The mucous membrane of the upper respiratory tract is the main portal entry of SARS-CoV-2. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated after type 2 transmembrane protease (TMPRSS2) cleaves the viral spike glycoprotein, which then binds to the angiotensin-converting enzyme 2 (ACE-2) receptor or cluster differentiation 147 (CD 147) of the host cell forming an antigen-receptor complex. Endocytosis of the virus then occurs and cathepsin L (CTSL) cleaves the virus to release viral single stranded RNA into cellular cytosol. Presence of ACE-2 receptors, TMPRSS2 and CTSL in the ocular surface makes it a potential port of entry for SARS-CoV-2(10, 11).
Two patients were positives Covid 19 from conjunctival swab in our study. However, they did not experience any ocular symptoms. Hence, viral entry through the ocular route is a cause of concern as detectable viral presence in the ocular surface is not always symptomatic and eye-hand-eye as well as hand-eye transmission are possible. Although the public has gained awareness in the proper usage of face masks, eye protection such as the use of face shield and goggles is less common. Emergence of variants with higher transmissibility might necessitate further protective measures such as the use of eye protection in conjunction with wearing double masks and also immediate vaccination(10, 12, 13). Viral entry into the ocular surface can be caused by direct exposure to droplets, aerosol, contact with contaminated ophthalmic instruments or hand to eye contact after touching a contaminated surface. Indirect entry into the ocular surface can occur through the reflux of NOP secretion into the lacrimal passage which then drains to the ocular surface, or through blood circulation or viraemia that causes entry of the virus into the ocular surface through ocular blood supply.(10, 14)
The possibility of ocular surface acting as port of entry was recently demonstrated by Deng et al whose study showed that conjunctival inoculation of SARS-CoV-2 in rhesus macaques yielded mild interstitial pneumonia and viral load was detected in oropharynx and nasopharynx samples. However, viral load of the conjunctival sample was detected only in the first day after conjunctival inoculation. Intra-tracheal inoculation of SARS-CoV-2 did not yield a detection of viral load in the conjunctival sample(15).
We found 2 cases of patients with positive conjunctival swabs and NOP swabs, 40 patients who tested positive for NOP swabs only and 11 who tested negative for both conjunctival and NOP swabs. The low rate of viral detection in conjunctival samples for our study (2 out of 42 patients with positive NOP samples (4.76%) might be due to several causes. First, majority of the patients in our sample group might be exposed to the virus via the upper respiratory tract pathway instead of the ocular surface. As the virus would descend from the upper to the lower respiratory tract, viral load was therefore not detected in the conjunctival samples. The second probable reason was a fast clearance rate of the virus from the ocular surface due to drainage via the nasolacrimal pathway, therefore SARS-CoV-2 was not detected in the conjunctival samples. This is supported by the study of Deng et al stated that conjunctival viral load was not detected after the first day of inoculation via the conjunctiva of rhesus macaques(15). Other studies have also found low rates of positive conjunctival swab results ranging from 0 to 11.1% (1, 2, 6, 11, 16, 17).
Two patients (patient no. 10 and 49) were diagnosed with viral keratoconjunctivitis related to SARS-CoV-2 infection. Symptoms included red eye, itchiness, and eye discharge. However, conjunctival samples were negative for SARS-CoV-2. NOP and conjunctival swabs were taken 2 days apart for both patients. The patients were given topical antiviral, topical anti-inflammatory eyedrops as well as artificial tears. Symptoms were relieved and the patients recovered without ocular complications. In contrast, for the 2 patients who tested positive for conjunctival swabs, ocular symptoms were not observed. NOP and conjunctival swabs were taken 0 and 1 day apart. Previous studies also showed low rates of positive conjunctival samples from confirmed COVID-19 cases that ranged between 1.6–7.1%. A low percentage of patients with conjunctivitis who had positive conjunctival swab results was reported(11). A study by Ranzenigo et al(18) revealed that the presence of ocular symptoms was related to the severity of illness. However, none of the patients in the study with ocular symptoms tested positive for conjunctival swab. These studies along with our results suggested that the occurrence of conjunctivitis is a systemic response rather than local activity of the virus on the ocular surface. However, ocular involvement in Covid-19 patients other than conjunctivitis has been described, including keratitis, uveitis, retinal pathologies, and neuro-ophthalmological involvement.(19) These clinical manifestations often occur in patients who required mechanical ventilation and in patients with more severe illness.(20) As our patients who had positive conjunctival swab results and mild symptoms of systemic Covid-19, ocular symptoms were not observed. Nevertheless, a link between presence of SARS-CoV-2 in conjunctival sample and ocular symptoms is difficult to establish and elusiveness of the virus on the ocular surface can be caused by nasolacrimal drainage of the virus. Furthermore, ocular involvement is often a result of systemic response, explaining the low positive conjunctival swab rate in Covid-19 patients with ocular involvement.
Laboratory results of patients with positive conjunctival swab results was not significantly different from patients with negative conjunctival swab results as shown in Table 3. A previous study by Atum et al also found no significant difference in laboratory result characteristics between the two groups(21). However, this might be due to the small number of patients who had positive conjunctival swab results and might not be statistically representative of the cohort.