Oral-ocular trans infection of Epstein Barr virus. A possible new way of transmission by wearing masks in the SARS-CoV-2 era.

Purpose: To describe a case of an infective vitreitis with an exudative retinal detachment in a 56-year-old lady who was previously affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Observations: A broad workup for infections including the main viruses and bacteria was performed. Salivary droplets, tear film and vitreous samples were collected, resulting positive only for Epstein-Barr virus (EBV). Viraemia and immunoglobulin M for EBV negative, whereas immunoglobulin G positive. The patient showed a simultaneous painless erosion on the right margin of the tongue that's with the lab swab demonstrated the presence of EBV at the same time the vitreitis in the left eye was present. Conclusions and Importance: Our speculation is that a continuous use of the mask, especially in immunocompromised subjects, it might create a new route for spreading infectious oral agents in the ocular area, and this case is a warning for all the ophthalmologists that have to be aware of this threatening possibility in the COVID era.

Introduction

Epstein-Barr Virus (EBV), also known as Human HerpesVirus-4 (HHV-4), is a γ-type herpesvirus with a global infection prevalence of over 95%. This was discovered in the 1964 by electron microscopy of cells cultured from Burkitt's lymphoma tissue by Epstein, Achong, and Barr. Four years later, EBV was shown to be the etiologic agent of heterophile-positive infectious mononucleosis. Subsequently in 1970, EBV DNA was detected in tissues from patients with nasopharyngeal carcinoma. Since then, EBV was found to be associated with non-Hodgkin's lymphoma, oral hairy leucoplakia in patients with the acquired immunodeficiency syndrome and in tissues from other cancer: T-cell lymphomas and Hodgkin's disease.4, 5, 6

The reported ocular manifestations of systemic EBV infection, described in all segments of the eye, commonly involve external and anterior segment surface. In this context, conjunctival inflammation has been reported in association with keratitis, with the description ranging from mild hyperaemia to mild follicular reaction of the superior and inferior tarsal conjunctiva. Ocular EBV infection was described also as uveitis, vitreitis and optic disc vasculitis. In this context, sporadic case reports described ocular manifestations involving the posterior segment in patients with evidence of EBV infection e.g. uveitis in two patients with clinical and serologic signs of “chronic” EBV infection or EBV retinitis., To date, there are four reports of Acute Retinal Necrosis (ARN) in immunodepressed patients.12, 13, 14 A recent case report described an immunocompetent patient who developed EBV-associated ARN (EBV–ARN).

We report herein a presumed case of EBV infection of the retina in a healthy woman who was previously affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Case report

A 51-year-old-woman was referred to our retina unit after 2 weeks from a previous diagnosis of unidentified panuveitis. She first attended our clinic complaining a progressive and painless vision loss in the left eye for the past 3–4 weeks. Her disorder occurred 10 days after the first positive swab for COVID. Until SARS-CoV-2 infection, her past medical history was unremarkable. In addition, she reported non-specific symptoms like fatigue, insomnia, headaches, myalgia, and confusion a few days before the worsening of visual acuity (VA). Therefore, physical and ophthalmological investigations were done. Concerning the latter, the VA was light perception in the left eye and 20/20 in the right eye. Anterior segment evaluation revealed anterior chamber cell traits and normal examination in the right eye. Intraocular pressure was 18 in both eyes. Fundus examination was not evaluable for a dense vitreitis. The right eye fundus was unremarkable. Moreover, a B-scan ultrasonography was performed, and it showed an exudative total retinal detachment (Fig. 1a). While, on physical examination no abnormalities were found, except for the oral district, where a painless erosion was reported on the right margin of her tongue (Fig. 1b). Considering these results, a broad workup for infections, inflammatory and masquerade aetiologies was done. Serum Test for HIV, Syphilis and Tuberculosis were negative. Blood titers were positive for Herpes Simplex Virus 1 IgG, Toxoplasmosis IgG, Rubeola IgG, Cytomegalovirus (CMV) IgG and SARS-CoV-2 IgG. Epstein Barr Virus (EBV) nuclear antigen IgG was elevated, whereas IgM specific antibodies to EBV capsid antigen were negative. Investigation including complete blood count, erythrocytes sedimentation rate, C-reactive protein, electrolytes, creatinine and liver panel were normal.

