには病原性を示さない。ボンバリウイルスはコウモリから発見された新種のウイルスであり、人への病原性は不明である[1]
  1. (ザイール)エボラウイルス(Ebolavirus:EBOV)
  1. スーダンエボラウイルス(Sudan ebolavirus:SUDV)
  1. ブンディブギョエボラウイルス(Bundibugyo ebolavirus:BDBV)
  1. レストンエボラウイルス(Reston ebolavirus:RESTV)
  1. タイフォレストエボラウイルス(Taï Forest ebolavirus:TAFV)
  1. ボンバリウイルス(Bombali ebolavirus:BOMV)
  1. 自然宿主に関しては、現在のところまだ明らかでないが、フルーツコウモリからウイルス特異抗体とRNAが検出されたことを受けて、フルーツコウモリが候補として挙げられている。
問診・診察のポイント  
ポイント:
  1. 症状は非特異的であるため、症状のみから診断することは困難である。問診でエボラウイルス病患者への接触歴、流行地でのリスク行動(コウモリや霊長類などとの接触)を確認することが重要である。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Tracey Goldstein, Simon J Anthony, Aiah Gbakima, Brian H Bird, James Bangura, Alexandre Tremeau-Bravard, Manjunatha N Belaganahalli, Heather L Wells, Jasjeet K Dhanota, Eliza Liang, Michael Grodus, Rohit K Jangra, Veronica A DeJesus, Gorka Lasso, Brett R Smith, Amara Jambai, Brima O Kamara, Sorie Kamara, William Bangura, Corina Monagin, Sagi Shapira, Christine K Johnson, Karen Saylors, Edward M Rubin, Kartik Chandran, W Ian Lipkin, Jonna A K Mazet
The discovery of Bombali virus adds further support for bats as hosts of ebolaviruses.
Nat Microbiol. 2018 Oct;3(10):1084-1089. doi: 10.1038/s41564-018-0227-2. Epub 2018 Aug 27.
Abstract/Text Here we describe the complete genome of a new ebolavirus, Bombali virus (BOMV) detected in free-tailed bats in Sierra Leone (little free-tailed (Chaerephon pumilus) and Angolan free-tailed (Mops condylurus)). The bats were found roosting inside houses, indicating the potential for human transmission. We show that the viral glycoprotein can mediate entry into human cells. However, further studies are required to investigate whether exposure has actually occurred or if BOMV is pathogenic in humans.

PMID 30150734
Betsy Wonderly, Sophie Jones, Michelle L Gatton, John Barber, Marian Killip, Chris Hudson, Lisa Carter, Tim Brooks, Andrew J H Simpson, Amanda Semper, Willy Urassa, Arlene Chua, Mark Perkins, Catharina Boehme
Comparative performance of four rapid Ebola antigen-detection lateral flow immunoassays during the 2014-2016 Ebola epidemic in West Africa.
PLoS One. 2019;14(3):e0212113. doi: 10.1371/journal.pone.0212113. Epub 2019 Mar 7.
Abstract/Text BACKGROUND: Without an effective vaccine, as was the case early in the 2014-2016 Ebola Outbreak in West Africa, disease control depends entirely on interrupting transmission through early disease detection and prompt patient isolation. Lateral Flow Immunoassays (LFI) are a potential supplement to centralized reference laboratory testing for the early diagnosis of Ebola Virus Disease (EVD). The goal of this study was to assess the performance of commercially available simple and rapid antigen detection LFIs, submitted for review to the WHO via the Emergency Use Assessment and Listing procedure. The study was performed in an Ebola Treatment Centre laboratory involved in EVD testing in Sierra Leone. In light of the current Ebola outbreak in May 2018 in the Democratic Republic of Congo, which highlights the lack of clarity in the global health community about appropriate Ebola diagnostics, our findings are increasingly critical.
METHODS: A cross-sectional study was conducted to assess comparative performance of four LFIs for detecting EVD. LFIs were assessed against the same 328 plasma samples and 100 whole EDTA blood samples, using the altona RealStar Filovirus Screen real-time RT-PCR as the bench mark assay. The performance of the Public Health England (PHE) in-house Zaire ebolavirus-specific real time RT-PCR Trombley assay was concurrently assessed. Statistical analysis using generalized estimating equations was conducted to compare LFI performance.
FINDINGS: Sensitivity and specificity varied between the LFIs, with specificity found to be significantly higher for whole EDTA blood samples compared to plasma samples in at least 2 LFIs (P≤0.003). Using the altona RT-PCR assay as the bench mark, sensitivities on plasma samples ranged from 79.53% (101/127, 95% CI: 71.46-86.17%) for the DEDIATEST EBOLA (SD Biosensor) to 98.43% (125/127, 95% CI: 94.43-99.81%) for the One step Ebola test (Intec). Specificities ranged from 80.20% (158/197, 95% CI: 74.07-88.60%) for plasma samples using the ReEBOV Antigen test Kit (Corgenix) to 100.00% (98/98, 95% CI: 96.31-100.00%) for whole blood samples using the DEDIATEST EBOLA (SD Biosensor) and SD Ebola Zaire Ag (SD Biosensor). Results also showed the Trombley RT-PCR assay had a lower limit of detection than the altona assay, with some LFIs having higher sensitivity than the altona assay when the Trombley assay was the bench mark.
INTERPRETATION: All of the tested EVD LFIs may be considered suitable for use in an outbreak situation (i.e. rule out testing in communities), although they had variable performance characteristics, with none possessing both high sensitivity and specificity. The non-commercial Trombley Zaire ebolavirus RT-PCR assay warrants further investigation, as it appeared more sensitive than the current gold standard, the altona Filovirus Screen RT-PCR assay.

