Can the Novel Coronavirus be found in the Ocular Tissues and Secretions? An Opinion

Evidence of Human Coronavirus (Hcovs)-NL63, SARS-Cov-1 in the Ocular Surface and Secretions

The first study released in March 2004 reported a new strand called HCOV-NL63 in a seven-year-old boy with symptoms of pneumonia, bronchiolitis, and conjunctivitis from nasopharyngeal aspirants [8]. One year later, in the 2005 retrospective report, 18 children tested positive for HCoV- NL63 with upper respiratory tract disease in their nasal swabs, 3(17%) with conjunctivitis [9]. Although they had not collected any ocular swabs. A case series reporting virus detection in conjunctical swabs is recorded from the SARS- CoV in 2003. One female healthcare worker yielded SARS positivity only in tears [10]. In a prospective interventional case series to identify SARS-CoV by RT-PCR in conjunctival scrapings of 17 confirmed patients, none of them was positive for viral RNA [11]. 126 specimens from conjunctiva, throat, and urine were collected between 6 and 8 weeks of illness [12]. Therefore the results are highly inconsistent. To the best of our knowledge to date, there are no reports of conjunctivitis or any other ocular complications reported for SARS-CoV-1 or MERS-CoV in humans.

Evidence of the Novel Coronavirus (SARS-Cov-2) in the Ocular Surface and Secretions Mode of Spread of Covid-19

Since the break-out of SARS-CoV in 2003, SARS-CoV RNA in conjunctival swabs examined by reverse-transcriptase polymerase chain reaction (RT-PCR) assay was positive for 3(37%) of 8 confirmed SARS patients in their early disease process [13].

After this incident, there is an increased awareness of ocular transmission. WHO suggested wearing protective eyewear when examining COVID-19 patients as the exposed ocular surface may be an alternative route for viral transmission? A detailed retrospective analysis was performed in March to identify 1099 laboratory-confirmed COVID-19 cases, conjunctival congestion found in 9(0.8 percent) cases [14]. Conjunctivitis was the first symptom of bilateral source, rubbing, and watering in an anesthesiologist when a patient without safe eyes was examined for Novel Coronavirus Pneumonia with fever and difficult hospitals. These conjunctival swabs were screened to be negative for viral RNA. This study recruited 67 patients of confirmed and suspected NCP patients, only one patient yielded conjunctival swabs positivity, and two were suspiciously positive for viral RNA. Still, none had ocular symptoms, whereas all nasopharyngeal swabs were positive [15]. In the meantime, some of the prospective studies also reported similar kind of results.

Conjunctival squabs were obtained from conjunctival test papers approximately 2 to 3 days after the onset and tested in RT-PCR in a prospective procedure sequence of 30 patients with reported NCP. Twice, one patient with conjunctivitis developed viral RNA in tears and conjunctive secretions with a very low fever. All other conjunctival swabs were negative, while 55/60 sputum samples were tested positive [16]. A cross-sectional study was conducted with 72 laboratory-confirmed cases where nasopharyngeal and conjunctival samples were collected using synthetic fiber swabs in a mean duration of 18.15 days of disease onset. Conjunctivitis was observed in 2 patients, where only one patient showed PCR positivity in conjunctival swabs. The other patient was a nurse working in the emergency department of ophthalmology, experienced excessive tearing and redness in both eyes with mild to moderate fever, gowned with PPE, including N95 respirators. Still, she gives a history of a dislocated eye mask and frequent hand-eye contact. Her nasopharyngeal and conjunctival swabs were both negative even after 5 days of onset of symptoms. Her diagnosis was confirmed by computerized tomography of the lungs. Her Conjunctivitis was resolved after 4 days and showed no recurrence [17]. In another prospective study of 17 confirmed COVID-19 patients, tear samples were collected using Schirmers strips weekly starting from day 3 of symptoms to day 30. These were analyzed using RT-PCR assay. It gave negative results in all the cases at all weeks. Among them one of the patients developed conjunctival congestion and chemosis during the hospital stay but showed negative findings in tears [18]. Similar findings were found in a large prospective sample of 114 patients, 80% were positive in their nasopharyngeal swabs. In comparison, none were positive in their conjunctival swab [19], in their conjunctival swabs were negative again in a retrospective analysis of 30 recorded instances of COVID-19 [20].

