Identifying Paucisymptomatic or Asymptomatic and Unrecognized Ebola Virus Disease Among Close Contacts Based on Exposure Risk Assessments and Screening Algorithms.

BACKGROUND: There is limited evidence to evaluate screening algorithms with rapid antigen testing and exposure assessments as identification strategies for paucisymptomatic or asymptomatic Ebola virus (EBOV) infection and unrecognized EBOV disease (EVD). METHODS: We used serostatus and self-reported postexposure symptoms from a cohort study to classify contact-participants as having no infection, paucisymptomatic or asymptomatic infection, or unrecognized EVD. Exposure risk was categorized as low, intermediate, or high. We created hypothetical scenarios to evaluate the World Health Organization (WHO) case definition with or without rapid diagnostic testing (RDT) or exposure assessments. RESULTS: This analysis included 990 EVD survivors and 1909 contacts, of whom 115 (6%) had paucisymptomatic or asymptomatic EBOV infection, 107 (6%) had unrecognized EVD, and 1687 (88%) were uninfected. High-risk exposures were drivers of unrecognized EVD (adjusted odds ratio, 3.5 [95% confidence interval, 2.4-4.9]). To identify contacts with unrecognized EVD who test negative by the WHO case definition, the sensitivity was 96% with RDT (95% confidence interval, 91%-99%), 87% with high-risk exposure (82%-92%), and 97% with intermediate- to high-risk exposures (93%-99%). The proportion of false-positives was 2% with RDT and 53%-93% with intermediate- and/or high-risk exposures. CONCLUSION: We demonstrated the utility and trade-offs of sequential screening algorithms with RDT or exposure risk assessments as identification strategies for contacts with unrecognized EVD.

A Longitudinal Study of Ebola Sequelae in Liberia.

BACKGROUND: Multiple health problems have been reported in survivors of Ebola virus disease (EVD). Attribution of these problems to the disease without a control group for analysis is difficult. METHODS: We enrolled a cohort of EVD survivors and their close contacts and prospectively collected data on symptoms, physical examination findings, and laboratory results. A subset of participants underwent ophthalmologic examinations. Persistence of Ebola virus (EBOV) RNA in semen samples from survivors was determined. RESULTS: A total of 966 EBOV antibody-positive survivors and 2350 antibody-negative close contacts (controls) were enrolled, and 90% of these participants were followed for 12 months. At enrollment (median time to baseline visit, 358 days after symptom onset), six symptoms were reported significantly more often among survivors than among controls: urinary frequency (14.7% vs. 3.4%), headache (47.6% vs. 35.6%), fatigue (18.4% vs. 6.3%), muscle pain (23.1% vs. 10.1%), memory loss (29.2% vs. 4.8%), and joint pain (47.5% vs. 17.5%). On examination, more survivors than controls had abnormal abdominal, chest, neurologic, and musculoskeletal findings and uveitis. Other than uveitis (prevalence at enrollment, 26.4% vs. 12.1%; at year 1, 33.3% vs. 15.4%), the prevalence of these conditions declined during follow-up in both groups. The incidence of most symptoms, neurologic findings, and uveitis was greater among survivors than among controls. EBOV RNA was detected in semen samples from 30% of the survivors tested, with a maximum time from illness to detection of 40 months. CONCLUSIONS: A relatively high burden of symptoms was seen in all participants, but certain symptoms and examination findings were more common among survivors. With the exception of uveitis, these conditions declined in prevalence during follow-up in both groups. Viral RNA in semen persisted for a maximum of 40 months. (Funded by the National Institute of Allergy and Infectious Diseases and the National Eye Institute; PREVAIL III ClinicalTrials.gov number, NCT02431923.).

Lesson learned from the investigation and response of Lassa fever outbreak, Margibi County, Liberia, 2018: case report.

BACKGROUND: Lassa fever (LF) is a viral hemorrhagic disease caused by the Lassa virus (LASV) and endemic in West African countries with an estimation of 300,000 to 500,000 cases and 5,000 deaths annually. The Margibi County Health Team of Liberia received a report of an unidentified febrile illness case from the Kakata district. We conducted the investigation to identify the causative agent and the source of infection to support treatment, control and prevention interventions. CASE PRESENTATION: We identified LASV in the blood specimens' of two patients by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). Both the confirmed cases have manifested respiratory distress, weakness, and difficulty of swallowing, muscle, joint and back pains, and vomiting with blood. The symptoms started with mild fever and gradually developed. Initially, the primary health facilities have miss-diagnosed the patients as malaria and respiratory tract infections. The primary health facilities have referred the patients to the referral hospital as the patients have failed to respond to antimalarial and antibiotics. The hospital suspected LF and sent blood specimens to the National Reference Laboratory while the patients were on supportive treatment in the isolation room. At the time when the laboratory result returned to the hospital, the patients died of LF illness before ribavirin administered. CONCLUSIONS: Our investigation revealed that the two hospitalized and deceased febrile cases were associated with LASV. The primary health facilities have failed to recognize the cases as suspected LF at the earliest time possible. The clinicians and health facilities, especially primary health facilities, need to consider LF as a differential diagnosis when the patient failed to respond to anti-malaria and broad-spectrum antibiotics.

