Ocular Immunology and Inflammation

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ioii20

COVID-19 and the Ocular Surface: A Review of

Transmission and Manifestations

Dawn Ho , Rebecca Low , Louis Tong , Vishali Gupta , Aravamudan

Veeraraghavan & Rupesh Agrawal

To cite this article: Dawn Ho , Rebecca Low , Louis Tong , Vishali Gupta , Aravamudan
Veeraraghavan & Rupesh Agrawal (2020): COVID-19 and the Ocular Surface: A
Review of Transmission and Manifestations, Ocular Immunology and Inflammation, DOI:
10.1080/09273948.2020.1772313

To link to this article: https://doi.org/10.1080/09273948.2020.1772313

Published online: 16 Jun 2020.

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OCULAR IMMUNOLOGY AND INFLAMMATION
https://doi.org/10.1080/09273948.2020.1772313

INVITED REVIEW

COVID-19 and the Ocular Surface: A Review of Transmission and Manifestations

Dawn Ho, MBBSa*, Rebecca Low, MBBSa*, Louis Tong, FRCS (Ed), DM (Nott), FRCSOphth, PhD (NUS)b,c,d, Vishali Gupta, MS
(Ophthal)e, Aravamudan Veeraraghavan, MRCP (UK), FAMS (Singapore)f, and Rupesh Agrawal, FRCS, FAMS, MMed a,b,d,g
a
Department of Ophthalmology, National Healthcare Group Eye Institute, Singapore, Singapore; bSingapore Eye Research Institute, Singapore,
Singapore; cDepartment of Cornea and External Diseases, Singapore National Eye Centre, Singapore, Singapore; dDepartment of Ophthalmology,
Duke-NUS Medical School, Singapore, Singapore; eDepartment of Ophthalmology, Post Graduate Institute of Medical Education and Research,
Chandigarh, India; fDepartment of Internal Medicine, Woodlands Health Campus, Singapore, Singapore; gDepartment of Uveitis, Moorfields Eye
Hospital NHS Foundation Trust, London, UK

ABSTRACT ARTICLE HISTORY

Purpose: The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory Received 4 May 2020
syndrome coronavirus 2 (SARS-CoV-2) has reached pandemic proportions within an unprecedented span Revised 16 May 2020
of time. It is controversial whether the virus can be transmitted via tears and its ocular implications have Accepted 17 May 2020
not been widely studied. In this article, the current evidence related to ocular transmission and ocular KEYWORDS
manifestations is reviewed. COVID-19; sars CoV-2; ocular
Results: Several mechanisms for the ocular transmission of the virus are proposed with highlight on the surface; conjunctivitis
nasolacrimal system as a conduit between the eye and the respiratory tract, and the role of the lacrimal
gland in hematogenous spread. Ocular surface manifestations such as conjunctivitis are more commonly
reported.
Conclusion: The exact pathophysiology of ocular transmission of the virus remains incompletely under-
stood, although there is preliminary evidence of SARS-CoV-2 being detected in ocular secretions. The
ocular tropism of the virus and its potential to cause localized ocular disease are worth considering.

