Understanding the pathogenesis of uveitis in Ebola virus disease survivors: a study protocol for clinical, molecular virologic, and immunologic characterization

Abstract

The 2013-2016 Western African outbreak of the Ebola virus disease (EVD), the largest recorded outbreak since the discovery of Ebola virus (EBOV) in 1976, destabilized local health systems and left thousands of survivors at risk for post-acute sequelae, including vision-threatening uveitis. In an EVD survivor with severe panuveitis, the detection of persistent EBOV in the aqueous humor, long after clearance of acute viremia, focused clinical and research attention on the host-EBOV interaction in the unique terrain of ocular immune-privilege. Despite the recognition that uveitis is common and consequential in EVD survivors, our understanding of pathogenesis is extremely limited, including the contributions of viral persistence and ocular-specific and systemic immune responses to disease expression. In this study protocol, we outline a multifaceted approach to characterize EVD-associated intraocular inflammation (EVD-IOI), including the clinical phenotype and complications; the presence of EBOV (or EBOV RNA/antigen) in ocular fluids and tissues; and associated local ocular-specific and peripheral immune responses. We utilize an observational cohort design, which includes EVD survivors and close contacts of EVD survivors (i.e., no documented history of EVD), and we propose disease (clinical examination and imaging), as well as molecular, virologic and immunologic characterization, to meet research objectives. Comprehensive findings emerging from the research will inform local stakeholders and global partners to understand and effectively address the individual and public health implications of EVD-associated uveitis, including to optimize clinical decision-making and medical intervention, identify potential ocular and peripheral biomarkers of viral persistence and ocular disease, and ensure effective infection prevention and control.

Figure 1.

Study schematic highlighting the three studies that will address research aims. Aim 1 will assess EVD survivors for the prevalence of uveitis and ophthalmic outcomes and is entitled the Sierra Leone Ministry of Health and Lowell and Ruth Gess Hospital Ebola Survivor (SMILE) study, in which at least 750 patients will be recruited (i.e., 250 EVD survivors and 500 close-contacts). In Aim 2, the Ebola Virus Persistence in Ocular Tissues and Fluids Study-Vitreoretinal (EVICT-VR) will assess vitreous fluid for molecular and immunologic evidence of EBOV antigen or nucleic acid persistence. In Aim 3, EBOV antigen-specific immune responses will be assessed in EVD survivors with and without uveitis. The referral process is outlined by the arrows and include Ministry of Health and Sanitation, Sierra Leone engagement, along with the Sierra Leone Association of Ebola Survivors.

Figure 2.

Schematic diagram of operating room for ophthalmic surgery targeting the pars plana vitrectomy procedure with maximum containment IPC precautions. Key features of the operating room design include: a clear space for doffing where one transitions from high-risk to low-risk areas; a specimen (dirty) table is available for placement of specimens; disinfection of primary and secondary specimen containers; and a hand sanitizing station for specimen packaging and transport to appropriate refrigeration. Strict disinfection protocols are implemented for instrument entry into and exit from the eye, as per the protocol outlined in the Supplemental Material.