Ebola Virus Disease Survivors Research Articles

Distinct antibody profiles against Ebola virus track with the development of Post-Ebola Syndrome.

Abstract Survivors of Ebola virus disease (EVD) have reported a wide range of symptoms following recovery from infection. These long-term sequelae, collectively termed post-Ebola syndrome (PES), can significantly impact the daily lives of EVD survivors, yet little is known about the underlying mechanism of PES pathogenesis. Antibodies against Ebola virus provide protection against infection through both neutralization and recruitment of innate immune effector functions via the antibody Fc region, yet persistent antibody-mediated inflammation may contribute to PES manifestations. To investigate the potential role that virus-specific antibodies have in PES, we analyzed the antibody immune profiles in a cohort of EVD survivors and household contacts that had been previously characterized for clinical sequelae. Antibodies isolated from survivors an average of 2.5 years after recovery were measured for induction of Fc-mediated innate effector function against the immunodominant antigen Ebola glycoprotein-coated targets. We found that antibodies in asymptomatic EVD survivors were qualitatively different from survivors experiencing musculoskeletal and gastrointestinal manifestations of PES. Specifically, antibodies from asymptomatic individuals induced higher levels of antibody-dependent complement deposition and monocyte-mediated phagocytosis, but not neutrophil-mediated phagocytosis, and differed in NK cell activation profiles compared with individuals with PES. Together, these data suggest that the development of qualitatively different antibodies may shape susceptibility to/protection from the development of PES and may help identify potential therapeutic targets for EVD survivors suffering from PES. Supported by Washington State University, College of Veterinary Medicine

Ebola virus persistence and disease recrudescence in the brains of antibody-treated nonhuman primate survivors.

Effective therapeutics have been developed against acute Ebola virus disease (EVD) in both humans and experimentally infected nonhuman primates. However, the risk of viral persistence and associated disease recrudescence in survivors receiving these therapeutics remains unclear. In contrast to rhesus macaques that survived Ebola virus (EBOV) exposure in the absence of treatment, we discovered that EBOV, despite being cleared from all other organs, persisted in the brain ventricular system of rhesus macaque survivors that had received monoclonal antibody (mAb) treatment. In mAb-treated macaque survivors, EBOV persisted in macrophages infiltrating the brain ventricular system, including the choroid plexuses. This macrophage infiltration was accompanied by severe tissue damage, including ventriculitis, choroid plexitis, and meningoencephalitis. Specifically, choroid plexus endothelium-derived EBOV infection led to viral persistence in the macaque brain ventricular system. This resulted in apoptosis of ependymal cells, which constitute the blood-cerebrospinal fluid barrier of the choroid plexuses. Fatal brain-confined recrudescence of EBOV infection manifested as severe inflammation, local pathology, and widespread infection of the ventricular system and adjacent neuropil in some of the mAb-treated macaque survivors. This study highlights organ-specific EBOV persistence and fatal recrudescent disease in rhesus macaque survivors after therapeutic treatment and has implications for the long-term follow-up of human survivors of EVD.

A post-outbreak assessment of exposure proximity and Ebola virus disease-related stigma among community members in Kono District, Sierra Leone: A cross-sectional study