Fig. 1

(A). Left eye ultrasound shows a V shaped elevation of the neurosensory layers (yellow arrow) with diffuse mobile opacities on high gain, taking on a “snow globe” appearance. (B). Tongue erosion bigger than 1,5 cm on the right margin (yellow arrow) in which EBV DNA has been found (C). Viral titre (genomes/mL) detected in three biological samples(D). Mouth-eye contamination through simulation with medical manikin wearing surgical mask (yellow arrow). It is possible to notice how the aerosol coming from the mouth is directed into the ocular area. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Therefore, a diagnostic vitrectomy was performed, and a vitreous sample was sent to the laboratory to perform Polymerase Chain Reaction (PCR) for Herpes Simplex Virus 1–2, CMV, EBV, Tuberculosis, Toxoplasmosis, Rubeola, SARS-CoV-2. PCR of vitreous sample was only positive for EBV virus. EBV DNA was also detected in the tear film of the left eye (2.5*103 viral genomes/mL real time qPCR method). (Fig. 1c). Further investigation revealed the presence of EBV DNA in the swab on the cheeks, on the tongue erosion, and in the saliva, with a viral titer 4.5*104 viral genomes/mL real time qPCR method. EBV-DNA was also detected in the salivary droplets of the breath air exhaled and was recovered by syringe, titer 1.7*102 viral genomes/mL air. (Fig. 1c). DNA blood samples analyzed daily for the subsequent two weeks, with cycle threshold (CT) in real time qPCR >40, confirmed the absence of both EBV and SARS-CoV-2 virus. The patient underwent pars plana vitrectomy combined with lens removal and silicone oil tamponade. The second vitreous sample, taken at the time of surgery, confirmed the only presence of EBV virus. Both one month and three months after surgery, the entire retina was attached and VA improved to 6/120.

Discussion

Vitreitis is a serious complication of inflammatory or infectious disease of the eye, once diagnosed, the challenge is to find the cause and eliminate it. To achieve this, the patient undergoes a battery of exams, that often turn out to be inadequate and further invasive investigations are necessary.

In this case, the patient's blood tests were negative for any kind of ongoing infection and as a result a diagnostic vitrectomy was required. The result of the analysis of the vitreous sample was a posterior uveitis caused by Epstein-Barr (EBV). EBV is a ubiquitous virus associated with a variety of different diseases and disorders. Acute EBV infection is associated with infectious mononucleosis, while chronic EBV infection is characterized by lifelong latency in transformed B lymphocytes, with the potential for reactivation. EBV can be reactivated as the result of a variety of stressor events. In a study by Gold et al. authors suggests that EBV reactivation occurred soon after or concurrently with contraction of the SARS-CoV-2 infection. The current patient was previously affected by Covid-19 and after a short period of time she manifested ocular and general symptoms. The ocular examination alone could only suggest EBV reactivation following a Sars-CoV-2 infection that resulted in uveitis, but negative blood tests prompted us to carry out additional investigations. The only finding detected was the presence of a painless erosion in the oral cavity on the right margin of patient's tongue. More extensive examinations revealed not only the presence of EBV DNA near this lesion, but also the presence of EBV-DNA in the saliva, droplets of the breath air exhaled and tear film of the left eye. In a recent article by Dbouk and Drikakis, the authors investigated the flow physics of respiratory droplets arising from coughing around and through a face mask. They reported that the mask to face fitting is important. Even in the case of a tight fitting scenario, if there exist some small openings, this can lead to additional leakage of droplets around the mask.

To our knowledge this is the first case of the simultaneous presentation of two lesions in two different district due to EBV reactivation in an immunocompetent patient after Covid-19. We can speculate that the SARS-CoV-2 infection played a role in the reactivation of the EBV specifically in oro-facial district, but not as a systemic reactivation, as the blood tests suggested. This scenario could be a consequence not only of the anatomical continuity of these districts but also of presence of a new path created by mask-wearing. Facial masks are currently required indoors and within human communities. Masks prevent the spread of infected salivary droplets to subjects nearby. Furthermore, droplet salivary flux changes direction in mask wearers (Fig. 1d), in particular towards the eyes. In this context, the oral and ocular mucosae, strongly connected by a continuous salivary bridge, could increase the risk of spreading oral pathogens to the ocular area. This hypothesis could be validated by a prompt clinical observation of simultaneous oral/ocular infection. Although more cases are necessary to confirm this hypothesis, we speculate that oral-ocular infection due to mask could be possible.

Conclusions

A concomitant oral-ocular Epstein Barr virus infection was observed in a 56-year-old patient, in whom “infection by mask” was confirmed by clinical and laboratory observations. In conclusion, this case is a warning for all the ophthalmologists that have to be aware of this threatening oral ocular condition in the COVID era, especially in immunocompromised patients.

Patient consent

The patient consented to publication of the case in writing.

Funding

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Research ethics

We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.

Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).

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The Corresponding Author declared on the title page of the manuscript is: ENRICO PEIRETTI.

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Declaration of competing interest

The following authors have no financial disclosures: (E.P., G.D., C.C.,A.S., G.O.)