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In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality. Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses. ClinicalTrials.gov NCT02329054.
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Performing patient care while wearing high-level personal protective equipment presents risks to healthcare providers. Our failure mode effects analysis identified 81 overall risks associated with providing hygienic care and linen change to a patient with continuous watery stool. Implementation of checklists and scheduled pauses could potentially mitigate 76.5% of all risks. Infect Control Hosp Epidemiol 2016;37:867-871.
Few fetuses survive childbirth when the mother is positive for Ebola virus, with almost all being miscarried or stillborn, or dying shortly after birth. Before 2019, only two infants had been reported surviving past 28 days, of whom one tested positive for Ebola virus and subsequently received experimental therapies. Little is understood regarding the care of surviving neonates born to Ebola virus-positive mothers in the postnatal period and how novel anti-Ebola virus therapies might affect neonatal outcomes. In this case series, we report on two neonates liveborn during the 2018-20 North Kivu Ebola epidemic in the Democratic Republic of the Congo who, along with their Ebola virus-positive mothers, received investigational monoclonal antibody treatment (mAB114 or REGN-EB3) as part of a randomised controlled trial (NCT03719586). Both infants were born Ebola-negative and progressed well while in the Ebola Treatment Centre. Neither neonate developed evidence of Ebola virus disease during the course of the admission, and both were Ebola-negative at 21 days and remained healthy at discharge. To our knowledge these neonates are the first documented as Ebola virus-negative at birth after being born to Ebola virus-positive mothers, and only the third and fourth neonates ever documented to have survived into infancy. Although no conclusions can be drawn from this small case series, and further research is required to investigate the neonatal effects of antibody therapies, these cases warrant review regarding whether post-delivery antibody therapy should be considered for all liveborn neonates of Ebola virus-positive mothers. In the context of a low resource setting, where survival of low-birthweight infants is poor, these cases also highlight the importance of adequate neonatal care. None.
ZMAb is a promising treatment against Ebola virus (EBOV) disease that has been shown to protect 50% (two of four) of nonhuman primates (NHPs) when administered 2 days post-infection (dpi). To extend the treatment window and improve protection, we combined ZMAb with adenovirus-vectored interferon-α (Ad-IFN) and evaluated efficacy in EBOV-infected NHPs. Seventy-five percent (three of four) and 100% (four of four) of cynomolgus and rhesus macaques survived, respectively, when treatment was initiated after detection of viremia at 3 dpi. Fifty percent (two of four) of the cynomolgus macaques survived when Ad-IFN was given at 1 dpi, followed by ZMAb starting at 4 dpi, after positive diagnosis. The treatment was able to suppress viremia reaching ~10(5) TCID50 (median tissue culture infectious dose) per milliliter, leading to survival and robust specific immune responses. This study describes conditions capable of saving 100% of EBOV-infected NHPs when initiated after the presence of detectable viremia along with symptoms.
Ebola virus disease (EVD) is a serious illness with mortality rates of 20-90% in various outbreaks. EVD is characterized by robust virus replication and strong host inflammatory response. Analyzing host immune responses has increasingly involved multimodal approaches including transcriptomics to profile gene expression. We studied cynomolgus macaques exposed to Ebola virus Makona via different routes with the intent of comparing RNA-Seq to a NanoString nCounter codeset targeting 769 non-human primate (NHP) genes. RNA-Seq analysis of serial blood samples showed different routes led to the same overall transcriptional response seen in previously reported EBOV-exposed NHP studies. Both platforms displayed a strong correlation in gene expression patterns, including a strong induction of innate immune response genes at early times post-exposure, and neutrophil-associated genes at later time points. A 41-gene classifier was tested in both platforms for ability to cluster samples by infection status. Both NanoString and RNA-Seq could be used to predict relative abundances of circulating immune cell populations that matched traditional hematology. This demonstrates the complementarity of RNA-Seq and NanoString. Moreover, the development of an NHP-specific NanoString codeset should augment studies of filoviruses and other high containment infectious diseases without the infrastructure requirements of RNA-Seq technology.
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Treatment of infections that require high-level isolation can cause anxiety and fear among health care workers. Adequate and complete multi-professional simulation-based training could reduce those feelings and improve patient care. The purpose of this study was to assess the impact of multi-professional simulation-based training on the risk perception and preparedness of health care workers (registered nurses, doctors and ancillary staff) who care for patients assessed to be at risk or confirmed to have Ebola, level 3-4 biohazard. A prospective before-after study was designed. Health care workers who participated in a multi-professional simulation training course to improve the care of patients potentially infected with Level 3 and 4 biohazards were evaluated about their risk perception. The training was based on clinical scenarios. The evaluation was conducted using questionnaire based on Likert scale. After the training, a satisfaction survey about the most important aspects of the course was also conducted. Fifty-eight health care workers participated in the training course, 22 of whom were registered nurses. Participants presented positive changes after the training, increasing their sense of security, predisposition and confidence (p < 0.000001 for all). Multi-professional simulation-based training significantly improves the perception of safety and preparedness of health care workers regarding the care of patients potentially infected with Ebola virus and other Level 3-4 biohazards. The implementation of educational training strategies - such as simulations - is beneficial in improving the capacity of response and coping, as well as in reducing feelings of fear and insecurity.