BackgroundBased on findings from other contexts, informed by intergroup contact theory, that more contact is associated with less stigma, we hypothesized that community members with greater exposure to cases of Ebola virus disease (EVD) were less likely to report EVD-related stigma towards EVD survivors. We assessed personal stigmatizing attitudes towards Ebola survivors, which reflects personal fear and judgement, as well as perceived stigma towards EVD survivors, which reflects an individual’s perception of the attitudes of the community towards a stigmatized group. MethodsFrom September 2016 to July 2017, we conducted a cross-sectional, community-based study of EVD-related stigma among individuals who did not contract Ebola in four EVD-affected rural communities of Kono District, Sierra Leone. We identified individuals from all quarantined households and obtained a random sample of those who were unexposed. Exposed individuals either lived in a quarantined household or were reported to have been in contact with an EVD case. Our explanatory variable was proximity to an EVD case during the outbreak. Our primary outcome was stigma towards EVD survivors, measured by a 6-item adapted HIV-related stigma index validated in Zambia and South Africa, with 1 item reflecting personal stigmatizing attitudes and 5 items reflecting perceived community stigma. The 6-item EVD stigma index had good internal consistency (Cronbach's alpha=0.82). We used modified Poisson and negative binomial regression models, adjusting for potential confounders, to estimate the association between exposure proximity and EVD stigma. ResultsWe interviewed 538 participants aged 12 to 85 years. Most (57%) had been quarantined. Over one-third (39%) reported personal stigmatizing attitudes or perceived community stigma; the most frequently endorsed item was fear and judgment towards EVD survivors. Having contact with someone with EVD was significantly associated with a lower likelihood of perceived community stigma (prevalence ratio [PR], 0.26; 95% CI, 0.13–0.54) and personal stigmatizing attitudes (PR, 0.44; 95% CI, 0.29–0.65). In contrast, being quarantined was significantly associated with a higher likelihood of perceived community stigma (PR, 3.9; 95% CI, 1.5–10.1) ConclusionsIn this cross-sectional study, we found evidence of an inverse relationship between EVD-related stigma and contact with an EVD case. This finding substantiates intergroup contact theory and may form the basis for anti-stigma interventions.

Health-related quality of life among Ebola survivors in Sierra Leone: the role of socio-demographic, health-related and psycho-social factors

BackgroundEvidence of how social factors affect the health-related quality of life (HRQoL) of Ebola virus disease (EVD) survivors is limited. Our study explores the association between socio-demographic, health-related and psycho-social (stigma) factors and EVD survivors' health-related quality of life (HRQoL) in Sierra Leone.MethodsWe conducted a nationwide cross-sectional study among 358 EVD survivors between January and August 2018. We used a multistage sampling method to recruit EVD survivors, and the RAND 36-Item Health Survey item was used to assess the HRQoL. Data were analysed using descriptive statistics and multiple linear regression.ResultsWhen comparing by each dimension in relation to their respective summary scores, role limitation physical [0.00 (50.00)] and role limitation emotional [0.00 (33.33)] were the most affected physical health and mental health domains among EVD survivors respectively. EVD survivors who were older (β = − 3.90, 95% CI − 6.47 to − 1.32, p = 0.003), had no formal education (β = − 2.80, 95% CI − 5.16 to − 0.43, p = 0.021), experienced a unit increase in the number of post-Ebola symptoms (β = − 1.08, 95% CI − 1.74 to − 0.43, p < 0.001) and experienced a unit increase in enacted stigma (β = − 2.61, 95% CI − 4.02 to − 1.20, p < 0.001) were more likely to report a decreased level of physical health. EVD survivors who experienced a unit increase in the time spent in the Ebola treatment centre (β = − 0.60, 95% CI − 0.103 to − 0.18, p = 0.006) and those who experienced a unit increase in enacted Stigma were more likely to report decreased levels of mental health (β = − 1.50, 95% CI − 2.67 to − 0.33, p = 0.012).ConclusionSociodemographic, health-related, and psycho-social factors were significantly associated with decrease levels of HRQoL. Our findings improve our understanding of the factors that might influence the HRQoL and suggest the need for EVD survivors to be provided with a comprehensive healthcare package that caters for their physical and mental health needs.

Triangulating Evidence to Infer Pathways that Influence Ebola Virus Disease-Related Stigma and Clinical Findings among Survivors: An Observational Cohort Study.

Visible signs of disease can evoke stigma while stigma contributes to depression and mental illness, sometimes manifesting as somatic symptoms. We assessed these hypotheses among Ebola virus disease (EVD) survivors, some of whom experienced clinical sequelae. Ebola virus disease survivors in Liberia were enrolled in an observational cohort study starting in June 2015 with visits every 6 months. At baseline and 18 months later, a seven-item index of EVD-related stigma was administered. Clinical findings (self-reported symptoms and abnormal findings) were obtained at each visit. We applied the generalized estimating equation method to assess the bidirectional concurrent and lagged associations between clinical findings and stigma, adjusting for age, gender, educational level, referral to medical care, and HIV serostatus as confounders. When assessing the contribution of stigma to later clinical findings, we restricted clinical findings to five that were also considered somatic symptoms. Data were obtained from 859 EVD survivors. In concurrent longitudinal analyses, each additional clinical finding increased the adjusted odds of stigma by 18% (95% CI: 1.11, 1.25), particularly palpitations, muscle pain, joint pain, urinary frequency, and memory loss. In lagged associations, memory loss (adjusted odds ratio [AOR]: 4.6; 95% CI: 1.73, 12.36) and anorexia (AOR: 4.17; 95% CI: 1.82, 9.53) were associated with later stigma, but stigma was not significantly associated with later clinical findings. Stigma was associated with select symptoms, not abnormal objective findings. Lagged associations between symptoms and later stigma substantiate the possibility of a pathway related to visible symptoms identified by community members and leading to fear of contagion.