Coronaviruses (CoV) are enveloped positive-sense single-
stranded RNA viruses belonging to the family Coronaviridae
that are known to cause a range of illnesses from the common
cold to the severe acute respiratory syndrome.1
Although most human coronavirus infections are mild, the
past two decades witnessed the epidemics of two corona-
viruses, severe acute respiratory syndrome coronavirus
(SARS-CoV) and Middle East respiratory syndrome corona-
virus (MERS-CoV), which have caused more than 10000
cumulative cases, with mortality rates of 10% for SARS-CoV
and 37% for MERS-CoV.1
In December 2019, a cluster of pneumonia cases of
unknown cause was reported in Wuhan, Hubei province,
China.1,2 Deep sequencing analysis from lower respiratory
tract samples indicated a novel coronavirus.1 World Health
Organization (WHO) later named the disease, coronavirus
disease 2019 (COVID-19), and the coronavirus, severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2).
On 30th January 2020, WHO officially declared the
COVID-19 epidemic as a public health emergency of interna-
tional concern. The emergence of SARS-CoV-2 marked the
third introduction of a highly pathogenic, large-scale epidemic
coronavirus into the human population in the twenty-first
century. In the 4 months following its identification,
COVID-19 has spread across the globe, reaching unprece-
dented pandemic proportions. WHO has recommended
personal protection equipment including eye protection (gog-
gles) or facial protection (face mask) for healthcare workers
managing suspected cases of COVID-19. They are also
advised to refrain from touching any mucous membranes
(eyes, nose, or mouth) when managing these suspects.3
From the ophthalmology perspective, the evidence for trans-
mission of CoVs through the eye is not well studied but has been
suggested. In 2004, toward the end of the SARS-CoV crisis,
polymerase chain reaction (PCR) on tears from patients with
SARS-CoV infection demonstrated the presence of the virus.4
Tear samples were used to confirm SARS in one patient, who
was positive only from the tears. The finding of SARS-CoV in
tears was the first of its kind in emphasizing the need for appro-
priate precautions to prevent potential transmission through
ocular tissues and secretions. There is further evidence that
CoVs can cause conjunctivitis in humans. In fact, human cor-
onavirus NL 63 (HCoV-NL63) was first isolated in a 7-month-
old child with bronchiolitis and conjunctivitis before being
identified in seven other individuals.5 Subsequently, in 28 cases
of HCoV-NL63-infected children, 17% had conjunctivitis.6
Recognizing the possibility of ocular transmission and man-
ifestation of the virus is of significant concern to ophthalmic and
healthcare professionals. Contact with tears containing viable
virus potentially puts eye care providers at higher risk of con-
tracting the virus by virtue of their job. Conjunctivitis is
a common condition overall, and patients with conjunctivitis

