Ophthalmological manifestations and plasma markers of inflammation in Ebola survivors in post-treatment era

Abstract

This study aimed to characterize ophthalmological manifestations and associated inflammatory markers in EVD survivors in post-treatment era. Case-control study of ophthalmological manifestations and plasma inflammatory biomarker profile in EVD survivors (n = 120) from the 2018-2020 outbreak in DRC, their gender- and age-matched close contacts (n = 120) and non-contact (healthy) controls (n = 120). Expressions of inflammatory markers were assessed using the Olink Explore 384 Assay and compared across study groups before and after stratification by treatment with monoclonal antibodies (mAB114, ZMapp, or Regeneron) or antiviral drug (Remdesivir). Protein profiling was carried out using the Olink statistical package. Mean age (years) was comparable among survivors (29.7 ± 10.6), close contacts (28.9 ± 11.1) and non-contact controls (29.3 ± 10.6) (p = 0.85). Mean time from disease onset to clinical assessment was 3.5 ± 0.5 (2.5-4.2) years in survivors. Optic neuropathy was more common in survivors (6.7%) than in close contacts (0.8%) and non-contacts (0.0%) (p = 0.003). Survivors with optic neuropathy had significantly worse visual acuity in both eyes than those without optic neuropathy (all p < 0.001). Clinical evidence of past anterior uveitis was observed in 2.5% of survivors, 2.9% of close contacts, and 1.8% of healthy controls (p = 0.86). Plasma circulating DGKZ, INFGR1, ERBB3, and MICA-MICB showed differential expression patterns between survivors and controls (all p < 0.05). However, no clear separation could be detected on principal component analysis of multiplexed proteomic data between survivor and control samples. Three proteins (ITM2A, CLEC4D, NCLN) were differentially expressed and related to optic neuropathy. The comparison between treatment groups revealed a trend toward lower protein inflammatory markers in survivors treated with Remdesivir than those treated with monoclonal antibodies. We conclude that in treated EVD survivors, optic neuropathy was the only neuro-ophthalmologic abnormality. Uveitis was far less frequent than reported in West African cohorts. ITM2A, CLEC4D, and NCLN were differentially expressed in EVD survivors with optic neuropathy long after the acute phase of the infection. The true meaning of these findings will need further investigations.

Keywords: Ebola treatment; Ebola virus disease; Inflammatory markers; Optic neuropathy; Uveitis.

Fig. 1

Heat map of all tested proteins in EVD survivors stratified by treatment, close contacts, and healthy controls.

Fig. 2

Volcano plot depicting differential expression of inflammatory proteins in EVD survivors vs. controls (combined close contacts and healthy controls). Scattered points represent individual proteins. The x-axis displays log2 fold changes (L2fc) in protein expression, with positive and negative values indicating upregulated and downregulated expressions, respectively. P-values are shown on -Log10 scale on the y-axis. Proteins determined to be significantly and differentially regulated are indicated in the uppermost segment (above the dashed line). Proteins differentially expressed at p < 0.050, but not reaching the adjusted threshold, are in the central segment, close to 0. Proteins not differentially expressed are scattered away from the central segment and below the dashed line.

Fig. 3

Boxplots of select protein of interest (DGKZ, IFNGR1, ERBB3, and MICA-MICB) and respective expression levels in plasma of EVD survivors and controls.

Fig. 4

PCA score plot obtained on proteomics of EVD survivors (dark dots) and controls (gray dots). No separation is visualized between the two batches of measurements.

Fig. 5

PCA score Boxplots of CXCL9 expression in EVD survivors stratified by treatment received during hospitalization in ETC. There is no clear separation between measurements of the four groups, but Remdesivir tended to be associated with lower levels of protein inflammatory biomarkers.