Fear, distress, and perceived risk shape stigma toward Ebola survivors: a prospective longitudinal study

BackgroundDuring the 2014–15 Ebola Virus Disease (EVD) epidemic, thousands of people in Sierra Leone were infected with the devastating virus and survived. Years after the epidemic was declared over, stigma toward EVD survivors and others affected by the virus is still a major concern, but little is known about the factors that influence stigma toward survivors. This study examines how key personal and ecological factors predicted EVD-related stigma at the height of the 2014–2015 epidemic in Sierra Leone, and the personal and ecological factors that shaped changes in stigma over time.MethodsUsing three waves of survey data from a representative sample in the Western Urban and Western Rural districts of Sierra Leone, this study examines factors associated with self-reported personal stigma toward Ebola survivors (11 items, α = 0.77) among 1008 adults (74.6% retention rate) from 63 census enumeration areas of the Western Rural and Western Urban districts of Sierra Leone. Participants were randomly sampled at the height of the EVD epidemic and followed up as the epidemic was waning and once the epidemic had been declared over by the WHO. Three-level mixed effects models were fit using Stata 16 SE to examine cross-sectional associations as well as predictors of longitudinal changes in stigma toward EVD survivors.ResultsAt the height of the EVD epidemic, female sex, household wealth, post-traumatic stress, EVD-related fear and perceived infection risk are a few of the factors which predicted higher levels of stigma toward survivors. On average, stigma toward EVD survivors decreased significantly as the epidemic declined in Sierra Leone, but female sex, EVD fear, and risk perceptions predicted a slower rate of change.ConclusionThis study identified key individual and psychosocial characteristics which may predict higher levels of stigma toward infectious disease survivors. Future studies should pursue a better understanding of how personal characteristics and perceptions, including psychosocial distress, fear, and perceived infection risk serve as pathways for stigma in communities affected by infectious disease.

Temporal evolution of the humoral antibody response after Ebola virus disease in Guinea: a 60-month observational prospective cohort study

Insufficient long-term data are available on antibody kinetics in survivors of Ebola virus disease (EVD). Likewise, few studies, with very small sample sizes, have investigated cross-reactions between Ebolavirus spp. In this study, we aimed to assess the humoral antibody response and its determinants in survivors of EVD and assess cross-reactivity of antibodies between diverse Ebolavirus spp. In this observational, prospective cohort study, we collected blood samples from patients from three recruitment sites in Guinea included in the Postebogui study, and we assessed IgG antibody binding to recombinant glycoprotein, nucleoprotein, and 40-kDa viral protein (VP40) of Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) Ebolaviruses. Participants from the PostEbogui study, from whom we had at least one blood sample that could be tested for the presence of antibodies, were eligible for this analysis. Patients in the PostEbogui study were assessed clinically at inclusion, 1 month and 3 months later, and subsequently every 6 months for up to 60 months after discharge from the Ebola treatment centre. We explored predictors of glycoprotein, nucleoprotein, and VP40 antibody concentrations through a linear mixed model. A logistic mixed model was done to estimate the probability of seropositivity and associated determinants. We assessed cross-reactivity by use of hierarchical cluster analysis. Of the 802 patients included in the Postebogui study, 687 were included in our analyses. 310 (45%) patients were men and 377 (55%) were women, with an overall median age at the time of the first blood sample of 27·3 years (IQR 19·5-38·2). We observed an overall significant decrease over time of EBOV antibodies, with antibodies against nucleoproteins decreasing more rapidly. At 60 months after discharge from the Ebola treatment centre, the probability of having antibodies against glycoproteins was 76·2% (95% CI 67·2-83·3), against nucleoproteins was 59·4% (46·3-71·3), and against VP40 was 60·9% (51·4-69·8). Persistence of EBOV RNA in semen was associated with higher concentrations of IgG antibodies against nucleoprotein EBOV antigens. Individually, we observed in some survivors an antibody wax-and-wane pattern. The proportion of cross-reactions was highest between glycoproteins from Kissidougou and Mayinga EBOV strains (94·5%, 95% CI 92·5-96·1), followed by EBOV VP40 and BDBV VP40 (88·3%, 85·7-90·6), and EBOV VP40 and SUDV VP40 (83·3%, 80·3-86·1). The probability for survivors of EVD to have antibodies against one or more EBOV antigens remained high, although approximately 25% of survivors had undetectable antibodies, which could have implications, such as a possible decreasing population immunity, for future Ebola outbreaks in the same region. Reacting-Institut National de la Santé et de la Recherche Médicale, Institut de Recherche pour le Developpement, and Montpellier Université d'Excellence.