CONTACT Rupesh Agrawal rupeshttsh@gmail.com Senior Consultant Ophthalmologist National Healthcare Group Eye Institute, Tan Tock Seng Hospital,
Singapore 308433, Singapore.
*These authors contributed equally to this work.
© 2020 Taylor & Francis Group, LLC
2 D. HO ET AL.
frequently present to emergency departments or eye clinics. It
may be possible that frontline providers including family physi-
cians, emergency physicians, and ophthalmologists are the first
point of encounter in the clinical setting of a patient presenting
with red eye or conjunctivitis and will be the initial providers to
evaluate patients infected with SARS-CoV-2.
For the purpose of this paper, we reviewed the current
literature to firstly, elucidate the ocular transmission of the
virus and secondly, expound its possible ocular surface
manifestations.
Method of Literature Selection
A primary literature search was performed in literature data-
bases including PubMed, EMBASE, Google Scholar, and
Medrixv. Keywords were used in combination, including:
“COVID-19,” “SARS-CoV-2,” “coronavirus,” “eye,” “ocular,”
“ocular surface,” “ophthalmic,” “conjunctivitis,” last accessed
on April 27, 2020. A secondary literature search was con-
ducted by identifying relevant references of initially included
articles. Inclusion criteria were as follows: All case series or
reports (including both published and pre-print articles) that
described ocular manifestations of patients with COVID-19
and/or documented testing of SARS-COV-2 in ocular secre-
tions via various sampling or detection methods. We excluded
studies that described other systemic manifestations of
COVID-19 but did not mention any ocular manifestations
related to the disease, nor present original data related to
the eye.
Transmission of SARS-CoV-2
SARS-CoV-2 is believed to be zoonotically transmitted, as are
other coronaviruses, including SARS-CoV and MERS-CoV.7
Phylogenetic studies showed that the genome sequence of
SARS-CoV-2 is 96% identical to a bat CoV RaTG13, and
shared 79% nucleotide homology to SARS-CoV.7,8 Based on
viral genome sequencing and evolutionary analysis, the bat
has been suspected to be the natural host of the virus, and
SARS-CoV-2 might be transmitted from bats via unknown
intermediate hosts to infect humans.8
Angiotensin-converting enzyme II (ACE2) is known to be
the cell receptor for SARS-CoV.7,8 The human ACE2 protein
is expressed in epithelial cells in lungs and other tissues such
as intestines and kidney.8 Genomic and structural analyses
found that the receptor-binding domain of SARS-CoV-2 was
sufficiently similar to that of SARS-CoV to efficiently use the
Figure 1. Illustration of the possible modes of transmission for COVID-19.
human ACE2 receptor for entry to human cells and infect
humans.7,8
Human-to-human transmission of SARS-CoV-2 has been
widely demonstrated in community, healthcare and family
settings. The dominant mode of transmission is from the
respiratory tract either via droplets (coughing, sneezing, or
talking) or indirectly via fomites (contaminated surfaces by
bodily fluids), and to a lesser extent via aerosols.7 In addition,
as SARS-CoV and MERS-CoV can infect the human gastro-
intestinal tract, it has been suggested that fecal-oral spread
may occur for SARS-CoV-2.7
Ocular Transmission of SARS-CoV-2 and Proposed
Mechanisms
Infectious droplets and bodily fluids can easily contaminate
the human conjunctival epithelium.9 Respiratory viruses are
known to possess an ocular tropism.10 It appears that the
presence of permissive receptors not only contributes to the
tropism of respiratory viruses to an ocular tissue, but also
allows the viruses to use the eye as a primary site of replica-
tion as well as a portal of entry to extraocular tissues to
establish a clinical infection.10
Although SARS-CoV-2 is known to be transmitted by
droplets, alternative modes of transmission remain unknown.
Anecdotally, it has been observed that physicians most at risk
of becoming infected include ophthalmologists, otolaryngolo-
gists, and anesthesiologists because of the proximity of the
examiners to mucosal surfaces including the eye.11
Transmission by tears and whether the eye can serve a dual
purpose for the establishment of an infection by being a portal
of entry on one hand and a primary site of virus replication
on the other hand remains controversial but there are a few
proposed theories Figure 1. It is hypothesized that the con-
junctiva as a mucous membrane can be a direct inoculation
site of infected droplets.12 The nasolacrimal system can act as
a conduit for viral migration, thus enabling transmission of
tears to the respiratory tract via the nasolacrimal duct or vice
versa, migration of upper respiratory tract infection through
the nasolacrimal duct to the eye.12 Hematogenous infection of
the lacrimal gland or hematogenous spread from it are addi-
tional possibilities.12
Virus from infected tears can be taken up by conjunctiva,
cornea, or epithelium of nasolacrimal duct or drained to the
nasopharynx through the nasolacrimal duct.13 Microvilli
within the epithelial lining of the nasolacrimal duct further
permit both secretion and reabsorption of tear fluid
components.13 Beyond these anatomical links, the molecular

