2017 Outbreak of Ebola Virus Disease in Northern Democratic Republic of Congo.

BACKGROUND: In 2017, the Democratic Republic of the Congo (DRC) recorded its eighth Ebola virus disease (EVD) outbreak, approximately 3 years after the previous outbreak. METHODS: Suspect cases of EVD were identified on the basis of clinical and epidemiological information. Reverse transcription-polymerase chain reaction (RT-PCR) analysis or serological testing was used to confirm Ebola virus infection in suspected cases. The causative virus was later sequenced from a RT-PCR-positive individual and assessed using phylogenetic analysis. RESULTS: Three probable and 5 laboratory-confirmed cases of EVD were recorded between 27 March and 1 July 2017 in the DRC. Fifty percent of cases died from the infection. EVD cases were detected in 4 separate areas, resulting in > 270 contacts monitored. The complete genome of the causative agent, a variant from the Zaireebolavirus species, denoted Ebola virus Muyembe, was obtained using next-generation sequencing. This variant is genetically closest, with 98.73% homology, to the Ebola virus Mayinga variant isolated from the first DRC outbreaks in 1976-1977. CONCLUSION: A single spillover event into the human population is responsible for this DRC outbreak. Human-to-human transmission resulted in limited dissemination of the causative agent, a novel Ebola virus variant closely related to the initial Mayinga variant isolated in 1976-1977 in the DRC.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

Clinical Management of Ebola Virus Disease Patients in Low-Resource Settings.

The low-resource environment deprives healthcare providers caring for patients with Ebola virus disease (EVD) of many of the means employed for the critically ill that are available in better resourced settings, such as advanced therapeutic interventions and abundant staff. In addition to these limitations may be added those imposed by the remote tropical locations, where EVD outbreaks occur. In this setting, a safe environment is created where healthcare workers may care for their patients over the evolving course of their acute illness into their convalescent period. Clinical management of EVD combines supportive and symptomatic care while also addressing the patient's emotional and mental health needs. A variety of specific therapies directly targeting the virus has become available, but none of these has, as of yet, conclusively demonstrated an impact. Healthcare workers caring for EVD patients must be constantly aware that they are part of a larger epidemic control operation, and their actions have consequences that go beyond their patients to their families and the community affected by the outbreak.

First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease.

A neonate born to an Ebola virus-positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus.

Operational Research during the Ebola Emergency.

Operational research aims to identify interventions, strategies, or tools that can enhance the quality, effectiveness, or coverage of programs where the research is taking place. Médecins Sans Frontières admitted ≈5,200 patients with confirmed Ebola virus disease during the Ebola outbreak in West Africa and from the beginning nested operational research within its emergency response. This research covered critical areas, such as understanding how the virus spreads, clinical trials, community perceptions, challenges within Ebola treatment centers, and negative effects on non-Ebola healthcare. Importantly, operational research questions were decided to a large extent by returning volunteers who had first-hand knowledge of the immediate issues facing teams in the field. Such a method is appropriate for an emergency medical organization. Many challenges were also identified while carrying out operational research across 3 different countries, including the basic need for collecting data in standardized format to enable comparison of findings among treatment centers.

Emergence of Zaire Ebola virus disease in Guinea.

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.

Dilemmas in Managing Pregnant Women With Ebola: 2 Case Reports.

We report 2 cases of Ebola viral disease (EVD) in pregnant women who survived, initially with intact pregnancies. Respectively 31-32 days after negativation of the maternal blood EVD-polymerase chain reaction (PCR) both patients delivered a stillborn fetus with persistent EVD-PCR amniotic fluid positivity.

Feasibility of Xpert Ebola Assay in Médecins Sans Frontières Ebola Program, Guinea.

Rapid diagnostic methods are essential in control of Ebola outbreaks and lead to timely isolation of cases and improved epidemiologic surveillance. Diagnosis during Ebola outbreaks in West Africa has relied on PCR performed in laboratories outside this region. Because time between sampling and PCR results can be considerable, we assessed the feasibility and added value of using the Xpert Ebola Assay in an Ebola control program in Guinea. A total of 218 samples were collected during diagnosis, treatment, and convalescence of patients. Median time for obtaining results was reduced from 334 min to 165 min. Twenty-six samples were positive for Ebola virus. Xpert cycle thresholds were consistently lower, and 8 (31%) samples were negative by routine PCR. Several logistic and safety issues were identified. We suggest that implementation of the Xpert Ebola Assay under programmatic conditions is feasible and represents a major advance in diagnosis of Ebola virus disease without apparent loss of assay sensitivity.