PMID 30845203
Rupa Kanapathipillai
Ebola virus disease--current knowledge.
N Engl J Med. 2014 Sep 25;371(13):e18. doi: 10.1056/NEJMp1410741.
Abstract/Text
PMID 25251632
WHO Ebola Response Team
Ebola virus disease in West Africa--the first 9 months of the epidemic and forward projections.
N Engl J Med. 2014 Oct 16;371(16):1481-95. doi: 10.1056/NEJMoa1411100. Epub 2014 Sep 22.
Abstract/Text BACKGROUND: On March 23, 2014, the World Health Organization (WHO) was notified of an outbreak of Ebola virus disease (EVD) in Guinea. On August 8, the WHO declared the epidemic to be a "public health emergency of international concern."
METHODS: By September 14, 2014, a total of 4507 probable and confirmed cases, including 2296 deaths from EVD (Zaire species) had been reported from five countries in West Africa--Guinea, Liberia, Nigeria, Senegal, and Sierra Leone. We analyzed a detailed subset of data on 3343 confirmed and 667 probable Ebola cases collected in Guinea, Liberia, Nigeria, and Sierra Leone as of September 14.
RESULTS: The majority of patients are 15 to 44 years of age (49.9% male), and we estimate that the case fatality rate is 70.8% (95% confidence interval [CI], 69 to 73) among persons with known clinical outcome of infection. The course of infection, including signs and symptoms, incubation period (11.4 days), and serial interval (15.3 days), is similar to that reported in previous outbreaks of EVD. On the basis of the initial periods of exponential growth, the estimated basic reproduction numbers (R0 ) are 1.71 (95% CI, 1.44 to 2.01) for Guinea, 1.83 (95% CI, 1.72 to 1.94) for Liberia, and 2.02 (95% CI, 1.79 to 2.26) for Sierra Leone. The estimated current reproduction numbers (R) are 1.81 (95% CI, 1.60 to 2.03) for Guinea, 1.51 (95% CI, 1.41 to 1.60) for Liberia, and 1.38 (95% CI, 1.27 to 1.51) for Sierra Leone; the corresponding doubling times are 15.7 days (95% CI, 12.9 to 20.3) for Guinea, 23.6 days (95% CI, 20.2 to 28.2) for Liberia, and 30.2 days (95% CI, 23.6 to 42.3) for Sierra Leone. Assuming no change in the control measures for this epidemic, by November 2, 2014, the cumulative reported numbers of confirmed and probable cases are predicted to be 5740 in Guinea, 9890 in Liberia, and 5000 in Sierra Leone, exceeding 20,000 in total.
CONCLUSIONS: These data indicate that without drastic improvements in control measures, the numbers of cases of and deaths from EVD are expected to continue increasing from hundreds to thousands per week in the coming months.

PMID 25244186
Mark G Kortepeter, Daniel G Bausch, Mike Bray
Basic clinical and laboratory features of filoviral hemorrhagic fever.
J Infect Dis. 2011 Nov;204 Suppl 3:S810-6. doi: 10.1093/infdis/jir299.
Abstract/Text The filoviruses Marburg and Ebola cause severe hemorrhagic fever (HF) in humans. Beginning with the 1967 Marburg outbreak, 30 epidemics, isolated cases, and accidental laboratory infections have been described in the medical literature. We reviewed those reports to determine the basic clinical and laboratory features of filoviral HF. The most detailed information was found in descriptions of patients treated in industrialized countries; except for the 2000 outbreak of Ebola Sudan HF in Uganda, reports of epidemics in central Africa provided little controlled or objective clinical data. Other than the case fatality rate, there were no clear differences in the features of the various filovirus infections. This compilation will be of value to medical workers responding to epidemics and to investigators attempting to develop animal models of filoviral HF. By identifying key unanswered questions and gaps in clinical data, it will help guide clinical research in future outbreaks.

PMID 21987756
G Marshall Lyon, Aneesh K Mehta, Jay B Varkey, Kent Brantly, Lance Plyler, Anita K McElroy, Colleen S Kraft, Jonathan S Towner, Christina Spiropoulou, Ute Ströher, Timothy M Uyeki, Bruce S Ribner, Emory Serious Communicable Diseases Unit
Clinical care of two patients with Ebola virus disease in the United States.
N Engl J Med. 2014 Dec 18;371(25):2402-9. doi: 10.1056/NEJMoa1409838. Epub 2014 Nov 12.
Abstract/Text West Africa is currently experiencing the largest outbreak of Ebola virus disease (EVD) in history. Two patients with EVD were transferred from Liberia to our hospital in the United States for ongoing care. Malaria had also been diagnosed in one patient, who was treated for it early in the course of EVD. The two patients had substantial intravascular volume depletion and marked electrolyte abnormalities. We undertook aggressive supportive measures of hydration (typically, 3 to 5 liters of intravenous fluids per day early in the course of care) and electrolyte correction. As the patients' condition improved clinically, there was a concomitant decline in the amount of virus detected in plasma.