link at the level of cellular receptors may play a major role in
the ocular tropism of respiratory viruses. In the case of SARS-
CoV-2, initial studies showed that the virus attacks human
host cells through the ACE2 receptor,13 and more recent
studies have found that viral invasion can also be mediated
by the novel route of the CD147 receptor.13
Remarkably, the renin-angiotensin system (RAS) that is
known for its endocrine role in blood pressure regulation as
well as fluid and electrolyte homeostasis also has complicated
tissue-specific autocrine functions in human organs including
the eye.14 As early as 1988, ACE activity was demonstrated in the
human eye.13 An independent ocular RAS system13,14 is the
target of new anti-glaucomatous drugs under development.14
The expression of ACE2 has been reported in aqueous
humor,13 as well as more anterior tissues, such as the conjunctiva
or cornea.15
The discovery of the novel route of CD147 is a landmark
finding. Prior localization studies using immunohistochemis-
try have confirmed the presence of CD147 in tears and dif-
ferent ocular tissues including conjunctiva, corneal epithelium
and endothelium, stromal keratocytes, and retinal pigment
epithelium.13 More recently, the localization of CD147 was
similarly observed in SARS-CoV-2 infected cells.13
Detection of SARS-CoV-2 in Ocular Secretions
Methods of sampling for ocular secretions include direct
conjunctival swabs, Schirmer’s test strips, and glass capillary
micropipettes. The mainstay for virus detection is reverse
transcriptase–polymerase chain reaction (RT-PCR), viral cul-
ture, or cytopathic effects (CPE).
A study previously detected SARS-CoV-2 by RT-PCR of
a patient’s tears.16 A more recent study of 17 patients found
no evidence of SARS-CoV-2 shedding in tears.17 There is
probably a low risk of SARS-CoV-2 transmission through
tears, but varying results may be attributable to differences
in the volume of fluid collected, collection technique, or tim-
ing of sampling.
RT-PCR of conjunctival secretions also yielded positive
results in numerous case series. In a prospective study, Xia
et al. evaluated the conjunctival secretions of 30 confirmed
cases of COVID-19.16 One patient had conjunctivitis and
SARS-CoV-2 was positive in nucleic acid test. Likewise,
Liang et al.18 and Wu et al.19 yielded positive results, although
in the study by Liang et al., the patient whose nucleic acid test
was positive did not have conjunctivitis,18 highlighting that
there may be viral shedding in asymptomatic patients even in
the absence of localized ocular disease. Viral shedding may
continue after recovery from disease, and may not represent
a viable virus. Still, the limitation lies in the small sampling
nature of published studies, owing to the logistical challenges
of managing these patients at this point in time.
To date, the virus itself has not been cultured from any
ocular secretions.
Clinical Manifestations
Individuals infected with SARS-CoV-2 may remain asympto-
matic or have very mild symptoms, while remaining highly
OCULAR IMMUNOLOGY AND INFLAMMATION 3
contagious. According to the WHO-China Joint Mission
report on 28th February 2020, approximately 80% of patients
will have mild to moderate disease and recover without
complications.
The incubation period varies between 1 and 15 days, and
infected individuals can develop symptoms up to 28 days after
infection.20 Fever, cough, and fatigue are the most common
symptoms at onset of illness. Other symptoms include sputum
production, sore throat, myalgia, or arthralgia, headache,
hemoptysis, diarrhea, anosmia, or dyspnea along with chest
radiographic abnormalities.2,20
Ocular Manifestations
A total of 20 case series and case reports were included,
comprising 2228 patients diagnosed with COVID-19. 1875
(84.2%) subjects were tested positive for SARS-COV-2 in
nasopharyngeal swab. Ninety-five (4.3%) patients reported to
have ocular manifestations during the course of their disease.
Out of these, 21 (0.9%) patients were reported to have ocular
manifestations as the first presenting complaint or sole man-
ifestation of COVID-19. Four hundred and twelve patients
had ocular swabs performed, with only 12 (2.9%) patients