We sought to summarize knowledge, misconceptions, beliefs, and practices about Ebola that might impede the control of Ebola outbreaks in Africa. We searched Medline, EMBASE, CINAHL, and Google Scholar (through May 2019) for publications reporting on knowledge, attitudes, and practices (KAP) related to Ebola in Africa. In total, 14 of 433 articles were included. Knowledge was evaluated in all 14 articles, and they all highlighted that there are misconceptions and risk behaviors during an Ebola outbreak. Some communities believed that Ebola spreads through the air, mosquito bites, malice from foreign doctors, witchcraft, and houseflies. Because patients believe that Ebola was caused by witchcraft, they sought help from traditional healers. Some people believed that Ebola could be prevented by bathing with salt or hot water. Burial practices where people touch Ebola-infected corpses were common, especially among Muslims. Discriminatory attitudes towards Ebola survivors or their families were also prevalent. Some Ebola survivors were not accepted back in their communities; the possibility of being ostracized from their neighborhoods was high and Ebola survivors had to lead a difficult social life. Most communities affected by Ebola need more comprehensive knowledge on Ebola. Efforts are needed to address misconceptions and risk behaviors surrounding Ebola for future outbreak preparedness in Africa.
We recently described a simple model through which we assessed what effect subjecting travellers to a single on-arrival test might have on reducing risk of importing disease cases during simulated outbreaks of coronavirus disease 2019 (COVID-19), influenza, severe acute respiratory syndrome (SARS) and Ebola. We build upon this work to allow for the additional requirement that inbound travellers also undergo a period of self-isolation upon arrival, where upon completion the traveller is again tested for signs of infection prior to admission across the border. Prior results indicated that a single on-arrival test has the potential to detect 9% of travellers infected with COVID-19, compared to 35%, 10% and 3% for travellers infected with influenza, SARS and Ebola, respectively. Our extended model shows that testing administered after a 2-day isolation period could detect up to 41%, 97%, 44% and 15% of COVID-19, influenza, SARS and Ebola infected travellers, respectively. Longer self-isolation periods increase detection rates further, with an 8-day self-isolation period suggesting detection rates of up to 94%, 100%, 98% and 62% for travellers infected with COVID-19, influenza, SARS and Ebola, respectively. These results therefore suggest that testing arrivals after an enforced period of self-isolation may present a reasonable method of protecting against case importation during international outbreaks.
Blood transfusion in sub-Saharan Africa (SSA) is at a crossroad. Significant recent developments may help meet local needs in safe blood products and fulfil a global health target, as highlighted by the World Health Organization (WHO) Millennium and Sustainable Development Goals, in improving supply and safety, and ensuring the gradual implementation of selective haemotherapy. When WHO recommended the evaluation of convalescent blood or plasma to treat Ebola-infected patients during the recent epidemics, substantial gaps in local blood collection, testing and technology infrastructure and safety, as compared to best accepted quality standards, became evident. This evidence should now serve as an 'electro-shock'/awakening call used to highlight the needs for local governments to support National Blood Transfusion Services and establish robust national regulatory authorities that are mandated to bear regulatory responsibilities of blood establishments. A nationally co-ordinated blood programme is the best tool to gather reliable epidemiological data, address local needs in blood and blood products and serve public health. A literature review using WHO website and PubMed was conducted in this article to outline the current clinical use of blood products and plasma derivatives in SSA. This text also intends to highlight the gaps to be filled in the coming years with respect to quality, safety, supply and efficacy of blood and plasma products, in line with WHO guidelines for transfusion.
In the current COVID-19 pandemic, evidence to justify the use of any specific antiviral drug with proven efficacy is not yet available. Antiviral drug development always remains a challenge to the scientists. Remdesivir has emerged as a promising molecule, based on results of clinical trials and observational studies and has receieved marketing approval for COVID-19 treatment under "emergency use authorization" in countries such as United States. Remdesivir is a newer antiviral drug that acts as an RNA-dependent RNA polymerase (RdRp) inhibitor targeting the viral genome replication process. Therapeutic efficacy was first demonstrated by suppressing viral replication in Ebola-infected rhesus monkeys. It is available for parenteral use with reasonable safety and tolerability profile. Multiple clinical trials are going on in many countries to evaluate its safety, efficacy and tolerability. Positive outcome will make the drug capable of meeting the demand generated by both the current pandemic and future outbreak. Choudhury S, Chakraborty DS, Lahiry S, Chatterjee S. Past, Present, and Future of Remdesivir: An Overview of the Antiviral in Recent Times. Indian J Crit Care Med 2020;24(7):570-574.