Electrolyte and Metabolic Disturbances in Ebola Patients during a Clinical Trial, Guinea, 2015.

By using data from a 2015 clinical trial on Ebola convalescent-phase plasma in Guinea, we assessed the prevalence of electrolyte and metabolic abnormalities at admission and their predictive value to stratify patients into risk groups. Patients underwent testing with a point-of-care device. We used logistic regression to construct a prognostic model and summarized the predictive value with the area under the receiver operating curve. Abnormalities were common among patients, particularly hypokalemia, hypocalcemia, hyponatremia, raised creatinine, high anion gap, and anemia. Besides age and PCR cycle threshold value, renal dysfunction, low calcium levels, and low hemoglobin levels were independently associated with increased risk for death. A prognostic model using all 5 factors was highly discriminatory (area under the receiver operating curve 0.95; 95% CI 0.90-0.99) and enabled the definition of risk criteria to guide targeted care. Most patients had a very low (<5%) or very high (>80%) risk for death.

Prognostic Indicators for Ebola Patient Survival.

To determine whether 2 readily available indicators predicted survival among patients with Ebola virus disease in Sierra Leone, we evaluated information for 216 of the 227 patients in Bo District during a 4-month period. The indicators were time from symptom onset to healthcare facility admission and quantitative real-time reverse transcription PCR cycle threshold (Ct), a surrogate for viral load, in first Ebola virus-positive blood sample tested. Of these patients, 151 were alive when detected and had reported healthcare facility admission dates and Ct values available. Time from symptom onset to healthcare facility admission was not associated with survival, but viral load in the first Ebola virus-positive blood sample was inversely associated with survival: 52 (87%) of 60 patients with a Ct of >24 survived and 20 (22%) of 91 with a Ct of <24 survived. Ct values may be useful for clinicians making treatment decisions or managing patient or family expectations.

The Contribution of Ebola Viral Load at Admission and Other Patient Characteristics to Mortality in a Médecins Sans Frontières Ebola Case Management Centre, Kailahun, Sierra Leone, June-October 2014.

This paper describes patient characteristics, including Ebola viral load, associated with mortality in a Médecins Sans Frontières Ebola case management centre (CMC).Out of 780 admissions between June and October 2014, 525 (67%) were positive for Ebola with a known outcome. The crude mortality rate was 51% (270/525). Ebola viral load (whole-blood sample) data were available on 76% (397/525) of patients. Univariate analysis indicated viral load at admission, age, symptom duration prior to admission, and distance traveled to the CMC were associated with mortality (P < .05). The multivariable model predicted mortality in those with a viral load at admission greater than 10 million copies per milliliter (P < .05, odds ratio >10), aged ≥ 50 years (P = .08, odds ratio = 2) and symptom duration prior to admission less than 5 days (P = .14). The presence of confusion, diarrhea, and conjunctivitis were significantly higher (P < .05) in Ebola patients who died.These findings highlight the importance viral load at admission has on mortality outcomes and could be used to cohort cases with viral loads greater than 10 million copies into dedicated wards with more intensive medical support to further reduce mortality.

Field Evaluation of Capillary Blood Samples as a Collection Specimen for the Rapid Diagnosis of Ebola Virus Infection During an Outbreak Emergency.

BACKGROUND: Reliable reverse transcription polymerase chain reaction (RT-PCR)-based diagnosis of Ebola virus infection currently requires a blood sample obtained by intravenous puncture. During the current Ebola outbreak in Guinea, we evaluated the usability of capillary blood samples collected from fingersticks of patients suspected of having Ebola virus disease (EVD) for field diagnostics during an outbreak emergency. METHODS: A total of 120 venous and capillary blood samples were collected from 53 patients admitted to the Ebola Treatment Centre in Guéckédou, Guinea, between July and August 2014. All sample specimens were analyzed by RT-PCR using the RealStar Filovirus Screen RT-PCR Kit 1.0 from altona Diagnostics (Germany). We compared samples obtained by venipuncture and those obtained by capillary blood sampling absorbed onto swab devices. RESULTS: The resulting sensitivity and specificity of tests performed with capillary blood samples were 86.8% (95% confidence interval [CI], 71.9%-95.6%; 33/38 patients) and 100% (95% CI, 84.6%-100%; 22/22 patients), respectively. CONCLUSIONS: Our data suggest that capillary blood samples could serve as an alternative to venous blood samples for the diagnosis of EVD in resource-limited settings during a crisis. This can be of particular advantage in cases when venipuncture is difficult to perform-for example, with newborns and infants or when adult patients reject venipuncture for cultural or religious reasons.