Proteo-Genomic Analysis Identifies Two Major Sites of Vulnerability on Ebolavirus Glycoprotein for Neutralizing Antibodies in Convalescent Human Plasma.

Three clinically relevant ebolaviruses – Ebola (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) viruses, are responsible for severe disease and occasional deadly outbreaks in Africa. The largest Ebola virus disease (EVD) epidemic to date in 2013-2016 in West Africa highlighted the urgent need for countermeasures, leading to the development and FDA approval of the Ebola virus vaccine rVSV-ZEBOV (Ervebo®) in 2020 and two monoclonal antibody (mAb)-based therapeutics (Inmazeb® [atoltivimab, maftivimab, and odesivimab-ebgn] and Ebanga® (ansuvimab-zykl) in 2020. The humoral response plays an indispensable role in ebolavirus immunity, based on studies of mAbs isolated from the antibody genes in peripheral blood circulating ebolavirus-specific human memory B cells. However, antibodies in the body are not secreted by circulating memory B cells in the blood but rather principally by plasma cells in the bone marrow. Little is known about the protective polyclonal antibody responses in convalescent plasma. Here we exploited both single-cell antibody gene sequencing and proteomic sequencing approaches to assess the composition of the ebolavirus glycoprotein (GP)-reactive antibody repertoire in the plasma of an EVD survivor. We first identified 1,512 GP-specific mAb variable gene sequences from single cells in the memory B cell compartment. Using mass spectrometric analysis of the corresponding GP-specific plasma IgG, we found that only a portion of the large B cell antibody repertoire was represented in the plasma. Molecular and functional analysis of proteomics-identified mAbs revealed recognition of epitopes in three major antigenic sites - the GP head domain, the glycan cap, and the base region, with a high prevalence of neutralizing and protective mAb specificities that targeted the base and glycan cap regions on the GP. Polyclonal plasma antibodies from the survivor reacted broadly to EBOV, BDBV, and SUDV GP, while reactivity of the potently neutralizing mAbs we identified was limited mostly to the homologous EBOV GP. Together these results reveal a restricted diversity of neutralizing humoral response in which mAbs targeting two antigenic sites on GP – glycan cap and base – play a principal role in plasma-antibody-mediated protective immunity against EVD.

Implementation of the Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) study: Lessons learned for vision health systems strengthening in Sierra Leone.

