COVID-19—Considerations for the Practice of Ophthalmology 

In December 2019, authorities in Wuhan, China reported the first case of COVID-19, the disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹ Although coronaviruses are common pathogens in humans, the SARS-CoV-2 variant is particularly virulent. Disease transmission occurs through a viral “spike” protein that binds human (angiotensin-converting enzyme 2) ACE2 receptors to facilitate virus entry into human cells.^2,3 Although primarily transmitted through respiratory droplets and direct contact,^4,5 live virus has also be found in feces and ocular secretions.^6–8 Since its discovery, the virus has led to over 3.67 million cases and more than 250,000 deaths world-wide.⁹ This pandemic has had a profound impact on daily life, global economies, and to the practice of medicine. The possibility of ocular transmission of SARS-CoV-2 and reported ocular manifestations of COVID-19 have also greatly impacted the field of ophthalmology.

Several reports from China have looked for the presence of SARS-CoV-2 RNA in the ocular secretions of patients with COVID-19. In Hubei province, the epicenter of the COVID-19 outbreak, four patients with pneumonia had SARS-CoV-2 RNA isolated from their conjunctival sacs.⁷ Three of these patients also had accompanying conjunctival congestion and inflammation. One patient tested positive for SARS-CoV-2 RNA in the conjunctival sac but had no ocular symptoms. In a case series from the First Affiliated Hospital of Zhejiang University, one of 30 patients with COVID-19 pneumonia had RNA detected in ocular secretions. This particular patient had symptoms of conjunctivitis.⁸ At Wuhan’s Tongji hospital, two out of 72 patients had RNA detected in ocular secretions. Only one of these two patients had symptoms of conjunctivitis.¹⁰ In Italy, a patient with COVID-19 with bilateral conjunctivitis had SARS-CoV-2 RNA detected in the ocular secretions at day 27 of infection, 5 days after ocular symptoms had resolved and viral RNA had become undetectable in nasopharyngeal swabs.¹¹ Although some patients with COVID-19 develop ocular symptoms, it is not currently known whether ocular secretion itself plays a significant role in transmission of the disease.

Conjunctivitis has been reported in a small percentage of patients with COVID-19. A large retrospective study of 1,099 patients from 552 hospitals in 30 provinces in China found that nine of 1,099 (0.8%) patients experienced conjunctival congestion.¹² Other studies have similarly described conjunctival congestion or inflammation in patients with SARS-CoV-2 RNA detected in ocular secretions.^7,8,13 More recent reports have further characterized the ocular manifestations seen in patients with COVID-19. A case series study of 38 patients with COVID-19 in Hubei province found that 12 of 38 (32%) experienced ocular manifestations.¹⁴ The majority of these patients experienced chemosis and epiphora, although it is unclear whether the chemosis was due to fluid overload or conjunctivitis. A smaller number of patients experienced conjunctival hyperemia. The researchers of this study further note that the 12 patients experiencing ocular manifestations were more likely to be have severe disease than other patients with COVID-19. A recent meta-analysis of 1,167 patients with COVID-19 similarly found that patients with severe disease had an increased incidence of conjunctivitis (3%), compared to patients with non-severe disease (0.7%).¹⁵ These studies introduce the possibility that conjunctivitis may be a poor prognostic indicator in patients with COVID-19.

Unfortunately, the existing cases in the literature have not been extensively characterized and ophthalmologists currently have no way to distinguish COVID-19 conjunctivitis from other causes of viral conjunctivitis. Zhang et al. at Tongji hospital report that one of the patients with ocular secretions positive for SARS-CoV-2 experienced “conjunctival congestion and watery discharges” in both eyes.¹⁰ This patient had normal visual acuity and corneal epithelium and no enlargement of preauricular lymph nodes. A patient in Argentina similarly experienced conjunctival hyperemia with preserved visual acuity. However, this patient had unilateral involvement of the eyes with no secretions.¹⁶ There are little data on the time course of conjunctivitis symptoms, although anecdotal reports have described the onset of conjunctivitis symptoms prior to the development of respiratory symptoms.^13,16,17 Although different strains of coronavirus have been associated with more extensive ocular manifestations such as anterior uveitis, retinitis, and optic neuritis in animal models,¹⁸ there have been no such reports among patients with COVID-19.

Whether ocular involvement of COVID-19 occurs through direct inoculation of ocular tissue or from secondary spread of systemic infection is not currently known. Viral infections such as the common cold are known to enter to the body through contact with mucosal surfaces including the eyes. Similarly, COVID-19 may initially gain entry when respiratory droplets make contact with the ocular surface. The virus may then travel through the nasolacrimal duct and into the respiratory tract.¹⁹ Some scientists hypothesize that SARS-CoV-2 directly binds to ACE2 receptors expressed in the cornea and conjunctiva.^2,7

Current Centers for Disease Control and Prevention (CDC) guidelines recommend eye protection when caring for patients with COVID-19.²⁰ In one report from Wuhan, a taskforce member who was treating patients with COVID-19 without ocular protection later developed eye redness and contracted the disease.¹³ Dr Li Wenliang, the ophthalmologist who is credited with alerting the public to the COVID-19 outbreak, reportedly contracted COVID-19 from a patient with asymptomatic glaucoma.²¹

In addition to risk of COVID-19 transmission through direct contact with ocular secretions, ophthalmologists are also at risk for contracting COVID-19 due to their close proximity to patients when performing slit lamp examinations and ophthalmoscopy. In order to mitigate these risks, ophthalmologists in Hong Kong implemented three levels of control measures.²² At the administrative level, all non-urgent elective services were suspended. Secondly, plastic shields were placed over slip-lamps in order to act as a barrier against respiratory droplets. Finally, all ophthalmologists wore surgical masks and eye protection when in the hospital and in clinic. When ophthalmologists were in contact with a high-risk patient, gowns, gloves, and caps were also implemented.