The 2013-2016 Ebola virus outbreak in West Africa was the largest and deadliest outbreak to date. Here we conducted a serological study to examine the antibody levels in survivors and the seroconversion in close contacts who took care of Ebola-infected individuals, but did not develop symptoms of Ebola virus disease. In March 2017, we collected blood samples from 481 individuals in Makeni, Sierra Leone: 214 survivors and 267 close contacts. Using commercial, quantitative ELISAs, we tested the plasma for IgG-specific antibodies against three major viral antigens: GP, the only viral glycoprotein expressed on the virus surface; NP, the most abundant viral protein; and VP40, a major structural protein of Zaire ebolavirus. We also determined neutralizing antibody titers. In the cohort of Ebola survivors, 97.7% of samples (209/214) had measurable antibody levels against GP, NP, and/or VP40. Of these positive samples, all but one had measurable neutralizing antibody titers against Ebola virus. For the close contacts, up to 12.7% (34/267) may have experienced a subclinical virus infection as indicated by detectable antibodies against GP. Further investigation is warranted to determine whether these close contacts truly experienced subclinical infections and whether these asymptomatic infections played a role in the dynamics of transmission.
Human Ebola infection is characterized by a paralysis of the immune system. A signature of αβ T cells in fatal Ebola infection has been recently proposed, while the involvement of innate immune cells in the protection/pathogenesis of Ebola infection is unknown. Aim of this study was to analyze γδ T and NK cells in patients from the Ebola outbreak of 2014-2015 occurred in West Africa, and to assess their association with the clinical outcome. Nineteen Ebola-infected patients were enrolled at the time of admission to the Ebola Treatment Centre in Guinea. Patients were divided in two groups on the basis of the clinical outcome. The analysis was performed by using multiparametric flow cytometry established by the European Mobile Laboratory in the field. A low frequency of Vδ2 T-cells was observed during Ebola infection, independently from the clinical outcome. Moreover, Vδ2 T-cells from Ebola patients massively expressed CD95 apoptotic marker, suggesting the involvement of apoptotic mechanisms in Vδ2 T-cell loss. Interestingly, Vδ2 T-cells from survivors expressed an effector phenotype and presented a lower expression of the CTLA-4 exhaustion marker than fatalities, suggesting a role of effector Vδ2 T-cells in the protection. Furthermore, patients with fatal Ebola infection were characterized by a lower NK cell frequency than patients with non fatal infection. In particular, both CD56bright and CD56dim NK frequency were very low both in fatal and non fatal infections, while a higher frequency of CD56neg NK cells was associated to non-fatal infections. Finally, NK activation and expression of NKp46 and CD158a were independent from clinical outcome. Altogether, the data suggest that both effector Vδ2 T-cells and NK cells may play a role in the complex network of protective response to EBOV infection. Further studies are required to characterize the protective effector functions of Vδ2 and NK cells.
In response to the unprecedented Ebola virus disease (Ebola) outbreak in West Africa, the U.S. government deployed approximately 2,500 military personnel to support the government of Liberia. Their primary missions were to construct Ebola treatment units (ETUs), train health care workers to staff ETUs, and provide laboratory testing capacity for Ebola. Service members were explicitly prohibited from engaging in activities that could result in close contact with an Ebola-infected patient or coming in contact with the remains of persons who had died from unknown causes. Military units performed twice-daily monitoring of temperature and review of exposures and symptoms ("unit monitoring") on all persons throughout deployment, exit screening at the time of departure from Liberia, and post-deployment monitoring for 21 days at segregated, controlled monitoring areas on U.S. military installations. A total of 32 persons developed a fever during deployment from October 25, 2014, through February 27, 2015; none had a known Ebola exposure or developed Ebola infection. Monitoring of all deployed service members revealed no Ebola exposures or infections. Given their activity restrictions and comprehensive monitoring while deployed to Liberia, U.S. military personnel constitute a unique population with a lower risk for Ebola exposure compared with those working in the country without such measures.
