Key Summary Points
The purpose of this review is to summarize the evidence
currently available on COVID-19 and its ocular implications and
manifestations, in both animals and humans, with the aim to facilitate
prevention and educate the ophthalmological community on this
subject. |
Conjunctivitis is not a common manifestation of the disease,
but contact with infected eyes could be one route of disease
transmission. |
Some guidelines regarding prevention and management of
ophthalmology clinic are reviewed. |
Introduction
Since December 2019, humanity has been having to deal with the emergence of
a severe and acute respiratory coronavirus disease (COVID-19), caused by the strain of
coronavirus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The respiratory problems caused by this pathogen is well known, but the ophthalmological
implications of the syndrome have not yet been well described.
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Coronavirus disease is not a new pathology. Three human coronaviruses have
been known to exist since the mid-1960s: human coronavirus 229E (HCoV-229E),
human coronavirus OC43 (HCoV-OC43) and severe acute respiratory syndrome
(SARS)-associated coronavirus (SARS-CoV) [1‐9]. In 2004, human coronavirus NL63 (HCoV-NL63), a
novel human coronavirus to date, was reported in a 7-month-old child suffering from
bronchiolitis and conjunctivitis [10,
11]. The Coronaviridae family of viruses consist of enveloped viruses with a large
plus-strand RNA genome (27–32 kb) that is capped and polyadenylated. Each serology type
is characterized by a specific host range and genome sequence.
The most pathogenic of these four types of coronaviruses is SARS-CoV, which
causes a life-threatening pneumonia [12‐14]. This virus is likely to reside in animals and can affect humans
through zoonotic transmission [15,
16]. Coronaviruses have been identified
in mice, rats, chickens, turkeys, swine, dogs, horses, rabbits, cats and humans. They
can cause a variety of health problems in humans, including gastroenteritis, respiratory
tract problems [17, 18] and conjunctivitis [10, 11,
19‐31].
The authors of a recent study concluded that one-third of patients with
COVID-19 had ocular abnormalities, a frequent manisfestation in patients with more
severe disease and that although there is a low prevalence of SARS-CoV-2 in tears, it is
possible to transmit the disease through ocular secretions [31]. Therefore, taking into consideration that there
are more reports in the literature associating coronavirus and ophthalmic problems, the
aim of this narrative review is to summarize, from an ophthalmological perspective, the
pathogeny, the portal of entry and implantation of the virus at the conjunctiva, its
ophthalmic implications, ocular complications, prevention in the ophthalmology context
and possible treatment of the ocular disease. The relationship between COVID-19 and the
ocular surface (conjunctiva, corneal epithelium and tear film) as a potencial portal of
entry and as a transmission mechanism is currently under discussion due to the high
transmission rate of the disease.
This article is based on previously conducted studies and does not contain any
studies with human participants or animals performed by any of the authors.
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Clinical Evidence on Covid-19 and Eye Disease
Etiology and Pathogenesis of COVID-19
In general, coronaviruses are able to cause a wide range of upper
respiratory infections (common cold: alphacoronavirus HCoV-229E, alphacoronavirus
HCoV-NL63, betacoronavirus HCoV-OC43 and HCoV-HKU1), whereas other betacoronaviruses,
such as SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), are
responsible for more aggressive lower respiratory problems considered to be atypical
pneumonias. The different infection sites are likely to be related to the presence of
a viral surface spike composed of a dipeptidyl peptidase 4 glycoprotein that has a
human receptor in the lower respiratory tract, known as angiotensin converting enzyme
2 (ACE2). Both SARS-CoV and MERS-CoV have this surface spike glycoprotein
[32‐34].
From the genetic point of view, SARS-CoV-2 is about 70% similar to
SARS-CoV and, therefore, it is capable of using the same cell entry receptor (ACE2)
to infect human cells [35, 36]. However, the SARS-CoV-2 glycoprotein spike
binds to ACE2 human receptors at a 10- to 20-fold higher affinity than SARS-CoV
[37].
Once SARS-CoV-2 enters the alveolar epithelial cells, its fast
replication rate triggers a strong immune response causing cytokine storm syndrome
(hypercytokinemia) and subsequence pulmonary tissue damage. In general,
hypercytokinemias consist of a group of disorders that produce an elevation of the
pro-inflammatory cytokines. These cytokines are an important cause of acute
respiratory distress syndrome (ARDS) and multiple organ failure [38‐40]. One analysis of the first 99 cases of
SARS-CoV-2 revealed that a cytokine storm occurred in patients with severe COVID-19,
of whom 17% had ARDS; among the latter patients, 11% deteriorated very rapidly and
died of multiple organ failure [41]. In
addition, the number of T cells (CD4 and CD8) are decreased in patients infected with
SARS-CoV-2, suggesting a decreased immune function that subsequently allows a
secondary infection that could worsen the respiratory failure [42].
Both viral diseases and immune problems can lead to ocular
manifestations, such as conjunctivitis, uveitis, retinitis, among others. It is
difficult to determine the pathogeny of the ophthalmic involvement. However, since
the virus has been cultured from conjunctival secretions [43], COVID-19 ophthalmopathy is more likely to be
related to the own virus infestation rather than the secondary immune reaction that
the infection may cause.
