Since 2017, Reunion Island has witnessed dengue outbreaks that have become more and more important each year, until 2022. This study describes one of the largest series of dengue cases with ophthalmologic complications.
The mean age of the patients in this study was higher (41.9 years) than in a systematic review, (33.0 years) [12] and in our review of cases report with available data (32.7 years, min 6 years – max 70, Appendices 1-2). It could be related to the recent appearance on Reunion Island of these epidemics in contrast to Asian countries which are endemic areas for this arbovirus. Ophthalmologic symptoms occurred 9.2 days (min: 5.0 days – max: 21.0 days) after the onset of dengue symptoms; a delay higher than in the literature (7.0 days) [13]. However, symptoms have appeared months later in other studies [2,12,14]. As found in certain studies, sudden decrease of the visual acuity and scotoma are the two main ocular symptoms [15–19]. Eighteen patients had macula involvement including several abnormalities: retinal thickening on OCT (39%), hyperreflectivity (32%), macular edema (25%) and foveolitis (25%). One study identified 3 groups to describe macular involvement: diffuse retinal thickening, cystoid macular edema and foveolitis [20].
This macular involvement seems to be related to serotype 1 [19,21]. In our study, the microbiology departments were only able to serotype 14 out of the 28 patients. All serotyped viruses were type 1, while serotype 2 was the majority in 2018 and 2019 on the island [5].
Some hypotheses could be raised to explain this specific injury: (i) The main hypothesis could be an immunological response. Indeed, the late onset of ocular symptoms around the seventh day corresponds to the nadir of thrombocytopenia and the increase in the systemic immunological response [19,20]. The decrease in C3 and C4 complements has been observed in some case series (we observed this in 3 patients). This decrease could predispose to the formation of an immune complex and lead to vessel occlusion during dengue infection [13,14]. In fact, it has been reported from in vitro studies that the complement system activation products can opsonize virus particles, and DENV viral neutralization occurs in a C3- and C4-dependent manner after Mannose-Binding Lectin-mediated neutralization [22,23]. (ii) On the other hand Carr et al. have shown that dengue virus infects retinal pigment epithelial and endothelial cells, which are the main cells constituting the blood-retinal barrier [24]. Factors that are hypothesized as leading to the evolution of a severe form of the disease include the immunological background of the individual, the secretion of high amounts of cytokines, and the secondary infection by a heterologous serotype of the virus associated with a mechanism of facilitation of the infection by Antibody dependant enhancement (ADE) antibodies. Plasma components are important mediators during dengue infection [25] and specifically exosome fraction. Exosomes are nanoscale membrane vesicles released by almost all types of cells infected with a virus, bacteria or parasite. They serve as vectors for various mediators and participate in the organism's response to infection. Exosomes communicate with host cells through contact between exosomes and their recipient cells, via different kinds of mechanisms. Increased production of exosomes is a characteristic feature of DENV infection [26,27]. These cargo molecules, which carry biological information (mRNA, miRNA, transcription factors) from their cells of origin, are involved in the alteration of recipient cell behavior, regulating cellular responses, stress signals and enabling infection by DENV [28]. In DENV infection with ophthalmic complications, the relevance of exosomes could be instrumental since the majority of the immune responses in severe dengue involve heavy secretion and circulation of pro-inflammatory cytokines and chemokines [26]. (iii) Thirdly, leukopenia and hypoalbuminemia could predispose to opportunistic infection of the ocular tissues and increased vascular permeability, respectively [29].
Treatment with corticosteroids had been initiated in 14 patients. The use of treatments such as corticosteroids or intravenous immunoglobulins was mainly reserved for severe cases [18,20]. None of the 28 patients received immunoglobulins.
The evolution of ocular involvement is usually considered to be favorable 2-4 weeks later [12,18,30,31]. However, 1 year later, visual acuity remains diminished in some patients and the scotoma persists. Dengue-related macular damage could therefore become a public health issue.
The main limitations of our study are, firstly, the retrospective nature of the study, implying the presence of missing data and preventing the identification of relevant results allowing their extrapolation, and secondly, the absence of collegiality between the different collaborators which may have prevented a homogeneous management of patients. Other studies are now underway to better explore these phenomena in Reunion Island.