having positive viral nucleic acid detected in those swabs.
For positive ocular swabs, we noted the cycle threshold
value where documented. 3 out of the 12 (25%) patients had
no ocular signs and symptoms despite viral nucleic acid being
detected in conjunctival or tear secretions. Table 1 encom-
passes the published studies of ocular manifestations found
using our research strategy.
During the SARS outbreak in 2003, a prospective study
also showed detectable SARS-CoV in the conjunctival swabs
of 3 out of 8 (37.5%) patients diagnosed with SARS, as
discussed earlier.4 However, none of the three patients had
any ocular manifestations.
Ocular Surface Manifestations
The American Academy of Ophthalmology mentioned con-
junctivitis as a presenting symptom in patients infected with
SARS-CoV-2. Several published reports and studies suggest
that SARS-CoV-2 can cause conjunctivitis, either as an early
sign of disease, or during hospitalization for severe disease.
Conjunctival injection is one of the reported features of
COVID-19.18,22,25 In a large study of 534 patients, 4.68% had
conjunctival congestion and 3 patients had conjunctival con-
gestion as the initial symptom.25 In a larger study of 1099
patients, conjunctival congestion was found in 0.8% of the
patients.22 Chemosis, foreign body sensation, epiphora, dry
eye, blurred vision are other features that have been reported
(Figure 2 and Table 1).
Conjunctivitis specifically has been diagnosed in numerous
cases,16,,19,30 and could represent an early presentation of
COVID-19. It has even been documented to be the presenting
symptom of patients infected with SARS-CoV-2.,19,23,25 Yet
another study reported that SARS-CoV-2 is capable of causing
conjunctivitis in the middle phase of illness.30 In this case
report, the patient developed conjunctivitis 13 days after ill-
ness onset and it was of note that the conjunctival swab
specimens remained positive for SARS-CoV-2 up to 17 days
4 D. HO ET AL.
Figure 2. Illustration of the various ocular signs and symptoms of COVID-19.
after the onset of conjunctivitis.30 These questions if conjunc-
tival sampling might be useful for early diagnosis because the
virus may not appear initially in the conjunctiva. However, we
recommend to err on the side of overcaution in taking pre-
cautionary measures when examining infected patients
throughout the clinical course of the infection.
Notably, a separate study of 114 patients revealed negative
conjunctival swab samples from all patients.21 Additionally,
no obvious ocular symptoms were documented or noticed.
These negative findings could be attributed to poor
documentation of eye care especially in the face of viral
complications in the respiratory tract or other systems that
are life-threatening. Another inference from these negative
results could be that the virus may be present in the con-
junctival sac or tear fluid for only a very short period of time,
and at the time of sample collection, the virus may have
already entered the respiratory tract or been eliminated by
the local ocular immune system.21 In this context, the sus-
pected COVID-19 patients with red eyes as the first symptom
are likely to yield detectable viral nucleic acid in the conjunc-
tival sac or tears.
There are more anecdotal reports of ocular infection or
red-eye being the initial symptom. On January 22, 2020,
Guangfa Wang, a member of the national expert panel on
pneumonia, developed conjunctivitis during the management
of patients in Wuhan.9 He subsequently developed pneumo-
nia and tested positive for SARS-CoV-2. He was gowned with
a protective suit and N95 respirator but did not use eye
protection. Unprotected exposure of the eyes might have
thus allowed infection, suggesting ocular infection as
a possible alternative route of SARS-CoV-2 transmission.
There has been one case report of keratoconjunctivitis with
evolving corneal findings through subsequent visits.33 Corneal
findings included subepithelial infiltrate, epithelial defect, and
pseudodendrite. The appearance of the epithelial defect varied
from one visit to the next even appearing as a pseudodendrite,
possibly from a healing epithelial defect or a progressive
infiltrate.
The case report has two notable details. Firstly, the