The 2013-2016 West Africa Ebola virus disease pandemic was the largest, longest, deadliest, and most geographically expansive outbreak in the 40-year interval since Ebola was first identified. Fear-related behaviors played an important role in shaping the outbreak. Fear-related behaviors are defined as "individual or collective behaviors and actions initiated in response to fear reactions that are triggered by a perceived threat or actual exposure to a potentially traumatizing event. FRBs modify the future risk of harm." This review examines how fear-related behaviors were implicated in (1) accelerating the spread of Ebola, (2) impeding the utilization of life-saving Ebola treatment, (3) curtailing the availability of medical services for treatable conditions, (4) increasing the risks for new-onset psychological distress and psychiatric disorders, and (5) amplifying the downstream cascades of social problems. Fear-related behaviors are identified for each of these outcomes. Particularly notable are behaviors such as treating Ebola patients in home or private clinic settings, the "laying of hands" on Ebola-infected individuals to perform faith-based healing, observing hands-on funeral and burial customs, foregoing available life-saving treatment, and stigmatizing Ebola survivors and health professionals. Future directions include modeling the onset, operation, and perpetuation of fear-related behaviors and devising strategies to redirect behavioral responses to mass threats in a manner that reduces risks and promotes resilience.
Future infectious disease epidemics are likely to disproportionately affect countries with weak health systems, exacerbating global vulnerability. To decrease the severity of epidemics in these settings, lessons can be drawn from the Ebola outbreak in West Africa. There is a dearth of literature on public perceptions of the public health response system that required citizens to report and treat Ebola cases. Epidemiological reports suggested that there were delays in diagnosis and treatment. The purpose of our study was to explore the barriers preventing Sierra Leoneans from trusting and using the Ebola response system during the height of the outbreak. Using an experienced ethnographer, we conducted 30 semi-structured in-depth interviews in public spaces in Ebola-affected areas. Participants were at least age 18, spoke Krio, and reported no contact in the recent 21 days with an Ebola-infected person. We used inductive coding and noted emergent themes. Most participants feared that calling the national hotline for someone they believed had Ebola would result in that person's death. Many stated that if they developed a fever they would assume it was not Ebola and self-medicate. Some thought the chlorine sprayed by ambulance workers was toxic. Although most knew there was a laboratory test for Ebola, some erroneously assumed the ubiquitous thermometers were the test and most did not understand the need to re-test in the presence of Ebola symptoms. Fears and misperceptions, related to lack of trust in the response system, may have delayed care-seeking during the Ebola outbreak in Sierra Leone. Protocols for future outbreak responses should incorporate dynamic, qualitative research to understand and address people's perceptions. Strategies that enhance trust in the response system, such as community mobilization, may be particularly effective.
Newly returned from the frontline of the battle against Ebola in West Africa, Dr George Fu Gao talked to NSR on this largest Ebola epidemic in history. As Deputy Director-General of the Chinese Center for Disease Control and Prevention (China CDC), an Academician of the Chinese Academy of Sciences and a fellow of the Third World Academy of Sciences (TWAS), Dr Gao has been personally involved in the fight against acute infectious diseases both on the laboratory bench and in the field for many years. Recalling the sight of an Ebola-infected young man stumbling to his death on the street and observing the continuing climb of patient statistics, he anxiously calls for larger global help to affected countries. The help provided by the world community to West Africa was 'too late and insufficient', and in this age of globalization 'no country can care only for herself alone'. In this interview, Dr Gao also reviews the history, progression, and prognosis of the Ebola epidemic, the cause of failure in the early prevention and containment of the disease, the role of government policies and public health systems, and global prospects and strategies for similar acute infectious diseases in the future.
The current West African outbreak of the Ebola virus disease (EVD) began in Guinea in December 2013 and rapidly spread to Liberia and Sierra Leone. On 20 July 2014, a sick individual flew into Lagos, Nigeria, from Monrovia, Liberia, setting off an outbreak in Lagos and later in Port Harcourt city. The government of Nigeria, supported by the World Health Organization and other partners, mounted a response to the outbreak relying on the polio program experiences and infrastructure. On 20 October 2014, the country was declared free of EVD. We examined the organization and operations of the response to the 2014 EVD outbreak in Nigeria and how experiences and support from the country's polio program infrastructure accelerated the outbreak response. The deputy incident manager of the National Polio Emergency Operations Centre was appointed the incident manager of the Ebola Emergency Operations Centre (EEOC), the body that coordinated and directed the response to the EVD outbreak in the country. A total of 892 contacts were followed up, and blood specimens were collected from 61 persons with suspected EVD and tested in designated laboratories. Of these, 19 (31%) were positive for Ebola, and 11 (58%) of the case patients were healthcare workers. The overall case-fatality rate was 40%. EVD sensitization and training were conducted during the outbreak and for 2 months after the outbreak ended. The World Health Organization deployed its surveillance and logistics personnel from non-Ebola-infected states to support response activities in Lagos and Rivers states. The support from the polio program infrastructure, particularly the coordination mechanism adopted (the EEOC), the availability of skilled personnel in the polio program, and lessons learned from managing the polio eradication program greatly contributed to the speedy containment of the 2014 EVD outbreak in Nigeria.