BackgroundFollowing the West African Ebola virus disease (EVD) outbreak of 2013–2016 and more recent EVD outbreaks in the Democratic Republic of Congo, thousands of EVD survivors are at-risk for sequelae including uveitis, which can lead to unremitting inflammation and vision loss from cataract. Because of the known risk of Ebola virus persistence in ocular fluid and the need to provide vision-restorative, safe cataract surgery, the Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study was implemented in Sierra Leone. During implementation of this multi-national study, challenges included regulatory approvals, mobilization, community engagement, infection prevention and control, and collaboration between multiple disciplines. In this report, we address the multifacted approach to address these challenges and the impact of implementation science research to address an urgent clinical subspecialty need in an outbreak setting.Methodology/Principal findingsGiven the patient care need to develop a protocol to evaluate ocular fluid for Ebola virus RNA persistence prior to cataract surgery, as well as protocols to provide reassurance to ophthalmologists caring for EVD survivors with cataracts, the EVICT study was designed and implemented through the work of the Ministry of Health, Sierra Leone National Eye Programme, and international partnerships. The EVICT study showed that all 50 patients who underwent ocular fluid sampling at 19 and 34 months, respectively, tested negative for Ebola virus RNA. Thirty-four patients underwent successful cataract surgery with visual acuity improvement. Here we describe the methodology for study implementation, challenges encountered, and key issues that impacted EVD vision care in the immediate aftermath of the EVD outbreak. Key aspects of the EVICT study included defining the pertinent questions and clinical need, partnership alignment with key stakeholders, community engagement with EVD survivor associations, in-country and international regulatory approvals, study site design for infection prevention and control, and thorough plans for EVD survivor follow-up care and monitoring. Challenges encountered included patient mobilization owing to transportation routes and distance of patients in rural districts. Strong in-country partnerships and multiple international organizations overcame these challenges so that lessons learned could be applied for future EVD outbreaks in West and Central Africa including EVD outbreaks that are ongoing in Guinea and Democratic Republic of Congo.Conclusions/SignificanceThe EVICT Study showed that cataract surgery with a protocol-driven approach was safe and vision-restorative for EVD survivors, which provided guidance for EVD ophthalmic surgical care. Ophthalmologic care remains a key aspect of the public health response for EVD outbreaks but requires a meticulous, yet partnered approach with international and local in-country partners. Future efforts may build on this framework for clinical care and to improve our understanding of ophthalmic sequelae, develop treatment paradigms for EVD survivors, and strengthen vision health systems in resource-limited settings.

PTSD, depression and anxiety in Ebola virus disease survivors in Beni town, Democratic Republic of the Congo

BackgroundEbola Virus Disease (EVD) is a deadly and feared infectious disease, which can be responsible of debilitating physical and psychological sequelae in survivors including depression and anxiety disorders. Unfortunately, there are scarce data on survivor sequelae in Democratic Republic of the Congo. So this study assessed PTSD, depression and anxiety symptoms among EVD survivors enrolled in the follow-up program of the psychosocial care team of Beni town’s general hospital.MethodsA cross-sectional study used consecutive sampling to recruit 144 Ebola virus disease survivors who came for follow up from October 23 to November 13; 2019. Basic socio-demographic data, presence of headache and short-term memory function were assessed. The Post-traumatic Checklist Scale and Hospital Anxiety and Depression Scale were used to assess psychological burden among participants. Descriptive statistics were used to summarized data and Pearson’s or likelihood chi-square were used to test association between psychiatric disorders and associated factors.ResultsThe prevalence of PTSD, depression and anxiety was 24.3, 24.3 and 33.3% respectively. Being male (OR = 0.42, 95% CI: 0.16, 0.95, p = 0.049), suffering from persistent headache (OR = 2.62, 95% CI: 1.12, 6.14, p = 0.014), losing a loved one because of EVD (OR: 2.60, 95% CI: 1.11, 6.15, p = 0. 015) and being young − 18-24 years - (OR: 0. 261, 95% CI: 0. 08, 0.82, p = 0,026) were statistically associated with PTSD diagnosis. Having short-term memory impairment and suffering from persistent headache were statistically associated with depression and anxiety diagnoses (OR = 2.44, 95% CI: 1.03, 5.82, p = 0.026); (OR = 2.24, 95% CI: 1.04, 4.85, p = 0.025); (OR = 2.62, 95% CI: 1.12, 6.14, p = 0.014); (OR = 2.31, 95% CI: 1.06, 5.01, p = 0.020).ConclusionThe prevalence of PTSD, depression and anxiety is high among EVD survivors. Development of specialized psychiatric services to sustain psychiatric and psychological health amongst survivors in the cultural context of the Eastern part of the DRC should be considered by the teams fighting against EVD in the DRC.

Post-Ebola Syndrome Presents With Multiple Overlapping Symptom Clusters: Evidence From an Ongoing Cohort Study in Eastern Sierra Leone.