PMID 25390460
Timothy M Uyeki, Aneesh K Mehta, Richard T Davey, Allison M Liddell, Timo Wolf, Pauline Vetter, Stefan Schmiedel, Thomas Grünewald, Michael Jacobs, Jose R Arribas, Laura Evans, Angela L Hewlett, Arne B Brantsaeter, Giuseppe Ippolito, Christophe Rapp, Andy I M Hoepelman, Julie Gutman, Working Group of the U.S.–European Clinical Network on Clinical Management of Ebola Virus Disease Patients in the U.S. and Europe
Clinical Management of Ebola Virus Disease in the United States and Europe.
N Engl J Med. 2016 Feb 18;374(7):636-46. doi: 10.1056/NEJMoa1504874.
Abstract/Text BACKGROUND: Available data on the characteristics of patients with Ebola virus disease (EVD) and clinical management of EVD in settings outside West Africa, as well as the complications observed in those patients, are limited.
METHODS: We reviewed available clinical, laboratory, and virologic data from all patients with laboratory-confirmed Ebola virus infection who received care in U.S. and European hospitals from August 2014 through December 2015.
RESULTS: A total of 27 patients (median age, 36 years [range, 25 to 75]) with EVD received care; 19 patients (70%) were male, 9 of 26 patients (35%) had coexisting conditions, and 22 (81%) were health care personnel. Of the 27 patients, 24 (89%) were medically evacuated from West Africa or were exposed to and infected with Ebola virus in West Africa and had onset of illness and laboratory confirmation of Ebola virus infection in Europe or the United States, and 3 (11%) acquired EVD in the United States or Europe. At the onset of illness, the most common signs and symptoms were fatigue (20 patients [80%]) and fever or feverishness (17 patients [68%]). During the clinical course, the predominant findings included diarrhea, hypoalbuminemia, hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia; 14 patients (52%) had hypoxemia, and 9 (33%) had oliguria, of whom 5 had anuria. Aminotransferase levels peaked at a median of 9 days after the onset of illness. Nearly all the patients received intravenous fluids and electrolyte supplementation; 9 (33%) received noninvasive or invasive mechanical ventilation; 5 (19%) received continuous renal-replacement therapy; 22 (81%) received empirical antibiotics; and 23 (85%) received investigational therapies (19 [70%] received at least two experimental interventions). Ebola viral RNA levels in blood peaked at a median of 7 days after the onset of illness, and the median time from the onset of symptoms to clearance of viremia was 17.5 days. A total of 5 patients died, including 3 who had respiratory and renal failure, for a mortality of 18.5%.
CONCLUSIONS: Among the patients with EVD who were cared for in the United States or Europe, close monitoring and aggressive supportive care that included intravenous fluid hydration, correction of electrolyte abnormalities, nutritional support, and critical care management for respiratory and renal failure were needed; 81.5% of these patients who received this care survived.

PMID 26886522
Amanda E Semper, M Jana Broadhurst, Jade Richards, Geraldine M Foster, Andrew J H Simpson, Christopher H Logue, J Daniel Kelly, Ann Miller, Tim J G Brooks, Megan Murray, Nira R Pollock
Performance of the GeneXpert Ebola Assay for Diagnosis of Ebola Virus Disease in Sierra Leone: A Field Evaluation Study.
PLoS Med. 2016 Mar;13(3):e1001980. doi: 10.1371/journal.pmed.1001980. Epub 2016 Mar 29.
Abstract/Text BACKGROUND: Throughout the Ebola virus disease (EVD) epidemic in West Africa, field laboratory testing for EVD has relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays; an accurate sample-to-answer RT-PCR test would reduce time to results and potentially increase access to testing. We evaluated the performance of the Cepheid GeneXpert Ebola assay on clinical venipuncture whole blood (WB) and buccal swab (BS) specimens submitted to a field biocontainment laboratory in Sierra Leone for routine EVD testing by RT-PCR ("Trombley assay").
METHODS AND FINDINGS: This study was conducted in the Public Health England EVD diagnostic laboratory in Port Loko, Sierra Leone, using residual diagnostic specimens remaining after clinical testing. EDTA-WB specimens (n = 218) were collected from suspected or confirmed EVD patients between April 1 and July 20, 2015. BS specimens (n = 71) were collected as part of a national postmortem screening program between March 7 and July 20, 2015. EDTA-WB and BS specimens were tested with Xpert (targets: glycoprotein [GP] and nucleoprotein [NP] genes) and Trombley (target: NP gene) assays in parallel. All WB specimens were fresh; 84/218 were tested in duplicate on Xpert to compare WB sampling methods (pipette versus swab); 43/71 BS specimens had been previously frozen. In all, 7/218 (3.2%) WB and 7/71 (9.9%) BS samples had Xpert results that were reported as "invalid" or "error" and were excluded, leaving 211 WB and 64 BS samples with valid Trombley and Xpert results. For WB, 22/22 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 84.6%-100%), and 181/189 Trombley-negative samples were Xpert-negative (specificity 95.8%, 95% confidence interval (CI) 91.8%-98.2%). Seven of the eight Trombley-negative, Xpert-positive (Xpert cycle threshold [Ct] range 37.7-43.4) WB samples were confirmed to be follow-up submissions from previously Trombley-positive EVD patients, suggesting a revised Xpert specificity of 99.5% (95% CI 97.0%-100%). For Xpert-positive WB samples (n = 22), Xpert NP Ct values were consistently lower than GP Ct values (mean difference -4.06, 95% limits of agreement -6.09, -2.03); Trombley (NP) Ct values closely matched Xpert NP Ct values (mean difference -0.04, 95% limits of agreement -2.93, 2.84). Xpert results (positive/negative) for WB sampled by pipette versus swab were concordant for 78/79 (98.7%) WB samples, with comparable Ct values for positive results. For BS specimens, 20/20 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 83.2%-100%), and 44/44 Trombley-negative samples were Xpert-negative (specificity 100%, 95% CI 92.0%-100%). This study was limited to testing residual diagnostic samples, some of which had been frozen before use; it was not possible to test the performance of the Xpert Ebola assay at point of care.
CONCLUSIONS: The Xpert Ebola assay had excellent performance compared to an established RT-PCR benchmark on WB and BS samples in a field laboratory setting. Future studies should evaluate feasibility and performance outside of a biocontainment laboratory setting to facilitate expanded access to testing.

