SARS-Cov-2 is a Coronovirus in the subfamily Coronavirinae, in the family Coronaviridae and in the order of Nidovirales and is responsible for COVID-19 disease. General characteristics of the virus are discussed with an emphasis on ocular manifestations of infection. In addition, the potential of ocular secretions including tears are reviewed as a potential for human to human spread of the virus. Finally, a discussion is made of the latest information on the eye as a portal for exposure and development of COVID-19 infection.

Nidovirales, derived from the Latin nidus (nest) is an order of single stranded RNA genome viruses with both human and animal hosts and includes the family Coronaviridae, Roniviridae, Arteriviridae, and Mesoniviridae. All viruses in this order produce a 3' co-terminal nested set of subgenomic mRNA's during infection. With a genome of approximately 30 kb in length, they are among the largest known RNA viruses.^1,2 Coronavirus (derived from ancient Greek, korone, meaning crown or halo) is the common name for Coronaviridae and Orthocoronavirinae, also called Coronavirinae.³ Typical of the virus is petal shaped projections of approximately 20 nm, which by electron microscopy create an image similar to the solar corona or crown. Coronoviruses can cause disease in mammals and birds. In humans, Coronoviruses may lead to respiratory infections including the common cold. MERS, Sars-Cov-1, and Sars-Cov-2 are coronaviruses which have been associated with more severe human infections and a higher incidence of mortality. Middle East Respiratory Syndrome (MERS) was first reported in Saudi Arabia in 2012. SARS-CoV-1 was responsible for severe acute respiratory syndrome outbreak in 2003 in Asia with secondary cases around the world. SARS-CoV-2, another strain of severe acute respiratory syndrome-related coronavirus, is responsible for the 2019-2020 COVID-19 disease pandemic. This paper will discuss the ocular manifestations of COVID-19, whether ocular secretions may lead to human to human spread of the virus, and how the eye’s mucosal surfaces may represent a means of human exposure and eventual infection.

Ocular manifestations

Coronovirinae can cause ocular infections in animals including conjunctivitis, subconjunctival hemorrhage, uveitis, retinitis, and optic neuritis. Vision threatening ocular complications have been well documented by Coronovirus in murine and feline orders.⁴ In a study of 1099 COVID-19 patients, only 0.8% developed conjunctival congestion (9 of 1099 patients in 30 hospitals across China),⁵ however, conjunctivitis has been demonstrated as the initial presenting symptom of Sars-Cov-2 infection.⁶ Typically the conjunctivitis has been described as mild follicular conjunctivitis otherwise indistinguishable from other viral causes. The nurses at the Life Care Center Nursing Home in Kirkland, Washington noted that the single most important sign of infected patients was eye redness.⁷ A report by Wu et al described the findings of 38 patients with COVID-19 and severe pneumonia in Hubei Province, China. They found 31.6% of patients demonstrated ocular manifestations consistent with conjunctival hyperemia, chemosis, epiphora, or increased secretions.⁸ Only one patient presented with conjunctivitis as the first symptom.⁸ Of the 17 patients recruited, none presented with ocular symptoms and only 1 patient developed conjunctival injection and chemosis during the stay in the hospital.

Ocular secretions as a potential of human to human spread

Ocular transmission via infected ocular tissue or tears COVID-19 is uncertain.^4,9 In 2004, 36 tear samples from suspected SARS-CoV-1 patients were sent for RT-PCR and the SARS-CoV RNA was identified in three patients, suggesting that SARS-CoV-1 can be present in tears.⁹ A second study by Loon et al in the British Journal of Ophthalmology detected SARS-CoV-1 in tears early in the course of infection.¹⁰ A more recent study evaluating SAR-CoV-2 (COVID-19) showed a positive reverse-transcription polymerase chain reaction assay in tears and conjunctival secretions in patients with conjunctivitis and pneumonia, but for patients with pneumonia and no conjunctivitis, there was no virus detected in tears or conjunctival secretions¹¹ In a study by Ivan Seah Yu Jun et al out of Singapore in 2019,¹² 64 tear samples were collected via Schirmer’s strip tear collection from 17 COVID-19 patients between Day 3 to Day 20 from initial symptoms. Neither viral culture nor 36 reverse transcription polymerase chain reaction (RT-PCR) detected the virus. A study from Yichang Central People’s Hospital in Hubei Province by Wu et al in February 2020, found that of 38 patients with clinically confirmed COVID-19, two patients yielded positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens.⁸ It appears that the presence of virus in tears may be low, but none the less, virus can be present and can serve as a source of transmission of the virus.