BackgroundFollowing the 2013–2016 West African Ebola outbreak, distinct, persistent health complaints were recognized in Ebola virus disease (EVD) survivors. Here we provide an in-depth characterization of post-Ebola syndrome >2.5 years after resolution of disease. Additionally, we report subphenotypes of post-Ebola syndrome with overlapping symptom clusters in survivors from Eastern Sierra Leone.MethodsParticipants in Eastern Sierra Leone were identified by the Sierra Leone Association of Ebola survivors. Survivors and their contacts were administered a questionnaire assessing self-reported symptoms and a physical examination. Comparisons between survivors and contacts were conducted using conditional logistic regression. Symptom groupings were identified using hierarchical clustering approaches. Simplified presentation of incredibly complex evaluations (SPICE), correlation analysis, logistic regression, and principal component analysis (PCA) were performed to explore the relationships between symptom clusters.ResultsThree hundred seventy-five EVD survivors and 1040 contacts were enrolled into the study. At enrollment, EVD survivors reported significantly more symptoms than their contacts in all categories (P < .001). Symptom clusters representing distinct organ systems were identified. Correlation and logistic regression analysis identified relationships between symptom clusters, including stronger relationships between clusters including musculoskeletal symptoms (r = 0.63, P < .001; and P < .001 for correlation and logistic regression, respectively). SPICE and PCA further highlighted subphenotypes with or without musculoskeletal symptoms.ConclusionsThis study presents an in-depth characterization of post-Ebola syndrome in Sierra Leonean survivors >2.5 years after disease. The interrelationship between symptom clusters indicates that post-Ebola syndrome is a heterogeneous disease. The distinct musculoskeletal and non-musculoskeletal phenotypes identified likely require targeted therapies to optimize long-term treatment for EVD survivors.

Increased Likelihood of Detecting Ebola Virus RNA in Semen by Using Sample Pelleting.

Ebola virus RNA can reside for months or years in semen of survivors of Ebola virus disease and is probably associated with increased risk for cryptic sexual transmission of the virus. A modified protocol resulted in increased detection of Ebola virus RNA in semen and improved disease surveillance.

A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus

Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent invivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.

Understanding Long-term Evolution and Predictors of Sequelae of Ebola Virus Disease Survivors in Guinea: A 48-Month Prospective, Longitudinal Cohort Study (PostEboGui).

BackgroundLongitudinal analyses are needed to better understand long-term Ebola virus disease (EVD) sequelae. We aimed to estimate the prevalence, incidence, and duration of sequelae and to identify risk factors associated with symptom occurrence among EVD survivors in Guinea.MethodsWe followed 802 EVD survivors over 48 months and recorded clinical symptoms with their start/end dates. Prevalence, incidence, and duration of sequelae were calculated. Risk factors associated with symptom occurrence were assessed using an extended Cox model for recurrent events.ResultsOverall, the prevalence and incidence of all symptoms decreased significantly over time, but sequelae remained present 48 months after Ebola treatment center discharge with a prevalence of 30.68% (95% confidence interval [CI] 21.40–39.96) for abdominal, 30.55% (95% CI 20.68–40.41) for neurologic, 5.80% (95% CI 1.96–9.65) for musculoskeletal, and 4.24% (95% CI 2.26–6.23) for ocular sequelae. Half of all patients (50.70%; 95% CI 47.26–54.14) complained of general symptoms 2 years’ postdischarge and 25.35% (95% CI 23.63–27.07) 4 years’ post-discharge. Hemorrhage (hazard ratio [HR], 2.70; P = .007), neurologic (HR 2.63; P = .021), and general symptoms (HR 0.34; P = .003) in the EVD acute phase were significantly associated with the further occurrence of ocular sequelae, whereas hemorrhage (HR 1.91; P = .046) and abdominal (HR 2.21; P = .033) symptoms were significantly associated with musculoskeletal sequelae.ConclusionsOur findings provide new insight into the long-term clinical complications of EVD and their significant association with symptoms in the acute phase, thus reinforcing the importance of regular, long-term follow-up for EVD survivors.

Persistence of Ebola virus in semen among Ebola virus disease survivors in Sierra Leone: A cohort study of frequency, duration, and risk factors.