PMID 27023868
Wen-Gang Li, Wei-Wei Chen, Lei Li, Dong Ji, Ying-Jie Ji, Chen Li, Xu-Dong Gao, Li-Fu Wang, Min Zhao, Xue-Zhang Duan, Hui-Juan Duan
The etiology of Ebola virus disease-like illnesses in Ebola virusnegative patients from Sierra Leone.
Oncotarget. 2016 Apr 2;. doi: 10.18632/oncotarget.8558. Epub 2016 Apr 2.
Abstract/Text During the 2014 Ebola virus disease (EVD) outbreak, less than half of EVD-suspected cases were laboratory tested as Ebola virus (EBOV)-negative, but disease identity remained unknown. In this study we investigated the etiology of EVD-like illnesses in EBOV-negative cases. From November 13, 2014 to March 16, 2015, EVD-suspected patients were admitted to Jui Government Hospital and assessed for EBOV infection by real-time PCR. Of 278 EBOV negative patients, 223 (80.21%), 142 (51.08%), 123 (44.24%), 114 (41.01%), 59 (21.22%), 35 (12.59%), and 12 (4.32%) reported fever, headache, joint pain, fatigue, nausea/vomiting, diarrhea, hemorrhage, respectively. Furthermore, 121 (43.52%), 44 (15.83%), 36 (12.95%), 33 (11.87%), 23 (8.27%), 10 (3.60%) patients were diagnosed as infection with malaria, HIV, Lassa fever, tuberculosis, yellow fever, and pneumonia, respectively. No significant differences in clinical features and symptoms were found between non-EVD and EVD patients. To the best of our knowledge, the present study is the first to explore the etiology of EVD-like illnesses in uninfected patients in Sierra Leone, highlighting the importance of accurate diagnosis to EVD confirmation.

PMID 27058894
Elhadj Ibrahima Bah, Marie-Claire Lamah, Tom Fletcher, Shevin T Jacob, David M Brett-Major, Amadou Alpha Sall, Nahoko Shindo, William A Fischer, Francois Lamontagne, Sow Mamadou Saliou, Daniel G Bausch, Barry Moumié, Tim Jagatic, Armand Sprecher, James V Lawler, Thierry Mayet, Frederique A Jacquerioz, María F Méndez Baggi, Constanza Vallenas, Christophe Clement, Simon Mardel, Ousmane Faye, Oumar Faye, Baré Soropogui, Nfaly Magassouba, Lamine Koivogui, Ruxandra Pinto, Robert A Fowler
Clinical presentation of patients with Ebola virus disease in Conakry, Guinea.
N Engl J Med. 2015 Jan 1;372(1):40-7. doi: 10.1056/NEJMoa1411249. Epub 2014 Nov 5.
Abstract/Text 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%.

PMID 25372658
Heinz Feldmann, Thomas W Geisbert
Ebola haemorrhagic fever.
Lancet. 2011 Mar 5;377(9768):849-62. doi: 10.1016/S0140-6736(10)60667-8.
Abstract/Text Ebola viruses are the causative agents of a severe form of viral haemorrhagic fever in man, designated Ebola haemorrhagic fever, and are endemic in regions of central Africa. The exception is the species Reston Ebola virus, which has not been associated with human disease and is found in the Philippines. Ebola virus constitutes an important local public health threat in Africa, with a worldwide effect through imported infections and through the fear of misuse for biological terrorism. Ebola virus is thought to also have a detrimental effect on the great ape population in Africa. Case-fatality rates of the African species in man are as high as 90%, with no prophylaxis or treatment available. Ebola virus infections are characterised by immune suppression and a systemic inflammatory response that causes impairment of the vascular, coagulation, and immune systems, leading to multiorgan failure and shock, and thus, in some ways, resembling septic shock.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21084112
K Kibadi, K Mupapa, K Kuvula, M Massamba, D Ndaberey, J J Muyembe-Tamfum, M A Bwaka, A De Roo, R Colebunders
Late ophthalmologic manifestations in survivors of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo.
J Infect Dis. 1999 Feb;179 Suppl 1:S13-4. doi: 10.1086/514288.
Abstract/Text Three (15%) of 20 survivors of the 1995 Ebola outbreak in the Democratic Republic of the Congo enrolled in a follow-up study and 1 other survivor developed ocular manifestations after being asymptomatic for 1 month. Patients complained of ocular pain, photophobia, hyperlacrimation, and loss of visual acuity. Ocular examination revealed uveitis in all 4 patients. All patients improved with a topical treatment of 1% atropine and steroids.

PMID 9988158
Daniel S Chertow, Christian Kleine, Jeffrey K Edwards, Roberto Scaini, Ruggero Giuliani, Armand Sprecher
Ebola virus disease in West Africa--clinical manifestations and management.
N Engl J Med. 2014 Nov 27;371(22):2054-7. doi: 10.1056/NEJMp1413084. Epub 2014 Nov 5.
Abstract/Text
PMID 25372854
John S Schieffelin, Jeffrey G Shaffer, Augustine Goba, Michael Gbakie, Stephen K Gire, Andres Colubri, Rachel S G Sealfon, Lansana Kanneh, Alex Moigboi, Mambu Momoh, Mohammed Fullah, Lina M Moses, Bethany L Brown, Kristian G Andersen, Sarah Winnicki, Stephen F Schaffner, Daniel J Park, Nathan L Yozwiak, Pan-Pan Jiang, David Kargbo, Simbirie Jalloh, Mbalu Fonnie, Vandi Sinnah, Issa French, Alice Kovoma, Fatima K Kamara, Veronica Tucker, Edwin Konuwa, Josephine Sellu, Ibrahim Mustapha, Momoh Foday, Mohamed Yillah, Franklyn Kanneh, Sidiki Saffa, James L B Massally, Matt L Boisen, Luis M Branco, Mohamed A Vandi, Donald S Grant, Christian Happi, Sahr M Gevao, Thomas E Fletcher, Robert A Fowler, Daniel G Bausch, Pardis C Sabeti, S Humarr Khan, Robert F Garry, KGH Lassa Fever Program, Viral Hemorrhagic Fever Consortium, WHO Clinical Response Team
Clinical illness and outcomes in patients with Ebola in Sierra Leone.
N Engl J Med. 2014 Nov 27;371(22):2092-100. doi: 10.1056/NEJMoa1411680. Epub 2014 Oct 29.
Abstract/Text 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.).