Ocular Manifestations of Coronavirus in Experimental Animal Models

It has been reported in experimental animal models, the feline coronavirus (feline infectious peritonitis) and the murine coronavirus (mouse hepatitis virus) nare infective. Apart from viral conjunctivitis, they are capable to produce granulomatous anterior uveitis, retinal vasculitis, choroiditis, retinal detachment, virus-induced macular degeneration and optic neuritis with poor prognosis [1]. In a recent study, rhesus macaques were theoretically contaminated with infectious doses of SARS-CoV-2 via the conjunctival sac. Viral load was detectable in the throat, nasal and conjunctival swabs post day 1 of inoculation. Lacrimal glands, the nasolacrimal region, the optic nerve, the alimentary tract, the lower lobe of the lungs were few of the anatomical areas affected. Radiologic investigations showed interstitial pneumonia. Thus, the findings are suggestive of the infection of SARS- CoV-2 via the conjunctival route [21]. Absorption from the ocular tissues like conjunctiva and corneal epithelial, lining of the lacrimal system epithelial cells, and the inner lining is possible. The virus can retrograde into the nasal and ocular fluids. The distribution of cellular receptors in the ocular surface mucosa and the respiratory tract give a chance for higher risk of viral tissue adherence and transmission. The receptors of some species of adenovirus and avian influenza (α-2-3-linked sialic acid, CD 46, desmoglein-2) and the human influenza virus (α-2-6-linked sialic acid) are abundantly present in the corneal, conjunctival epithelium as well as nasal and tracheal mucosal lining [22, 23, 24]. The cellular binding receptor, angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and HCoV-NL63 is extensively expressed in the lung alveoli and intestinal epithelial cells. In the eye, ACE2 expressions are found on the corneal, conjunctival epithelium, aqueous and vitreous humor, although less than lungs and gastrointestinal tissues [25, 26]. The virus can be transmitted through the lacrimal passage system into the lower respiratory tissues to bind to the ACE2 receptors. The ocular immune system consists of mucous membranes; tears a significant role in the ocular defense mechanisms, therefore the eye can manifest as conjunctivitis and show viral conjunctivitis features as an initial symptom. It has reported that lactoferrinlipocalin 2 and immunoglobin present in the external secretions of saliva, mucous, gastrointestinal fluids, including tears, can inhibit viral attachment by interfering with ACE2 receptors. There is a 150 fold increment in the levels of lactoferrin in SARS –CoV-1patients [25, 26]. PCR of the nasopharyngeal swabs is presently the standard for confirmation of COVID-19 [19]. However, the few reported ocular manifestations and test positivity in PCR serve as preliminary evidence of the ocular surface’s virus presence. The sensitivity of the PCR test kits is likely to have an impact on the results. False-negative test reports can arise where the viral load is below the detectable range. The inadequate quantity of the sample for that kit [27]. Viral concentrations can also vary at different sample collection sites throughout the disease. According to a report published, the viral load of SARS-CoV detected in the nasopharyngeal swab peaked on the 10th day after the onset of symptoms. Moreover, the study also reported that similar concentrations of viral load were seen in an asymptomatic carrier [28]. Repeated sample collections are usually required to confirm the diagnosis. In any circumstance of repeated negative results in a suspected case, the lungs serve as an alternative diagnostic tool for early diagnosing [29]. Furthermore, the low expressions of ACE2 in the ocular surface are probably another explanation of low or undetectable viral load in the PCR. A Negative report in PCR might not be conclusive for the disease. In the above studies, conjunctivitis and conjunctival swabs’ were primarily in the disorder’s early phase. Conjunctivitis is usually self-healing within few days and does not seems to have a recurrence. The measurable concentration of the virus in the ocular surface might be for a short period, probably in the early phase, and goes down to undetectable concentrations afterward.