Brief statement of the problem: Although we made significant scientific advances in our understanding of the natural history and epidemiology of Ebola virus during the 2013-2016 Ebola virus disease (EVD) epidemic in West Africa, Ebola virus research has almost exclusively focused on moderate to severe disease rather than asymptomatic and milder infections. Conceptualizing and studying asymptomatically or symptomatically infected individuals as two different groups of unrecognized, Ebola virus-infected individuals has a great potential for paradigm shifts in public health, clinical care, and global policies. There has been a growing body of literature demonstrating a significant burden of pauci-/asymptomatic infection and unrecognized EVD, but the public health and clinical consequences have been unclear, potentially leading to unknown transmission and untreated clinical sequelae. This dissertation has the following objectives: 1) to assess exposure risk in a dose-dependent relationship with severity of illness, 2) examine whether clinical sequelae occur after mild EVD, and 3) identify inflammatory markers that may partially explain how survivors recover from clinical sequelae. Description of the methods and procedures used to gather data or study the problem: This dissertation leverages two cohorts of Ebola cases and contacts. In Chapter 1, from September 2016 to July 2017, we conducted a cross-sectional, community-based study of Ebola virus disease (EVD) cases and household contacts of several transmission chains in Kono District, Sierra Leone. We used epidemiological surveys and blood samples to define severity of illness as no infection, pauci-/asymptomatic infection, unrecognized EVD, reported EVD cases who survived, or reported EVD decedents. We determine seropositivity with the Filovirus Animal Non-Clinical Group (FANG) EBOV glycoprotein IgG antibody test. We defined levels of exposure risk from eight questions and considered contact with body fluid as maximum exposure risk. In Chapter 2, from June 2015 through June 2017, we studied a cohort of EVD survivors and their contacts in Liberia. Surveys, current symptoms and physical exam findings, and serology characterized disease status of reported EVD, unrecognized EVD, pauci-/asymptomatic EBOV infection, or no infection. We pre-specified findings known to be differentially prevalent among EVD survivors than contacts. We estimated the prevalence and incidence of selected clinical findings by disease status. In Chapter 3, we used baseline data from a longitudinal cohort of confirmed EVD survivors (seropositive) and their uninfected contacts (seronegative) in Liberia to generate a cytokine profile from stored plasma samples. These data included a sub-cohort of men assessed for Ebola viral shedding in semen. We investigated pre-specified clinical findings previously reported to be differentially prevalent among EVD survivors. Outcomes were self-reported symptoms, physical examination findings, and viral persistence in semen. Using generalized estimating equations, we compared inflammatory markers among survivors and contacts; statistically significant markers (p<0.01) were assessed for associations among survivors with and without sequelae.
Summary of the findings: In Chapter 1, this community-based study of EVD cases and contacts provides epidemiological evidence of a dose-dependent relationship between exposure risk and severity of illness, which may partially explain why pauci-/asymptomatic EBOV infection, less severe disease, and unrecognized EVD occurs. In Chapter 2, the findings provide evidence of post-EVD clinical sequelae among contacts with unrecognized EVD but not pauci-/asymptomatic EBOV infection. In Chapter 3, we found evidence of persistent inflammation among survivors, which may be partially explained by ongoing viral shedding. Multiple clinical sequelae were less likely to be associated with two macrophage and pro-inflammatory markers, suggesting that a process of downregulation may be occurring as these survivors experienced clinical recovery.