Ebola outbreak in rural West Africa: epidemiology, clinical features and outcomes.

OBJECTIVE: To describe Ebola cases in the district Ebola management centre of in Kailahun, a remote rural district of Sierra Leone, in terms of geographic origin, patient and hospitalisation characteristics, treatment outcomes and time from symptom onset to admission. METHODS: Data of all Ebola cases from June 23rd to October 5th 2014 were reviewed. Ebola was confirmed by reverse-transcriptase-polymerase-chain-reaction assay. RESULTS: Of 489 confirmed cases (51% male, median age 28 years), 166 (34%) originated outside Kailahun district. Twenty-eight (6%) were health workers: 2 doctors, 11 nurses, 2 laboratory technicians, 7 community health workers and 6 other cadres. More than 50% of patients had fever, headache, abdominal pain, diarrhoea/vomiting. An unusual feature was cough in 40%. Unexplained bleeding was reported in 5%. Outcomes for the 489 confirmed cases were 227 (47%) discharges, 259 (53%) deaths and 3 transfers. Case fatality in health workers (68%) was higher than other occupations (52%, P = 0.05). The median community infectivity time was 6.5 days for both general population and health workers (P = 0.4). CONCLUSIONS: One in three admitted cases originated outside Kailahun district due to limited national access to Ebola management centres - complicating contact tracing, safe burial and disinfection measures. The comparatively high case fatality among health workers requires attention. The community infectivity time needs to be reduced to prevent continued transmission.

Assessment of the MSF triage system, separating patients into different wards pending Ebola virus laboratory confirmation, Kailahun, Sierra Leone, July to September 2014.

Prevention of nosocomial Ebola virus (EBOV) infection among patients admitted to an Ebola management centre (EMC) is paramount. Current Médecins Sans Frontières (MSF) guidelines recommend classifying admitted patients at triage into suspect and highly-suspect categories pending laboratory confirmation. We investigated the performance of the MSF triage system to separate patients with subsequent EBOV-positive laboratory test (true-positive admissions) from patients who were initially admitted on clinical grounds but subsequently tested EBOV-negative (false-positive admissions). We calculated standard diagnostic test statistics for triage allocation into suspect or highly-suspect wards (index test) and subsequent positive or negative laboratory results (reference test) among 433 patients admitted into the MSF EMC Kailahun, Sierra Leone, between 1 July and 30 September 2014. 254 (59%) of admissions were classified as highly-suspect, the remaining 179 (41%) as suspect. 276 (64%) were true-positive admissions, leaving 157 (36.3%) false-positive admissions exposed to the risk of nosocomial EBOV infection. The positive predictive value for receiving a positive laboratory result after being allocated to the highly-suspect ward was 76%. The corresponding negative predictive value was 54%. Sensitivity and specificity were 70% and 61%, respectively. Results for accurate patient classification were unconvincing. The current triage system should be changed. Whenever possible, patients should be accommodated in single compartments pending laboratory confirmation. Furthermore, the initial triage step on whether or not to admit a patient in the first place must be improved. What is ultimately needed is a point-of-care EBOV diagnostic test that is reliable, accurate, robust, mobile, affordable, easy to use outside strict biosafety protocols, providing results with quick turnaround time.

An oral antiviral for Ebola disease.

For those exposed to filovirus, such as Sudan virus and Ebola virus, a new study offers hope.

Field evaluation of validity and feasibility of Pan-Lassa rapid diagnostic test for Lassa fever in Abakaliki, Nigeria: a prospective diagnostic accuracy study.