Initiation of a ring approach to infection prevention and control at non-Ebola health care facilities - Liberia, January-February 2015.

From mid-January to mid-February 2015, all confirmed Ebola virus disease (Ebola) cases that occurred in Liberia were epidemiologically linked to a single index patient from the St. Paul Bridge area of Montserrado County. Of the 22 confirmed patients in this cluster, eight (36%) sought and received care from at least one of 10 non-Ebola health care facilities (HCFs), including clinics and hospitals in Montserrado and Margibi counties, before admission to an Ebola treatment unit. After recognition that three patients in this emerging cluster had received care from a non-Ebola treatment unit, and in response to the risk for Ebola transmission in non-Ebola treatment unit health care settings, a focused infection prevention and control (IPC) rapid response effort for the immediate area was developed to target facilities at increased risk for exposure to a person with Ebola (Ring IPC). The Ring IPC approach, which provided rapid, intensive, and short-term IPC support to HCFs in areas of active Ebola transmission, was an addition to Liberia's proposed longer term national IPC strategy, which focused on providing a comprehensive package of IPC training and support to all HCFs in the country. This report describes possible health care worker exposures to the cluster's eight patients who sought care from an HCF and implementation of the Ring IPC approach. On May 9, 2015, the World Health Organization (WHO) declared the end of the Ebola outbreak in Liberia.

Pregnancy, pregnancy outcomes, and infant growth and development after recovery from Ebola virus disease in Liberia: an observational cohort study.

BACKGROUND: Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population. METHODS: In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff. FINDINGS: 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed. INTERPRETATION: The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola. FUNDING: National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health.

Clinical sequelae among individuals with pauci-symptomatic or asymptomatic Ebola virus infection and unrecognised Ebola virus disease in Liberia: a longitudinal cohort study.

BACKGROUND: Whether or not individuals with pauci-symptomatic or asymptomatic Ebola virus infection and unrecognised Ebola virus disease develop clinical sequelae is unknown. We assessed current symptoms and physical examination findings among individuals with pauci-symptomatic or asymptomatic infection and unrecognised Ebola virus disease compared with Ebola virus disease survivors and uninfected contacts. METHODS: Between June 17, 2015, and June 30, 2017, we studied a cohort of Ebola virus disease survivors and their contacts in Liberia. Surveys, current symptoms and physical examination findings, and serology were used to characterise disease status of reported Ebola virus disease, unrecognised Ebola virus disease, pauci-symptomatic or asymptomatic Ebola virus infection, or no infection. We pre-specified findings known to be differentially prevalent among Ebola virus disease survivors versus their contacts (urinary frequency, headache, fatigue, muscle pain, memory loss, joint pain, neurological findings, chest findings, muscle findings, joint findings, abdominal findings, and uveitis). We estimated the prevalence and incidence of selected clinical findings by disease status. FINDINGS: Our analytical cohort included 991 reported Ebola virus disease survivors and 2688 close contacts. The median time from acute Ebola virus disease onset to baseline was 317 days (IQR 271-366). Of 222 seropositive contacts, 115 had pauci-symptomatic or asymptomatic Ebola virus infection and 107 had unrecognised Ebola virus disease. At baseline, prevalent findings of joint pain, memory loss, muscle pain, and fatigue were lowest among those with pauci-symptomatic or asymptomatic infection or no infection, higher among contacts with unrecognised Ebola virus disease, and highest in reported survivors of Ebola virus disease. Joint pain was the most prevalent finding, and was reported in 434 (18%) of 2466 individuals with no infection, 14 (12%) of 115 with pauci-symptomatic or asymptomatic infection, 31 (29%) of 107 with unrecognised Ebola virus disease, and 476 (48%) of 991 with reported Ebola virus disease. In adjusted analyses, this pattern remained for joint pain and memory loss. Survivors had an increased odds of joint pain compared with unrecognised Ebola virus disease contacts (adjusted odds ratio [OR] 2·13, 95% CI 1·34-3·39); unrecognised Ebola virus disease contacts had an increased odds of joint pain compared with those with pauci-symptomatic or asymptomatic infection and uninfected contacts (adjusted OR 1·89, 95% CI 1·21-2·97). The adjusted odds of memory loss was more than four-times higher among survivors than among unrecognised Ebola virus disease contacts (adjusted OR 4·47, 95% CI 2·41-8·30) and two-times higher among unrecognised Ebola virus disease contacts than in those with pauci-symptomatic or asymptomatic infection and uninfected contacts (adjusted OR 2·05, 95% CI 1·10-3·84). By 12 months, prevalent findings had decreased in the three infected groups. INTERPRETATION: Our findings provide evidence of post-Ebola virus disease clinical sequelae among contacts with unrecognised Ebola virus disease but not in people with pauci-symptomatic or asymptomatic Ebola virus infection. FUNDING: National Cancer Institute and National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Strategy management in collaborative clinical research partnerships.