patient’s primary symptom and reason for seeking care was
a red eye with watery discharge. Secondly, the patient had
a positive conjunctival swab. This case and the above cases
emphasize the importance of a keen eye in considering SARS-
CoV-2 as the causative agent in patients presenting with viral
conjunctivitis, particularly in high-risk patients with signifi-
cant travel history or respiratory symptoms.
Intraocular Manifestations
To date, there is a scarcity of data about the intraocular
manifestations of SARS-CoV-2 or CoVs in humans, although
observational and experimental studies in animals have
shown the involvement of the posterior segment. A recent
study published in Lancet by Marinho et al. illustrated the
presence of hyperreflective lesions at ganglion cell layer and
also at inner plexiform layers (near papillomacular bundle) in
all 12 patients in the case series from Brazil. In addition, some
of the patients had features suggestive of retinal
microangiopathy.37 Apart from conjunctivitis, feline corona-
viruses were noted to cause granulomatous anterior uveitis,
choroiditis with retinal detachment, and retinal vasculitis.12
Murine coronaviruses have been studied to induce retinitis,
retinal degeneration, and optic neuritis.12 As the literature on
human ocular CoV infection is still lacking, an understanding
of the ocular manifestations of animal CoV infections may
open insights into the spectrum of ocular diseases that CoVs
can cause.
Neuro-ophthalmological Manifestations
Interestingly, there have been two cases reporting the rare
occurrence of Miller Fisher syndrome and polyneuritis
Table 1. Summary of studies documenting ocular manifestations of COVID-19 and detection of viral nucleic acid in ocular secretions.
No. of patients with No. of
No. of ocular No of patients No. of patients
patients manifestations as patients with with positive
with first presenting tested positive viral ocular swab Range of
No. of positive ocular symptom or only for nucleic acid but have no cycle
No. of nasopharyngeal signs/ Details of ocular symptom of COVID- ocular in ocular ocular Detection threshold
Study Type of study subjects swabs symptoms manifestations 19 swab swab manifestations method value Other remarks
1. Seah Prospective 17 17 0 Conjunctival 0 17 0 0 Schirmer test NA
et al, case series injection, chemosis strip, RT-PCR
202017
2. Xia et al, Prospective 30 30 1 Conjunctivitis 0 30 1 0 Conjunctival Not
202016 case series swab, RT-PCR documented
3. Deng Prospective 114 90 0 None 0 114 0 0 Conjunctival NA
et al, case series swab, RT-PCR
202021
4. Guan Retrospective 1099 1099 9 Conjunctival 0 0 0 0 NA NA
et al, case series congestion
202022
5. Wu et al, Retrospective 38 28 12 Conjunctival 1 38 2 0 Conjunctival Not 8 out of 12 patients with ocular
202019 case series hyperemia, swab, RT-PCR documented manifestations had severe to
chemosis, critical type COVID-19
epiphora
6. Zhou Retrospective 63 59 1 Conjunctivitis 1 63 1 1 Conjunctival Not 1 positive and 2 probably
et al, case series swab, RT-PCR documented positive conjunctival swab.
202023 None of the three patients had
ocular symptoms.
7. Sun Retrospective 102 72 2 Conjunctivitis 0 102 1 0 Conjunctival Not
et al, case series swab, RT-PCR documented
202024
8. Liang Prospective 37 Not 3 Conjunctival 0 37 1 0 Conjunctival Not Positive conjunctival swab from
et al, case series documented congestion and swab, RT-PCR documented patient with severe COVID-19
202018 other
inflammatory
appearance
9. Chen Retrospective 534 342 25 Dry eye, blurred 3 0 0 0 NA NA
et al, case series vision, foreign
202025 body sensation
10. Zhou Retrospective 121 121 8 Itching, redness, 0 8 3 2 Conjunctival <37 7 out of 8 patients were severe
et al, case series tearing, discharge, swab, RT-PCR cases. 2 out of 3 patients
202026 foreign body positive for conjunctival swab
sensation had no ocular symptoms.
11. Lescure Retrospective 5 5 1 Conjunctivitis 0 0 0 0 NA NA
et al, case series
202027
12. Scalinci Retrospective 5 5 5 Conjunctival 5 0 0 0 NA NA
et al, case series hyperemia,
202028 epiphora,
discharge,
photophobia
13. Hong Retrospective 56 21 Itching, foreign 6 0 0 NA NA
et al, survey body sensation,
2020[29 tearing, redness,
OCULAR IMMUNOLOGY AND INFLAMMATION

