Fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease in the Democratic Republic of the Congo: a case report study

Abstract

Background: During the 2018-20 Ebola virus disease outbreak in the Democratic Republic of the Congo, thousands of patients received unprecedented vaccination, monoclonal antibody (mAb) therapy, or both, leading to a large number of survivors. We aimed to report the clinical, virological, viral genomic, and immunological features of two previously vaccinated and mAb-treated survivors of Ebola virus disease in the Democratic Republic of the Congo who developed second episodes of disease months after initial discharge, ultimately complicated by fatal meningoencephalitis associated with viral persistence.

Methods: In this case report study, we describe the presentation, management, and subsequent investigations of two patients who developed recrudescent Ebola virus disease and subsequent fatal meningoencephalitis. We obtained data from epidemiological databases, Ebola treatment units, survivor programme databases, laboratory datasets, and hospital records. Following national protocols established during the 2018-20 outbreak in the Democratic Republic of the Congo, blood, plasma, and cerebrospinal fluid (CSF) samples were collected during the first and second episodes of Ebola virus disease from both individuals and were analysed by molecular (quantitative RT-PCR and next-generation sequencing) and serological (IgG and IgM ELISA and Luminex assays) techniques.

Findings: The total time between the end of the first Ebola virus episode and the onset of the second episode was 342 days for patient 1 and 137 days for patient 2. In both patients, Ebola virus RNA was detected in blood and CSF samples during the second episode of disease. Complete genomes from CSF samples from this relapse episode showed phylogenetic relatedness to the genome sequenced from blood samples collected from the initial infection, confirming in-host persistence of Ebola virus. Serological analysis showed an antigen-specific humoral response with typical IgM and IgG kinetics in patient 1, but an absence of an endogenous adaptive immune response in patient 2.

Interpretation: We report the first two cases of fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease who had received vaccination and mAb-based treatment in the Democratic Republic of the Congo. Our findings highlight the importance of long-term monitoring of survivors, including continued clinical, virological, and immunological profiling, as well as the urgent need for novel therapeutic strategies to prevent and mitigate the individual and public health consequences of Ebola virus persistence.

Funding: Ministry of Health of the Democratic Republic of the Congo, Institut National de Recherche Biomédicale, Infectious Disease Rapid Response Reserve Fund, US Centers for Disease Control and Prevention, US National Cancer Institute (National Institutes of Health), French National Research Institute for Development, and WHO.

Figure 1

Timeline of Ebola virus disease progression in two patients Timeline of events from the first and second episodes of Ebola virus disease for patient 1 from June, 2019, to June, 2020 (A) and for patient 2 from January to July, 2020 (B). CSF=cerebrospinal fluid. ETU=Ebola treatment unit. RT-qPCR=quantitative RT-PCR.

Figure 2

Maximum likelihood phylogenetic tree of the Ebola virus disease outbreak (2018–20) in Nord Kivu, Democratic Republic of the Congo A time-resolved phylogenetic tree was conducted with a Bayesian phylodynamic analysis of 677 genomes sequenced during this outbreak. Sequenced genomes from patients 1 and 2 during the first and second episodes of Ebola virus disease are highlighted in red.

Figure 3

RT-qPCR and serological results for two patients with recrudescent Ebola virus disease over time Data on RT-qPCR Ct values, IgM titres, and IgG titres (including NP, GP [Kissidougou and Mayinga strains], and VP40 proteins) provided for patient 1 (A–C) and patient 2 (D–F) from the onset of the first episode of Ebola virus disease. Patient 1 received REGN-EB3 on day 7 after symptom onset in the first episode of disease, corresponding to 1 day before the first sample shown. Patient 2 received REGN-EB3 2 days after symptom onset in the first episode of disease. CSF=cerebrospinal fluid. Ct=cycle threshold. GP=glycoprotein. NP=nucleoprotein. qRT-PCR=quantitative RT-PCR. VP40=viral protein 40.