PMID 25353969
Jonathan S Towner, Pierre E Rollin, Daniel G Bausch, Anthony Sanchez, Sharon M Crary, Martin Vincent, William F Lee, Christina F Spiropoulou, Thomas G Ksiazek, Mathew Lukwiya, Felix Kaducu, Robert Downing, Stuart T Nichol
Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome.
J Virol. 2004 Apr;78(8):4330-41.
Abstract/Text The largest outbreak on record of Ebola hemorrhagic fever (EHF) occurred in Uganda from August 2000 to January 2001. The outbreak was centered in the Gulu district of northern Uganda, with secondary transmission to other districts. After the initial diagnosis of Sudan ebolavirus by the National Institute for Virology in Johannesburg, South Africa, a temporary diagnostic laboratory was established within the Gulu district at St. Mary's Lacor Hospital. The laboratory used antigen capture and reverse transcription-PCR (RT-PCR) to diagnose Sudan ebolavirus infection in suspect patients. The RT-PCR and antigen-capture diagnostic assays proved very effective for detecting ebolavirus in patient serum, plasma, and whole blood. In samples collected very early in the course of infection, the RT-PCR assay could detect ebolavirus 24 to 48 h prior to detection by antigen capture. More than 1,000 blood samples were collected, with multiple samples obtained from many patients throughout the course of infection. Real-time quantitative RT-PCR was used to determine the viral load in multiple samples from patients with fatal and nonfatal cases, and these data were correlated with the disease outcome. RNA copy levels in patients who died averaged 2 log(10) higher than those in patients who survived. Using clinical material from multiple EHF patients, we sequenced the variable region of the glycoprotein. This Sudan ebolavirus strain was not derived from either the earlier Boniface (1976) or Maleo (1979) strain, but it shares a common ancestor with both. Furthermore, both sequence and epidemiologic data are consistent with the outbreak having originated from a single introduction into the human population.

PMID 15047846
Moumié Barry, Abdoulaye Touré, Fodé Amara Traoré, Fodé-Bangaly Sako, Djibril Sylla, Dimai Ouo Kpamy, Elhadj Ibrahima Bah, M'Mah Bangoura, Marc Poncin, Sakoba Keita, Thierno Mamadou Tounkara, Mohamed Cisse, Philippe Vanhems
Clinical predictors of mortality in patients with Ebola virus disease.
Clin Infect Dis. 2015 Jun 15;60(12):1821-4. doi: 10.1093/cid/civ202. Epub 2015 Mar 13.
Abstract/Text In an observational cohort study including 89 Ebola patients, predictive factors of death were analyzed. The crude mortality rate was 43.8%. Myalgia (adjusted odds ratio [OR], 4.04; P = .02), hemorrrhage (adjusted OR, 3.5; P = .02), and difficulty breathing (adjusted OR, 5.75; P = .01) were independently associated with death.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PMID 25770172
John G Mattia, Mathew J Vandy, Joyce C Chang, Devin E Platt, Kerry Dierberg, Daniel G Bausch, Tim Brooks, Sampha Conteh, Ian Crozier, Robert A Fowler, Amadu P Kamara, Cindy Kang, Srividya Mahadevan, Yealie Mansaray, Lauren Marcell, Gillian McKay, Tim O'Dempsey, Victoria Parris, Ruxandra Pinto, Audrey Rangel, Alex P Salam, Jessica Shantha, Vanessa Wolfman, Steven Yeh, Adrienne K Chan, Sharmistha Mishra
Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study.
Lancet Infect Dis. 2016 Mar;16(3):331-8. doi: 10.1016/S1473-3099(15)00489-2. Epub 2015 Dec 23.
Abstract/Text BACKGROUND: Limited data are available on the prevalence and predictors of clinical sequelae in survivors of Ebola virus disease (EVD). The EVD Survivor Clinic in Port Loko, Sierra Leone, has provided clinical care for 603 of 661 survivors living in the district. We did a cross-sectional study to describe the prevalence, nature, and predictors of three key EVD sequelae (ocular, auditory, and articular) in this cohort of EVD survivors.
METHODS: We reviewed available clinical and laboratory records of consecutive patients assessed in the clinic between March 7, 2015, and April 24, 2015. We used univariate and multiple logistic regression to examine clinical and laboratory features of acute EVD with the following outcomes in convalescence: new ocular symptoms, uveitis, auditory symptoms, and arthralgias.
FINDINGS: Among 277 survivors (59% female), median age was 29 years (IQR 20-36) and median time from discharge from an EVD treatment facility to first survivor clinic visit was 121 days (82-151). Clinical sequelae were common, including arthralgias (n=210, 76%), new ocular symptoms (n=167, 60%), uveitis (n=50, 18%), and auditory symptoms (n=67, 24%). Higher Ebola viral load at acute EVD presentation (as shown by lower cycle thresholds on real-time RT-PCR testing) was independently associated with uveitis (adjusted odds ratio [aOR] 3·33, 95% CI 1·87-5·91, for every five-point decrease in cycle threshold) and with new ocular symptoms or ocular diagnoses (aOR 3·04, 95% CI 1·87-4·94).
INTERPRETATION: Clinical sequelae during early EVD convalescence are common and sometimes sight threatening. These findings underscore the need for early clinical follow-up of survivors of EVD and urgent provision of ocular care as part of health systems strengthening in EVD-affected west African countries.
FUNDING: Canadian Institutes of Health Research.

Copyright © 2016 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
PMID 26725449
Jay B Varkey, Jessica G Shantha, Ian Crozier, Colleen S Kraft, G Marshall Lyon, Aneesh K Mehta, Gokul Kumar, Justine R Smith, Markus H Kainulainen, Shannon Whitmer, Ute Ströher, Timothy M Uyeki, Bruce S Ribner, Steven Yeh
Persistence of Ebola Virus in Ocular Fluid during Convalescence.
N Engl J Med. 2015 Jun 18;372(25):2423-7. doi: 10.1056/NEJMoa1500306. Epub 2015 May 7.
Abstract/Text Among the survivors of Ebola virus disease (EVD), complications that include uveitis can develop during convalescence, although the incidence and pathogenesis of EVD-associated uveitis are unknown. We describe a patient who recovered from EVD and was subsequently found to have severe unilateral uveitis during convalescence. Viable Zaire ebolavirus (EBOV) was detected in aqueous humor 14 weeks after the onset of EVD and 9 weeks after the clearance of viremia.