dry eyes, eye

secretions, floaters
(Continued )
5
 6
D. HO ET AL.

Table 1. (Continued).
No. of patients with No. of
No. of ocular No of patients No. of patients
patients manifestations as patients with with positive
with first presenting tested positive viral ocular swab Range of
No. of positive ocular symptom or only for nucleic acid but have no cycle
No. of nasopharyngeal signs/ Details of ocular symptom of COVID- ocular in ocular ocular Detection threshold
Study Type of study subjects swabs symptoms manifestations 19 swab swab manifestations method value Other remarks
14. Chen Case report 1 1 1 Bilateral follicular 0 1 1 0 Conjunctival 31–40 Systemic treatment started
et al, conjunctivitis, swab, RT-PCR before onset of ocular signs and
202030 foreign body symptoms. Normal fundus
sensation, exam and optical coherence
epiphora tomography.
15. Colavita Case report 1 1 1 Bilateral 1 1 1 0 Conjunctival 21.66–36.56 SARS-CoV-2 was detected in
et al, conjunctivitis swab, RT-PCR ocular swabs days after it was
202031 undetectable in nasal swabs
16. Guillen case report 1 1 1 Conjunctivitis 0 0 0 0 NA NA Patient had worsening
et al, respiratory symptoms with
202032 hypoxia in spite of the use of
high-flux nasal oxygen delivery
17. Cheema Case report 1 1 1 Unilateral 1 1 1 0 Retrospective 37 Anterior segment examination:
et al, conjunctivitis, testing of 1–2+ conjunctival injection, 3
202033 photophobia, conjunctival + follicles, 1 small
epiphora swab, RT-PCR pseudodendrite in the inferior,
and 8 subepithelial infiltrates
with epithelial defects
18. Salducci Case report 1 1 1 Bilateral 1 0 0 0 NA NA
et al, conjunctivitis,
202034 photophobia,
aqueous secretion,
chemosis,
pseudomembranes
19. Daruich Case report 1 1 1 Foreign body 1 0 0 0 NA NA
et al, sensation, red eye
202035
20. Wu et al, Case report - 1 1 1 Conjunctivitis, 1 0 0 0 NA NA
202036 letter to eyelid dermatitis
editor
2228 1875 95 0 21 412 12 3