Sexual transmission chains of Ebola virus (EBOV) have been verified and linked to EBOV RNA persistence in semen, post-recovery. The rate of semen persistence over time, including the average duration of persistence among Ebola virus disease (EVD) survivors, is not well known. This cohort study aimed to analyze population estimates of EBOV RNA persistence rates in semen over time, and associated risk factors in a population of survivors from Sierra Leone. In this cohort study from May 2015 to April 2017 in Sierra Leone, recruitment was conducted in 2 phases; the first enrolled 100 male participants from the Western Area District in the capital of Freetown, and the second enrolled 120 men from the Western Area District and from Lungi, Port Loko District. Mean age of participants was 31 years. The men provided semen for testing, analyzed by quantitative reverse transcription PCR (qRT-PCR) for the presence of EBOV RNA. Follow-up occurred every 2 weeks until the endpoint, defined as 2 consecutive negative qRT-PCR results of semen specimen testing for EBOV RNA. Participants were matched with the Sierra Leone EVD case database to retrieve cycle threshold (Ct) values from the qRT-PCR analysis done in blood during acute disease. A purposive sampling strategy was used, and the included sample composition was compared to the national EVD survivor database to understand deviations from the general male survivor population. At 180 days (6 months) after Ebola treatment unit (ETU) discharge, the EBOV RNA semen positive rate was 75.4% (95% CI 66.9%-82.0%). The median persistence duration was 204 days, with 50% of men having cleared their semen of EBOV RNA after this time. At 270 days, persistence was 26.8% (95% CI 20.0%-34.2%), and at 360 days, 6.0% (95% CI 3.1%-10.2%). Longer persistence was significantly associated with severe acute disease, with probability of persistence in this population at 1 year at 10.1% (95% CI 4.6%-19.8%) compared to the probability approaching 0% for those with mild acute disease. Age showed a dose-response pattern, where the youngest men (≤25 years) were 3.17 (95% CI 1.60, 6.29) times more likely to be EBOV RNA negative in semen, and men aged 26-35 years were 1.85 (95% CI 1.04, 3.28) times more likely to be negative, than men aged >35 years. Among participants with both severe acute EVD and a higher age (>35 years), persistence remained above 20% (95% CI 6.0%-50.6%) at 1 year. Uptake of safe sex recommendations 3 months after ETU discharge was low among a third of survivors. The sample was largely representative of male survivors in Sierra Leone. A limitation of this study is the lack of knowledge about infectiousness. In this study we observed that EBOV RNA persistence in semen was a frequent phenomenon, with high population rates over time. This finding will inform forthcoming updated recommendations on risk reduction strategies relating to sexual transmission of EBOV. Our findings support implementation of a semen testing program as part of epidemic preparedness and response. Further, the results will enable planning of the magnitude of testing and targeted counseling needs over time.

Posterior Segment Ophthalmic Manifestations in Ebola Survivors, Sierra Leone

The largest Ebola virus disease (EVD) outbreak occurred from 2013 to 2016 in West Africa, leading to more than 28 600 cases and 11 300 deaths and resulted in the largest cohort of EVD survivors to date.1 Another recent outbreak in the Democratic Republic of the Congo has resulted in 3481 cases with more than 1170 survivors since August 2018.2 In studies of large EVD survivor cohorts, uveitis is the most common ocular manifestation with a 13% to 34% reported prevalence.3,4 Cataract, with or without uveitis, is the second most common finding and has been reported in 10% of EVD survivors.

Efficacy and Safety Outcomes of Cataract Surgery in Survivors of Ebola Virus Disease: 12-Month Results From the PREVAIL VII Study.