BACKGROUND: Lassa fever is a viral haemorrhagic fever with few options for diagnosis and treatment; it is also under-researched with knowledge gaps on its epidemiology. A point-of-care bedside test diagnosing Lassa fever, adhering to REASSURED criteria, is not currently available but is urgently needed in west African regions with high Lassa fever burden. We aimed to assess the validity and feasibility of a rapid diagnostic test (RDT) to confirm Lassa fever in people in Nigeria. METHODS: We estimated the diagnostic performance of the ReLASV Pan-Lassa RDT (Zalgen Labs, Frederick, MD, USA) as a research-use-only test, compared to RT-PCR as a reference standard, in 217 participants at a federal tertiary hospital in Abakaliki, Nigeria. We recruited participants between Feb 17, 2022, and April 17, 2023. The RDT was performed using capillary blood at the patient bedside and using plasma at the laboratory. The performance of the test, based on REASSURED criteria, was assessed for user friendliness, rapidity and robustness, sensitivity, and specificity. FINDINGS: Participants were aged between 0 and 85 years, with a median age of 33·0 years (IQR 22·0-44·3), and 24 participants were younger than 18 years. 107 (50%) participants were women and 109 (50%) were men; one participant had missing sex data. Although the specificity of the Pan-Lassa RDT was high (>90%), sensitivity at bedside using capillary blood was estimated as 4% (95% CI 1-14) at 15 min and 10% (3-22) at 25 min, far below the target of 90%. The laboratory-based RDT using plasma showed better sensitivity (46% [32-61] at 15 min and 50% [36-64] at 25 min) but did not reach the target sensitivity. Among the 52 PCR-positive participants with Lassa fever, positive RDT results were associated with lower cycle threshold values (glycoprotein precursor [GPC] gene mean 30·3 [SD 4·3], Large [L] gene mean 32·3 [3·7] vs GPC gene mean 24·5 [3·9], L gene mean 28·0 [3·6]). Personnel conducting the bedside test procedure reported being hindered by the inconvenient use of full personal protective equipment and long waiting procedures before a result could be read. INTERPRETATION: The Pan-Lassa RDT is not currently recommended as a diagnostic or screening tool for suspected Lassa fever cases. Marked improvement in sensitivity and user friendliness is needed for the RDT to be adopted clinically. There remains an urgent need for better Lassa fever diagnostics to promote safety of in-hospital care and better disease outcomes in low-resource settings. FUNDING: Médecins Sans Frontières.

Filovirus hemorrhagic fever outbreak case management: a review of current and future treatment options.

Testing an innovative therapy for filovirus hemorrhagic fever (FHF) in an outbreak setting may be years away. Moreover, beyond anecdotal evidence, little is known about best practice for outbreak case management. Currently, Médecins Sans Frontières and others provide FHF patients with basic supportive treatment. We describe and discuss treatment possibilities, challenges, and potential next steps for FHF outbreak case management. More comprehensive supportive treatment, including vital sign monitoring, intensive care components, and goal-directed interventions may contribute to improved clinical outcome; the feasibility and effectiveness of this more comprehensive supportive treatment should be assessed. Our outlined summary may assist future FHF outbreak case management teams to create collaborative platforms and develop relevant treatment protocols aimed at improving clinical outcome.

Effectiveness of typhoid conjugate vaccine in Zimbabwe used in response to an outbreak among children and young adults: A matched case control study.

BACKGROUND: Zimbabwe suffers from regular outbreaks of typhoid fever (TF), worse since 2017. Most cases were in Harare and a vaccination campaign with Typhoid Conjugate Vaccine (TCV) was conducted in March 2019. The vaccine effectiveness (VE) was assessed against culture-confirmed S. Typhi in children six months to 15 years and in individuals six months to 45 years in Harare. METHODS: A matched case-control study was conducted in three urban suburbs of Harare targeted by the TCV vaccination campaign. Suspected TF cases were enrolled prospectively in four health facilities and were matched to facility (1:1) and community (1:5) controls. FINDINGS: Of 504 suspected cases from July 2019 to March 2020, 148 laboratory-confirmed TF cases and 153 controls confirmed-negative were identified. One hundred and five (47 aged six months to 15 years) cases were age, sex, and residence matched with 105 facility-based controls while 96 cases were matched 1:5 by age, sex, and immediate-neighbour with 229 community controls. The adjusted VE against confirmed TF was 75% (95%CI: 1-94, p = 0.049) compared to facility controls, and 84% (95%CI: 57-94, p < 0.001) compared to community controls in individuals six months to 15 years. The adjusted VE against confirmed TF was 46% (95%CI: 26-77, p = 0.153) compared to facility controls, and 67% (95%CI: 35-83, p = 0.002) compared to community controls six months to 45 years old. INTERPRETATION: This study confirms that one vaccine dose of TCV is effective to control TF in children between six months and 15 years old in an African setting.