cranialis, respectively, in patients with SARS-CoV-2.38
Diplopia was the presenting complaint in both cases. The
first patient had a preceding fever and respiratory symptoms
before his presentation with areflexia, ataxia as well as com-
plex ophthalmoplegia comprising right internuclear ophthal-
moparesis and right fascicular oculomotor palsy. The second
patient had fever and malaise prior to presenting with are-
flexia and bilateral abducens palsy areflexia.
Nonspecific, Noninfectious Ocular Manifestations of
Systemic Disease
Lastly, patients with more severe pneumonia or systemic
manifestations were reported to have a higher incidence of
ocular manifestations such as conjunctival congestion or
chemosis.19
A comprehensive study of the intensive care population
found that ocular surface disease affects up to 60% of its
patients.39 Chemosis is common, predisposed by the compro-
mised venous return from ocular structures, generalized
edema such as fluid overload or hypoalbuminemia, increased
hydrostatic pressure from prolonged recumbency or prone
ventilation, or increased capillary leak in systemic inflamma-
tory response syndromes.39 Exposure keratopathy, reduced
blink reflex, and drying effects of high flow oxygen also
contribute to the development of ocular surface disease.39
These are mechanisms that can be similarly disrupted
among COVID-19 patients with a more severe course of
disease or necessitating intensive care.
Moreover, conjunctival inflammatory reactions may be
part of the nonspecific, systemic manifestations of diseases
like renal failure,40 cardiopulmonary failure,41 and carbon
dioxide retention, rather than infectious conjunctivitis of
COVID-19. If SARS-CoV-2 can directly invade the ocular
tissues, we should expect a more significant inflammatory
response consistent with other viral infections such as the
herpetic ocular infections.
It would be essential to define if ocular manifestations are
due to infectious conjunctivitis or inflammatory, ocular man-
ifestations of COVID-19, and a dedicated ophthalmological
assessment of COVID-19 patients presenting with ocular fea-
tures would be ideal.
Thromboembolic Complications
Most recently, COVID-19 has been recognized as
a thromboembolic disease affecting multiple organs.42
D-dimer, which has very high sensitivity albeit low specificity
for thrombotic disease, has been observed to be in very high
levels in patients with COVID-19.42 While the coagulation
system can be triggered by pro-inflammatory cytokines sec-
ondary to systemic inflammation, Zhou et al. found
a discrepant 10-fold increase in D-dimer compared to inter-
leukin-6 (IL-6).42 The disproportionately higher D-dimer
levels reflect the interplay of true thrombotic disease, possibly
induced by cellular activation triggered by the virus.
Separate studies have consistently demonstrated a strong
association between elevated D-dimer levels and severe dis-
ease or poor prognosis,42 raising concerns about thrombotic
complications of COVID-19. There have been case reports of
thromboembolic complications including pulmonary
OCULAR IMMUNOLOGY AND INFLAMMATION 7
embolism, stroke, disseminated intravascular coagulation,
even limb, and digit infarcts.42,43
A pattern of cutaneous and pulmonary pathology involving
microvascular injury and thrombosis has been defined in
a subset of COVID-19, evinced by pulmonary and cutaneous
vasculature autopsy and biopsy samples in inter-alveolar septa
and retiform purpura or livedo racemosa, respectively.44 The
involvement of microvasculature conceivably opens up
a whole spectrum of eye diseases given that the retinal circu-
lation is an end arterial system, which is of clinical signifi-
cance given the potentially vision-threatening prognosis of
retinal vascular diseases.
Gaps in Literature
It is important to define if ocular manifestations are due to
infectious conjunctivitis or non-contagious ocular manifesta-
tions of COVID-19. Viral cultures can be attempted using
ocular isolates. Antiviral therapy for active infectious conjunc-
tivitis due to COVID-19 can be trialed. One potential area of
future study is to establish a critical threshold of virus experi-
mentally inoculated into tears that can cause pulmonary dis-
ease in primates. Lastly, there is room for further studies to
analyze retinal vascular and structural parameters over the
course of COVID-19 disease.
Conclusions and Future Directions
The ocular presentation of SARS-CoV-2 possibly varies and
fluctuates, however, it is likely that the virus does possess an
ocular tropism, as do other respiratory viruses. While we have
preliminary evidence of SARS-CoV-2 being detected in ocular
secretions of patients with ocular features, on top of previous
reports of other human coronaviruses causing ocular mani-
festations such as conjunctivitis, we acknowledge that con-
junctivitis-like features reported could be nonspecific and
a detailed ocular examination by an ophthalmologist is often
not performed.. In cases where an ophthalmic examination
has been performed, it can still be difficult to determine if the
ocular signs are purely reactive.
We perceived that there is generally a low incidence of
reported conjunctivitis or ocular symptoms in patients with
COVID-19, although ocular manifestations could be
neglected in light of the priority of disease management and
research on the respiratory tract or other life-threatening
complications. Eye care protocol is not always instigated and
documentation of eye care is often poor.
The ocular transmission of SARS-CoV-2 remains uncer-
tain, and the debate on its spread via tears continues to be of
interest. The expression of ACE2 in ocular tissue, coupled
with objective assays of positive conjunctival swabs in patients
without the ocular disease, suggest that there may be viral
shedding in asymptomatic patients in the absence of localized
ocular disease. However, we recognize that direct invasion of
ocular tissue by the virus is confounded by spread from
nasopharyngeal secretions given that the nasolacrimal system
is a conduit for viruses to travel from the upper respiratory
tract to the eye, and detection of the virus in ocular secretions
8 D. HO ET AL.
could be due to contamination with nasopharyngeal
secretions.
More well-designed trials and larger sample studies are
needed. Meanwhile, even with the currently limited informa-
tion, coronaviruses have posed a continuous threat to human
beings since the start of the twenty-first century. As the
pandemic continues, and even as this infection dies down,
crucial questions about viral transmission should not be left
unanswered.
The question of viral transmission via tears is pivotal not
only for its impact on infection control but the implications of
viral spread through tears. If the virus can spread by tears,
protocols for the eradication of the virus need to be in place.
A documented negative nasopharyngeal swab in COVID-19
patients often precedes deisolation. Similarly, if the virus can
infect via tears, close monitoring with repeated conjunctival
or tear sampling until swab negativity should be done as well.
If the virus can spread through ocular secretions, tear sam-
pling may be adjunctive in the diagnosis of SARS-COV-2.
Drawing lessons from the SARS epidemic in 2003, a patient
was diagnosed with SARS based on the positive conjunctival
swab, despite other negative laboratory investigations for
SARS-COV.4
An enhanced understanding of the relationship between
coronaviruses and the eye could mark a watershed in diag-
nostics (namely the use of tears or ocular secretions as
a simple, easily repeatable diagnostic tool) and infection con-
trol. In ophthalmology, treatment (i.e. the eradication of viral
infection in ocular tissues) and clinical protocol (such as out-
patient procedures in the eye clinic) can be further stream-
lined based on better knowledge of the ocular behavior of
coronaviruses. Retinal imaging may further offer promise in
the reflection of microangiopathies and thromboembolic phe-
nomena related to COVID-19. Retinal vascular caliber
changes or structural changes in the retina or optic nerve
head may correlate to both ocular and systemic implications.
As retinal imaging is relatively simple, cheap and noninvasive,
it can realistically be offered to the entire population in the
convalescent phase of COVID-19 infection, and in the later
part the disease, used in the monitoring of patients. Our
present experience and research of SARS-CoV-2 in ophthal-
mology can be useful to both clinicians and patients, world-
wide and in future pandemics.
Declaration of Interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.
ORCID
Rupesh Agrawal http://orcid.org/0000-0002-6662-5850
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