PMID 25950269
S F Dowell, R Mukunu, T G Ksiazek, A S Khan, P E Rollin, C J Peters
Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epidémies à Kikwit.
J Infect Dis. 1999 Feb;179 Suppl 1:S87-91. doi: 10.1086/514284.
Abstract/Text The surviving members of 27 households in which someone had been infected with Ebola virus were interviewed in order to define the modes of transmission of Ebola hemorrhagic fever (EHF). Of 173 household contacts of the primary cases, 28 (16%) developed EHF. All secondary cases had direct physical contact with the ill person (rate ratio [RR], undefined; P < .001), and among those with direct contact, exposure to body fluids conferred additional risk (RR, 3.6; 95% confidence interval [CI], 1.9-6.8). After adjusting for direct contact and exposure to body fluids, adult family members, those who touched the cadaver, and those who were exposed during the late hospital phase were at additional risk. None of the 78 household members who had no physical contact with the case during the clinical illness were infected (upper 95% CI, 4%). EHF is transmitted principally by direct physical contact with an ill person or their body fluids during the later stages of illness.

PMID 9988169
Daniel G Bausch, Jonathan S Towner, Scott F Dowell, Felix Kaducu, Matthew Lukwiya, Anthony Sanchez, Stuart T Nichol, Thomas G Ksiazek, Pierre E Rollin
Assessment of the risk of Ebola virus transmission from bodily fluids and fomites.
J Infect Dis. 2007 Nov 15;196 Suppl 2:S142-7. doi: 10.1086/520545.
Abstract/Text Although Ebola virus (EBOV) is transmitted by unprotected physical contact with infected persons, few data exist on which specific bodily fluids are infected or on the risk of fomite transmission. Therefore, we tested various clinical specimens from 26 laboratory-confirmed cases of Ebola hemorrhagic fever, as well as environmental specimens collected from an isolation ward, for the presence of EBOV. Virus was detected by culture and/or reverse-transcription polymerase chain reaction in 16 of 54 clinical specimens (including saliva, stool, semen, breast milk, tears, nasal blood, and a skin swab) and in 2 of 33 environmental specimens. We conclude that EBOV is shed in a wide variety of bodily fluids during the acute period of illness but that the risk of transmission from fomites in an isolation ward and from convalescent patients is low when currently recommended infection control guidelines for the viral hemorrhagic fevers are followed.

PMID 17940942
Suzanne E Mate, Jeffrey R Kugelman, Tolbert G Nyenswah, Jason T Ladner, Michael R Wiley, Thierry Cordier-Lassalle, Athalia Christie, Gary P Schroth, Stephen M Gross, Gloria J Davies-Wayne, Shivam A Shinde, Ratnesh Murugan, Sonpon B Sieh, Moses Badio, Lawrence Fakoli, Fahn Taweh, Emmie de Wit, Neeltje van Doremalen, Vincent J Munster, James Pettitt, Karla Prieto, Ben W Humrighouse, Ute Ströher, Joseph W DiClaro, Lisa E Hensley, Randal J Schoepp, David Safronetz, Joseph Fair, Jens H Kuhn, David J Blackley, A Scott Laney, Desmond E Williams, Terrence Lo, Alex Gasasira, Stuart T Nichol, Pierre Formenty, Francis N Kateh, Kevin M De Cock, Fatorma Bolay, Mariano Sanchez-Lockhart, Gustavo Palacios
Molecular Evidence of Sexual Transmission of Ebola Virus.
N Engl J Med. 2015 Dec 17;373(25):2448-54. doi: 10.1056/NEJMoa1509773. Epub 2015 Oct 14.
Abstract/Text A suspected case of sexual transmission from a male survivor of Ebola virus disease (EVD) to his female partner (the patient in this report) occurred in Liberia in March 2015. Ebola virus (EBOV) genomes assembled from blood samples from the patient and a semen sample from the survivor were consistent with direct transmission. The genomes shared three substitutions that were absent from all other Western African EBOV sequences and that were distinct from the last documented transmission chain in Liberia before this case. Combined with epidemiologic data, the genomic analysis provides evidence of sexual transmission of EBOV and evidence of the persistence of infective EBOV in semen for 179 days or more after the onset of EVD. (Funded by the Defense Threat Reduction Agency and others.).

PMID 26465384
Benno Kreuels, Dominic Wichmann, Petra Emmerich, Jonas Schmidt-Chanasit, Geraldine de Heer, Stefan Kluge, Abdourahmane Sow, Thomas Renné, Stephan Günther, Ansgar W Lohse, Marylyn M Addo, Stefan Schmiedel
A case of severe Ebola virus infection complicated by gram-negative septicemia.
N Engl J Med. 2014 Dec 18;371(25):2394-401. doi: 10.1056/NEJMoa1411677. Epub 2014 Oct 22.
Abstract/Text Ebola virus disease (EVD) developed in a patient who contracted the disease in Sierra Leone and was airlifted to an isolation facility in Hamburg, Germany, for treatment. During the course of the illness, he had numerous complications, including septicemia, respiratory failure, and encephalopathy. Intensive supportive treatment consisting of high-volume fluid resuscitation (approximately 10 liters per day in the first 72 hours), broad-spectrum antibiotic therapy, and ventilatory support resulted in full recovery without the use of experimental therapies. Discharge was delayed owing to the detection of viral RNA in urine (day 30) and sweat (at the last assessment on day 40) by means of polymerase-chain-reaction (PCR) assay, but the last positive culture was identified in plasma on day 14 and in urine on day 26. This case shows the challenges in the management of EVD and suggests that even severe EVD can be treated effectively with routine intensive care.