PurposeIn survivors of Ebola virus disease (EVD), intraocular viral persistence raises questions about the timing and safety of cataract surgery. To the best of our knowledge, this is the first controlled study evaluating Ebola virus persistence and cataract surgery safety and outcomes in EVD survivors.MethodsSeropositive EVD survivors and seronegative controls with vision worse than 20/40 from cataract and without active intraocular inflammation were enrolled. Aqueous humor from survivors was tested with reverse transcription–polymerase chain reaction for Ebola viral RNA. Participants underwent manual small-incision cataract surgery and 1 year of follow-up examinations.ResultsTwenty-two eyes of 22 survivors and 12 eyes of eight controls underwent cataract surgery. All of the aqueous samples tested negative for Ebola viral RNA. Median visual acuity improved from 20/200 at baseline to 20/25 at 1 year in survivors and from count fingers to 20/50 in controls (overall, P < 0.001; between groups, P = 0.07). After a 1-month course of topical corticosteroids, 55% of survivors and 67% of controls demonstrated at least 1+ anterior chamber cell. Twelve months after surgery, optical coherence tomography revealed a median increase in macular central subfield thickness of 42 µm compared with baseline (overall, P = 0.029; between groups, P = 0.995).ConclusionsEVD survivors and controls demonstrated significant visual improvement from cataract surgery. The persistence of intraocular inflammation highlights the importance of follow-up. The absence of detectable intraocular Ebola viral RNA provides guidance regarding the safety of eye surgery in Ebola survivors.Translational RelevanceThese findings demonstrate the safety and efficacy of cataract surgery in Ebola survivors and will inform ocular surgery guidelines in this population.

Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care

BackgroundEbola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient—perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD.MethodsSeveral different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood.ResultsThe findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a ‘fatal’ outcome to a ‘survival’ outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence—such as defective interfering genomes.ConclusionsThe data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.

Characterization of Ebola Virus–Associated Eye Disease

Survivors of Ebola virus disease (EVD) may experience ocular sequelae. Comparison with antibody-negative individuals from the local population is required to characterize the disease. To assess features of ophthalmic disease specific to EVD. This baseline cross-sectional analysis of survivors of EVD and their close contacts was conducted within PREVAIL III, a 5-year, longitudinal cohort study. Participants who enrolled at John F. Kennedy Medical Center in Liberia, West Africa from June 2015 to March 2016 were included in this analysis. Close contacts were defined as household members or sex partners of survivors of EVD. Data were analyzed from July 2016 to July 2020. All participants, both survivors and close contacts, underwent testing of IgG antibody levels against Ebola virus surface glycoprotein. Ocular symptoms, anterior and posterior ophthalmologic examination findings, and optical coherence tomography images were compared between antibody-positive survivors and antibody-negative close contacts. A total of 564 antibody-positive survivors (320 [56.7%] female; mean [SD] age, 30.3 [14.0] years) and 635 antibody-negative close contacts (347 [54.6%] female; mean [SD] age, 25.8 [15.5] years) were enrolled in this study. Survivors were more likely to demonstrate color vision deficit (28.9% vs 19.0%, odds ratio [OR], 1.6; 95% CI, 1.2-2.1) and lower intraocular pressure (12.4 vs 13.5 mm Hg; mean difference, -1.2 mm Hg; 95% CI, -1.6 to -0.8 mm Hg) compared with close contacts. Dilated fundus examination revealed a higher percentage of vitreous cells (7.8% vs 0.5%; OR, 16.6; 95% CI, 5.0-55.2) and macular scars (4.6% vs 1.6%; OR, 2.8; 95% CI, 1.4-5.5) in survivors than in close contacts. Uveitis was present in 26.4% of survivors and 12.1% of close contacts (OR, 2.4; 95% CI, 1.8-3.2). Among all participants with uveitis, survivors were more likely than close contacts to have intermediate uveitis (34.2% vs 6.5% of all cases; OR, 7.8; 95% CI, 3.1-19.7) and had thicker mean central subfield thickness on optical coherence tomography (222 vs 212 μm; mean difference, 14.4 μm; 95% CI, 1.9-26.9 μm). In this cross-sectional study, survivors of EVD had a distinct spectrum of ocular and neuro-ophthalmologic findings compared with close contacts that potentially require medical and surgical treatment.

The latest research findings on Ebola virus

013-2016 Ebola virus disease (EVD) outbreak was the largest EVD outbreak ever documented that started earlier in Guinea and later widely spread throughout West Africa, ending up a total of > 28,000 human infections. In this review, we outline research findings on Ebola virus (EBOV) variant Makona, a new EBOV variant isolated from the 2013-2016 EVD outbreak, and introduce the unique biological and pathogenic characteristics of Makona variant. We also discuss about the relevance of persistent infection of EBOV in EVD survivors with resurgence of EVD outbreak in Guinea in 2021. Moreover, this review covers a recent case report of EVD relapse and deliberates new interpretations of EBOV biology and EVD outbreak.