The eye as a portal for exposure and human infection

Even if COVID 19 positive patients have no virus shedding though tears, the eye remains a potential portal of entry for ocular and systemic disease from the virus. Both avian and human influenza A viruses have shown a capacity to cause disease via entry from ocular tissues.¹³ The conjunctival and corneal epithelium represents a mucosal surface that, similar to the respiratory tract, bears receptors for influenza virus¹⁴ and avian influenza virus.¹⁵ SARS-CoV-2 has been known to infect cells via ACE-2 receptors.¹⁶ Ace-2 is a type I transmembrane metallocarboxypeptidase enzyme part of the Renin-Angiotensin system and a target for the treatment of hypertension.¹⁷ It is mainly expressed in vascular endothelial cells, the renal tubular epithelium, and in Leydig cells in the testes.^18,19 SARS-CoV-2 may utilize ACE-2 as a cellular entry receptor to gain entry into ACE-2-expressing HeLa cells.²⁰ The presence of ACE2 has been found in the aqueous humor,²¹ however the human eye has its own intraocular renin-angiotensin system, a system that has been the interest of many projects focusing on developing anti-glaucomatous drugs.⁴ More studies are required to definitely prove the presence of ACE2 on corneal and conjunctival cells. Regardless of which receptor COVID-19 utilizes, many respiratory viruses have been shown to cause ocular complications which then leads to respiratory infection.²² Studies have demonstrated that in individuals wearing both ocular and respiratory protection exposed to live attenuated influenza have lower viral loads than individuals wearing respiratory protection alone.²³ Li Wenliang, MD, the whistleblower ophthalmologist from Wuhan, Hubei Province, China believed he was infected by an asymptomatic glaucoma patient. A clinician inspecting in Wuhan (Guangfa Wang) was infected while working with a N95 mask but no eye protection.²⁴ He first developed conjunctivitis and then later pneumonia. Transmission of COVID-19 through the ocular surface must not be ignored as it well could be an alternative route of transmission.^8,25

In summary, COVID-19 does affect the eye and may be the presenting sign of infection. Ocular transmission by exposure to tears may be low, but has not been ruled out. Finally, the eye may serve as a portal of entry for the COVID-19 virus leading to human infection. Ophthalmologists may be the first providers to evaluate patients possibly infected with COVID-19 as patients may present with conjunctivitis. Eye protection (including goggles or faceshields) is warranted to reduce viral infection especially in health care providers exposed to known positive viral patients. In addition, all people should avoid touching or rubbing their eyes to avoid potential inoculation of virus into the eye.

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Author declares that there is no conflict of interest.

1. Madhugiri R, Fricke M, Marz M, et al. Coronavirus cis-acting RNA elements. Adv Virus Res. 2016;96:127–163.
2. Antoine A F de Vries, Marian C Horzinek, Peter J M Rottier, et al. The Genome Organization of the Nidovirales: Similarities and Differences between Arteri-, Toro-, and Coronaviruses. Semi. Virol. 1997;8(1):33–47.
3. ICTV Taxonomy history: Orthocoronavirinae. International Committee on Taxonomy of Viruses (ICTV). 2020.
4. Seah I, Agrawal R.  Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals.  Ocul Immunol Inflamm. 2020;137:1‒5.
5. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.
6. Yan A. Chinese expert who came down with Wuhan coronavirus after saying it was controllable thinks he was infected through his eyes China: South China morning post. 2020. 
7. Care home nurse tells of terrifying and sudden ways coronavirus struck her patients. 2020. 
8. Wu P, Duan F, Luo C et al.  Characteristics of ocular finding of patients with coronovirus disease 2019 (COVID-19) in Hubei Province, China.  JAMA Ophthalmology. 2020.
9. Lu CW, Liu XF, Jia ZF. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet. 2020; 22;395(10224):e39. 
10. Loon S-C, Teoh SCB, Oon LLE, et al. The severe acute respiratory syndrome coronavirus in tears. British J Ophthalmol. 2004;88(7):861–863.
11. Xia J, Tong J, Liu M, et al. Evaluation of coronavirus in tears and conjunctival 144 secretions of patients with SARS-CoV-2 infection. J Med Virol. 2020.
12. Yu Jun, Ivan Seah.  Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients.  Ophthalmology.
13. Belser JA, Lash RR, et al.  The eyes have it: influenza virus infection beyond the repiratory tract.  Lancet Infect Dis. 2018;18(7):220‒227.
14. Belser JA, Rota PA, Tumpey TM. Ocular tropism of respiratory viruses.  Microbiol Mol Biol Rev. 2013;77:144‒156.
15. Olofsson S, Kumlin U, Dimock K, et al.  Avian influenza and sialic acid receptors: more than meets the eye?  Lancet Infect Dis. 2005;5:184‒188.
16. Wan Y, Shang J, Graham R, et al. Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol. 2020.
17. Riordan, JF. Angiotensin-I-converting enzyme and its relatives.  Genome Biology.  2003;225.
18. Kuba K, Imai Y, Ohto-Nakanishi, T et al.  Trilogy of ACE2: A peptidase in the renin–angiotensin system, a SARS receptor, and a partner for amino acid transporters.  Pharmacology & Therapeutics.  2010;128(1):119‒128.
19. Jiang F, Yang J, Zhang Y, et al. Angiotensin-converting enzyme 2 and angiotensin 1–7: novel therapeutic targets. Nat Rev Cardiol.  2014;11:413–426.
20. Hoffman, M., Kleine-Weber H, Schroeder S. et al.  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.  Cell.  2020;181(2):271‒280.e8.
21. Holappa M, Vapaatalo H, Vaajanen A. Many faces of renin-angiotensin system - focus on eye. Open Ophthalmol J. 2017. 
22. Belser JA, Rota PA, Tumpey TM.  Ocular tropism of respiratory viruses.  Microbiol Mol Biol Rev. 2013;77:144‒156.
23. Bischoff WE, Reid T, Russell GB, et al.  Transocular entry of seasonal influenza-attenuated virus aerosols and the efficacy of n95 respirators, surgical masks, and eye protection in humans. J Infect Dis. 2011;204:193‒199.
24. Dai X. Peking University Hospital Wang Guangfa disclosed treatment status on Weibo and suspected infection without wearing goggles. Beijing News, 2020.
25. Seah I, Su X, Lingam G. Revisiting the dangers of the coronavirus in the ophthalmology practice. Eye (London). 2020.