PMID 25337633
François Lamontagne, Christophe Clément, Thomas Fletcher, Shevin T Jacob, William A Fischer, Robert A Fowler
Doing today's work superbly well--treating Ebola with current tools.
N Engl J Med. 2014 Oct 23;371(17):1565-6. doi: 10.1056/NEJMp1411310. Epub 2014 Sep 24.
Abstract/Text
PMID 25251518
Yazdan Yazdanpanah, Jose Ramon Arribas, Denis Malvy
Treatment of Ebola virus disease.
Intensive Care Med. 2015 Jan;41(1):115-7. doi: 10.1007/s00134-014-3529-8. Epub 2014 Nov 11.
Abstract/Text
PMID 25385474
Sabue Mulangu, Lori E Dodd, Richard T Davey, Olivier Tshiani Mbaya, Michael Proschan, Daniel Mukadi, Mariano Lusakibanza Manzo, Didier Nzolo, Antoine Tshomba Oloma, Augustin Ibanda, Rosine Ali, Sinaré Coulibaly, Adam C Levine, Rebecca Grais, Janet Diaz, H Clifford Lane, Jean-Jacques Muyembe-Tamfum, PALM Writing Group, Billy Sivahera, Modet Camara, Richard Kojan, Robert Walker, Bonnie Dighero-Kemp, Huyen Cao, Philippe Mukumbayi, Placide Mbala-Kingebeni, Steve Ahuka, Sarah Albert, Tyler Bonnett, Ian Crozier, Michael Duvenhage, Calvin Proffitt, Marc Teitelbaum, Thomas Moench, Jamila Aboulhab, Kevin Barrett, Kelly Cahill, Katherine Cone, Risa Eckes, Lisa Hensley, Betsey Herpin, Elizabeth Higgs, Julie Ledgerwood, Jerome Pierson, Mary Smolskis, Ydrissa Sow, John Tierney, Sumathi Sivapalasingam, Wendy Holman, Nikki Gettinger, David Vallée, Jacqueline Nordwall, PALM Consortium Study Team
A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.
N Engl J Med. 2019 Dec 12;381(24):2293-2303. doi: 10.1056/NEJMoa1910993. Epub 2019 Nov 27.
Abstract/Text BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.
METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days.
RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs.
CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31774950
PLOS Medicine Staff
Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.
PLoS Med. 2016 Jun;13(6):e1002066. doi: 10.1371/journal.pmed.1002066. Epub 2016 Jun 10.
Abstract/Text [This corrects the article DOI: 10.1371/journal.pmed.1001967.].

PMID 27284977
Johan van Griensven, Tansy Edwards, Xavier de Lamballerie, Malcolm G Semple, Pierre Gallian, Sylvain Baize, Peter W Horby, Hervé Raoul, N'Faly Magassouba, Annick Antierens, Carolyn Lomas, Ousmane Faye, Amadou A Sall, Katrien Fransen, Jozefien Buyze, Raffaella Ravinetto, Pierre Tiberghien, Yves Claeys, Maaike De Crop, Lutgarde Lynen, Elhadj Ibrahima Bah, Peter G Smith, Alexandre Delamou, Anja De Weggheleire, Nyankoye Haba, Ebola-Tx Consortium
Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea.
N Engl J Med. 2016 Jan 7;374(1):33-42. doi: 10.1056/NEJMoa1511812.
Abstract/Text 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.).

PMID 26735992
Ana Maria Henao-Restrepo, Ira M Longini, Matthias Egger, Natalie E Dean, W John Edmunds, Anton Camacho, Miles W Carroll, Moussa Doumbia, Bertrand Draguez, Sophie Duraffour, Godwin Enwere, Rebecca Grais, Stephan Gunther, Stefanie Hossmann, Mandy Kader Kondé, Souleymane Kone, Eeva Kuisma, Myron M Levine, Sema Mandal, Gunnstein Norheim, Ximena Riveros, Aboubacar Soumah, Sven Trelle, Andrea S Vicari, Conall H Watson, Sakoba Kéïta, Marie Paule Kieny, John-Arne Røttingen
Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.
Lancet. 2015 Aug 29;386(9996):857-66. doi: 10.1016/S0140-6736(15)61117-5. Epub 2015 Aug 3.
Abstract/Text BACKGROUND: A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa.
METHODS: For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.
FINDINGS: Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing.
INTERPRETATION: The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy.
FUNDING: WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development.

Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
PMID 26248676
Andrew J Pollard, Odile Launay, Jean-Daniel Lelievre, Christine Lacabaratz, Sophie Grande, Neil Goldstein, Cynthia Robinson, Auguste Gaddah, Viki Bockstal, Aurelie Wiedemann, Maarten Leyssen, Kerstin Luhn, Laura Richert, Christine Bétard, Malick M Gibani, Elizabeth A Clutterbuck, Matthew D Snape, Yves Levy, Macaya Douoguih, Rodolphe Thiebaut, EBOVAC2 EBL2001 study group
Safety and immunogenicity of a two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Europe (EBOVAC2): a randomised, observer-blind, participant-blind, placebo-controlled, phase 2 trial.
Lancet Infect Dis. 2021 Apr;21(4):493-506. doi: 10.1016/S1473-3099(20)30476-X. Epub 2020 Nov 17.
Abstract/Text BACKGROUND: To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replication-deficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus.
METHODS: This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18-65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I-III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov, NCT02416453, and EudraCT, 2015-000596-27.
FINDINGS: Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I-III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99·5%) participants received at least one dose of vaccine or placebo. The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and per-protocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoprotein-binding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649-5867) in the 28-day interval group, 10 131 EU/mL (8554-11 999) in the 56-day interval group, and 11 312 mL (9072-14106) in the 84-day interval group, with antibody concentrations persisting at 1149-1205 EU/mL up to day 365.
INTERPRETATION: The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen.
FUNDING: Innovative Medicines Initiative and Janssen Vaccines & Prevention BV.
TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 33217361
Mary J Choi, Caitlin M Cossaboom, Amy N Whitesell, Jonathan W Dyal, Allison Joyce, Rebecca L Morgan, Doug Campos-Outcalt, Marissa Person, Elizabeth Ervin, Yon C Yu, Pierre E Rollin, Brian H Harcourt, Robert L Atmar, Beth P Bell, Rita Helfand, Inger K Damon, Sharon E Frey
Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020.
MMWR Recomm Rep. 2021 Jan 8;70(1):1-12. doi: 10.15585/mmwr.rr7001a1. Epub 2021 Jan 8.
Abstract/Text This report summarizes the recommendations of the Advisory Committee on Immunization Practices (ACIP) for use of the rVSVΔG-ZEBOV-GP Ebola vaccine (Ervebo) in the United States. The vaccine contains rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus (VSV) in which the gene encoding the glycoprotein of VSV was replaced with the gene encoding the glycoprotein of Ebola virus species Zaire ebolavirus. Persons with a history of severe allergic reaction (e.g., anaphylaxis) to rice protein should not receive Ervebo. This is the first and only vaccine currently licensed by the Food and Drug Administration for the prevention of Ebola virus disease (EVD). These guidelines will be updated based on availability of new data or as new vaccines are licensed to protect against EVD.ACIP recommends preexposure vaccination with Ervebo for adults aged ≥18 years in the U.S. population who are at highest risk for potential occupational exposure to Ebola virus species Zaire ebolavirus because they are responding to an outbreak of EVD, work as health care personnel at federally designated Ebola treatment centers in the United States, or work as laboratorians or other staff at biosafety level 4 facilities in the United States. Recommendations for use of Ervebo in additional populations at risk for exposure and other settings will be considered and discussed by ACIP in the future.