PURPOSE: Today's clinical trial partnerships frequently join multi-disciplinary investigators and stakeholders, from different countries and cultures, to conduct research with a broad array of goals. This diversity, while a strength, can also foster divergent views about priorities and what constitutes success, thereby posing challenges for management, operations, and evaluation. As a sponsor and partner in such collaborations, we seek to assist and support their development and implementation of sound research strategies, to optimize their efficiency, sustainability, and public health impact. This report describes our efforts using an adaptation of the well-established Kaplan-Norton strategy management paradigm, in our clinical trials setting. We share findings from our first test of the utility and acceptance of this approach for evaluating and managing research strategies in a collaborative clinical research partnership. RESULTS: Findings from pilot studies and our first implementation in an ongoing clinical research partnership in Liberia, provide initial support for our hypothesis that an adapted version of the Kaplan-Norton strategy management model can have use in this setting. With leadership from within the partnership, analysis artifacts were gathered, and assessments made using standardized tools. Practical feasibility, resonance of the findings with partners, and convergence with other empirical assessments lend initial support for the view that this approach holds promise for obtaining meaningful, useable results for assessing and improving clinical research management. CONCLUSIONS AND IMPLICATIONS: Engaged leadership, thoughtful timing to align with partnership planning cycles, support for the process, and an eye towards the collaboration's long-term goals appear important for developing model understanding and practice. Skepticism about evaluations, and unease at exposing weaknesses, may hinder the effort. Acceptance of findings and associated opportunities for improvement by group leadership, support a growing sense of validity. Next steps aim to test the approach in other partnerships, streamline the methodology for greater ease of use, and seek possible correlations of strategy management assessments with performance evaluation. There is hardly a better example than the COVID-19 pandemic, to spotlight the need for efficient and effective clinical research partnerships to address global health challenges. While heartened by the collaborative spirit driving the effort so far, we cannot let our enthusiasm lull us into thinking that nobility of purpose or an abundance of good will is sufficient. Careful monitoring and adjustment of clinical research strategy in response to changes (e.g., demographics, pathogen evolution, research acceptance, political and cultural environments) are vital to making the needed adjustments that can guide these programs toward successful outcomes. We hope that our work can raise awareness about the importance, relevance, and feasibility of sound strategy management in clinical research partnerships, especially during this time when there is so much at stake.

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.

Ebola virus disease-related stigma among survivors declined in Liberia over an 18-month, post-outbreak period: An observational cohort study.

BACKGROUND: While qualitative assessments of Ebola virus disease (EVD)-related stigma have been undertaken among survivors and the general public, quantitative tools and assessment targeting survivors have been lacking. METHODS AND FINDINGS: Beginning in June 2015, EVD survivors from seven Liberian counties, where most of the country's EVD cases occurred, were eligible to enroll in a longitudinal cohort. Seven stigma questions were adapted from the People Living with HIV Stigma Index and asked to EVD survivors over the age of 12 at initial visit (median 358 days post-EVD) and 18 months later. Primary outcome was a 7-item EVD-related stigma index. Explanatory variables included age, gender, educational level, pregnancy status, post-EVD hospitalization, referred to medical care and EVD source. Proportional odds logistic regression models and generalized linear mixed-effects models were used to assess stigma at initial visit and over time. The stigma questions were administered to 859 EVD survivors at initial visit and 741 (86%) survivors at follow-up. While 63% of survivors reported any stigma at initial visit, only 5% reported any stigma at follow-up. Over the 18-month period, there was a significant decrease in stigma among EVD survivors (Adjusted Odds Ratio [AOR], 0.02; 95% Confidence Interval [CI], 0.01-0.04). At initial visit, having primary, junior high or vocational education, and being referred to medical care was associated with higher odds of stigma (educational level: AOR, 1.82; 95%CI, 1.27-2.62; referred: AOR, 1.50; 95%CI, 1.16-1.94). Compared to ages of 20-29, those who had ages of 12-19 or 50+ experienced lower odds of stigma (12-19: AOR, 0.32; 95%CI, 0.21-0.48; 50+: AOR, 0.58 95%CI, 0.37-0.91). CONCLUSIONS: Our data suggest that EVD-related stigma was much lower more than a year after active Ebola transmission ended in Liberia. Among survivors who screened negative for stigma, additional probing may be considered based on age, education, and referral to care.