At this time in the United States, the American Academy of Ophthalmology has recommended postponing elective office visits and elective surgeries indefinitely.²³ Daruich et al. report that telemedicine may have utility in ophthalmologic practice, since some patients with COVID-19 presented initially with ocular symptoms.¹⁶ Although surgical postponement also helps to conserve personal protective equipment (PPE), the operating room may be a particularly fertile environment for COVID-19 transmission. In a recent article published in The Lancet, 14 healthcare workers who encountered an asymptomatic patient with COVID-19 undergoing surgery were infected despite standard operating room precautions such as surgical masks and gloves.²⁴ As the pandemic worsens in the United States, it may become necessary to presume that all patients are infected with COVID-19. The critical shortage of PPE is already impacting physicians across the country and several have died. In order to continue to deliver proper care to patients while protecting ophthalmologists and their staff, additional safety measures may become necessary including rapid, readily available COVID-19 testing for all patients and expanded availability of PPE including N95 respirators, gowns, gloves, and eye protection.

References

1. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–23. 
2. 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;94:e00127–20.
3. Zumla A, Chan JFW, Azhar EI, et al. Coronaviruses-drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15:327–47. 
4. Burki TK. Coronavirus in China. Lancet Respir Med. 2020;8:238. 
5. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382:1177–9. 
6. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA – J Am Med Assoc. 2020. doi:10.1001/jama.2020.3786 [Epub ahead of print].
7. Liang L, Wu P. There may be virus in conjunctival secretion of patients with COVID-19. Acta Ophthalmol. 2020;98:223.
8. Xia J, Tong J, Liu M, Shen Y, Guo D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS‐CoV‐2 infection. J Med Virol. 2020: doi: 10.1002/jmv.25725 [Epub ahead of print].
9. Worldometer. (2020). Coronavirus Cases. In Worldometer (pp. 1–22). Available at: https://doi.org/10.1101/2020.01.23.20018549V2 (accessed 5 May 2020).
10. Zhang X, Chen X, Chen L, et al. The infection evidence of SARS-COV-2 in ocular surface: a single-center cross-sectional study. medRxiv. 2020; doi: https://doi.org/10.1101/2020.02.26.20027938
11. Colavita F, Lapa D, Carletti F, et al. SARS-CoV-2 isolation from ocular secretions of a patient with COVID-19 in Italy with prolonged viral RNA detection. Ann Intern Med. 2020; doi:10.7326/M20-1176 [Epub ahead of print].
12. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
13. Lu C wei, Liu X fen, Jia Z fang. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet. 2020;395:e39. 
14. Wu P, Duan F, Luo C, et al. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. 2020; doi:10.1001/jamaophthalmol.2020.1291 [Epub ahead of print].
15. Loffredo L, Pacella F, Pacella E, et al. Conjunctivitis and COVID‐19: a meta‐analysis. J Med Virol. 2020; doi:10.1002/jmv.25938 [Epub ahead of print].
16. Daruich A, Martin D, Bremond-Gignac D. Ocular manifestation as first sign of Coronavirus Disease 2019 (COVID-19): Interest of telemedicine during the pandemic context. J Fr Ophtalmol. 2020; doi:10.1016/j.jfo.2020.04.002 [Epub ahead of print].
17. Sidner S. Washington coronavirus: Care home nurse tells of sudden ways the virus struck her patients. 2020. Available at: www.cnn.com/2020/03/23/health/coronavirus-nurses-inside-washington-care-home/index.html (accessed May 4, 2020).
18. 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;28:391–5. 
19. Qing H, Li Z, Yang Z, et al. The possibility of COVID-19 transmission from eye to nose. Acta Ophthalmol. 2020;98:e388.
20. CDC. What Healthcare Personnel Should Know about Caring for Patients with Confirmed or Possible Coronavirus Disease 2019 (COVID-19). Available at: www.cdc.gov/coronavirus/2019-ncov/hcp/caring-for-patients-H.pdf (accessed May 4, 2020).
21. Lee KJ. Coronavirus kills Chinese whistleblower ophthalmologist. 2020. Available at: www.aao.org/headline/coronavirus-kills-chinese-whistleblower-ophthalmol (accessed May 4, 2020).
22. Lai THT, Tang EWH, Chau SKY, et al. Stepping up infection control measures in ophthalmology during the novel coronavirus outbreak: an experience from Hong Kong. Graefe’s Arch Clin Exp Ophthalmol. 2020;258:1049–55.
23. American Academy of Ophthalmology. Important coronavirus updates for ophthalmologists. 2020. www.aao.org/headline/alert-important-coronavirus-context (accessed May 4, 2020).
24. Chang D, Xu H, Rebaza A, Sharma L, Dela Cruz CS. Protecting health-care workers from subclinical coronavirus infection. Lancet Respir Med. 2020;8:e13.