PMID 33417593
Stephen K Gire, Augustine Goba, Kristian G Andersen, Rachel S G Sealfon, Daniel J Park, Lansana Kanneh, Simbirie Jalloh, Mambu Momoh, Mohamed Fullah, Gytis Dudas, Shirlee Wohl, Lina M Moses, Nathan L Yozwiak, Sarah Winnicki, Christian B Matranga, Christine M Malboeuf, James Qu, Adrianne D Gladden, Stephen F Schaffner, Xiao Yang, Pan-Pan Jiang, Mahan Nekoui, Andres Colubri, Moinya Ruth Coomber, Mbalu Fonnie, Alex Moigboi, Michael Gbakie, Fatima K Kamara, Veronica Tucker, Edwin Konuwa, Sidiki Saffa, Josephine Sellu, Abdul Azziz Jalloh, Alice Kovoma, James Koninga, Ibrahim Mustapha, Kandeh Kargbo, Momoh Foday, Mohamed Yillah, Franklyn Kanneh, Willie Robert, James L B Massally, Sinéad B Chapman, James Bochicchio, Cheryl Murphy, Chad Nusbaum, Sarah Young, Bruce W Birren, Donald S Grant, John S Scheiffelin, Eric S Lander, Christian Happi, Sahr M Gevao, Andreas Gnirke, Andrew Rambaut, Robert F Garry, S Humarr Khan, Pardis C Sabeti
Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak.
Science. 2014 Sep 12;345(6202):1369-72. doi: 10.1126/science.1259657. Epub 2014 Aug 28.
Abstract/Text 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.

Copyright © 2014, American Association for the Advancement of Science.
PMID 25214632
Alpha Kabinet Keita, Fara R Koundouno, Martin Faye, Ariane Düx, Julia Hinzmann, Haby Diallo, Ahidjo Ayouba, Frederic Le Marcis, Barré Soropogui, Kékoura Ifono, Moussa M Diagne, Mamadou S Sow, Joseph A Bore, Sebastien Calvignac-Spencer, Nicole Vidal, Jacob Camara, Mamadou B Keita, Annick Renevey, Amadou Diallo, Abdoul K Soumah, Saa L Millimono, Almudena Mari-Saez, Mamadou Diop, Ahmadou Doré, Fodé Y Soumah, Kaka Kourouma, Nathalie J Vielle, Cheikh Loucoubar, Ibrahima Camara, Karifa Kourouma, Giuditta Annibaldis, Assaïtou Bah, Anke Thielebein, Meike Pahlmann, Steven T Pullan, Miles W Carroll, Joshua Quick, Pierre Formenty, Anais Legand, Karla Pietro, Michael R Wiley, Noel Tordo, Christophe Peyrefitte, John T McCrone, Andrew Rambaut, Youssouf Sidibé, Mamadou D Barry, Madeleine Kourouma, Cé D Saouromou, Mamadou Condé, Moussa Baldé, Moriba Povogui, Sakoba Keita, Mandiou Diakite, Mamadou S Bah, Amadou Sidibe, Dembo Diakite, Fodé B Sako, Fodé A Traore, Georges A Ki-Zerbo, Philippe Lemey, Stephan Günther, Liana E Kafetzopoulou, Amadou A Sall, Eric Delaporte, Sophie Duraffour, Ousmane Faye, Fabian H Leendertz, Martine Peeters, Abdoulaye Toure, N' Faly Magassouba
Resurgence of Ebola virus in 2021 in Guinea suggests a new paradigm for outbreaks.
Nature. 2021 Sep;597(7877):539-543. doi: 10.1038/s41586-021-03901-9. Epub 2021 Sep 15.
Abstract/Text Seven years after the declaration of the first epidemic of Ebola virus disease in Guinea, the country faced a new outbreak-between 14 February and 19 June 2021-near the epicentre of the previous epidemic1,2. Here we use next-generation sequencing to generate complete or near-complete genomes of Zaire ebolavirus from samples obtained from 12 different patients. These genomes form a well-supported phylogenetic cluster with genomes from the previous outbreak, which indicates that the new outbreak was not the result of a new spillover event from an animal reservoir. The 2021 lineage shows considerably lower divergence than would be expected during sustained human-to-human transmission, which suggests a persistent infection with reduced replication or a period of latency. The resurgence of Zaire ebolavirus from humans five years after the end of the previous outbreak of Ebola virus disease reinforces the need for long-term medical and social care for patients who survive the disease, to reduce the risk of re-emergence and to prevent further stigmatization.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
PMID 34526718

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