Portal of Entry
It is known that SARS-CoV-2 can be transmitted through direct or
indirect contact with mucous membranes in the eyes, mouth or nose [28, 44, 45] and that the
respiratory tract should not be considered the only route of transmission. In fact,
recent studies associate the enteric symptoms of COVID-19, such as diarrhea, nausea,
vomiting [46, 47], with invaded ACE2-expressing enterocytes
[48], with the oral–fecal route being
another potential portal of entry.
Additional studies are required to test different portal of entries.
Proposed theories include [30]:
1.
Direct inoculation of the conjunctiva from infected
droplets.
2.
Migration of upper respiratory tract infection through the
nasolacrimal duct.
3.
Hematogenous infection of the lacrimal gland.
Evidence of Ocular Manifestations
Our analysis of some of the studies included in this narrative review
(see Table 1) revealed that the most common
ophthalmologic sign related to coronavirus infection was inflammation of the
conjunctiva (conjunctivitis). Among the studies reviewed, six were performed in
animals (feline, murine, canine and bird experimental models) [19‐21, 24‐26] and the other 11 in humans [10, 11, 22, 23, 27‐31].
Table 1
Clinical evidence of coronavirus ophthalmic
manifestions
First author [reference] | Year | Type of study | Main ocular problem | Other problems | Upper respiratory tract problems | Gastrointestinal signs |
|---|---|---|---|---|---|---|
Hök K [19] | 1993 | Experimental | Conjunctivitis | Present | ||
Hök K [20] | 1993 | Experimental | Conjunctivitis | Present | Present | |
van der Hoek L [10] | 2004 | Clinical | Conjunctivitis | Present (bronchiolitis) | ||
Ahmad K [11] | 2004 | Clinical | Conjunctivitis | Present (bronchiolitis) | ||
Decaro N [24] | 2004 | Experimental | Conjunctivitis | Present (respiratory distress) | Present (enteritis) | |
Loon S-C [49] | 2004 | Clinical | Not specified | Present (SARS) | ||
Chan WM [51] | 2004 | Clinical | Not specified | Present (SARS) | ||
Fouchier RA [22] | 2005 | Clinical | Conjunctivitis | Present (pneumonia, SARS) | ||
Vabret A [23] | 2005 | Clinical | Conjunctivitis | Otitis, pharyngitis | Present (rhinitis, bronchiolitis) | Present |
Terregino C [24] | 2008 | Experimental | Conjunctivitis | Present | ||
Ledbetter EC [25] | 2009 | Experimental | Conjunctivitis | |||
Stiles J [26] | 2014 | Experimental | Uveitis | |||
Chang LY [27] | 2014 | Clinical | Conjunctivitis | |||
Xia J [28] | 2020 | Clinical | Conjunctivitis | |||
Lai THT [29] | 2020 | Clinical | Not specified | |||
Seah I [30] | 2020 | Clinical | Conjunctivitis | Uveitis, retinitis, optic neuritis | ||
Wu P [31] | 2020 | Clinical | Conjunctivitis | Epiphora | ||
Chen L [43] | 2020 | Clinical | Conjunctivitis | Present (sore throat) | Present (diarrhea) | |
Zhang H [48] | 2020 | No evidencea | ||||
Cheema M [67] | 2020 | Case report | Keratoconjunctivitis | Present (rhinorrhea, cough, nasal congestion) | ||
Lan QQ [70] | 2020 | Clinical | No evidencea | |||
Hu K [71] | 2020 | Clinical review | Conjunctivitis | Present | ||
A-Yong [72] | 2020 | Clinical review | Conjunctivitis |
The first time that conjunctivitis was associated to a human
coronavirus was in 2004, in a 7-month-old child [10, 11], then in 2005
[22, 23], due to the great interest in understanding the clinical
manifestations of coronavirus during the first SARS-CoV crisis. However, it is not
until this new 2019–2020 outbreak that conjunctivitis has once again been associated
to a coronavirus outbreak and taken to be a sign of COVID-19.
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In a retrospective study, Vabret et al. investigated HCoV-NL63
infection in hospitalized children diagnosed with respiratory tract infection
[23]. Of the 300 samples analyzed, 28
(9.3%) were positive for HCoV-NL63. The medical reports of 18 patients with
HCoV-NL63–positive samples were retrospectively examined and the following symptoms
noted: fever (61%, n = 11 patients), rhinitis
(39%, n = 7), lower respiratory tract illness
(bronchiolitis, pneumonia [39%, n = 7]), digestive
problems (diarrhea and abdominal pain [33%, n = 6]), otitis (28%, n = 5),
pharyngitis (22%, n = 4) and conjunctivitis (17%,n = 3) [23].
Xia et al. reported a prospective interventional case series involving
30 patients with confirmed novel coronavirus pneumonia [28]. Tear and conjunctival secretions were
collected for reverse‐transcription PCR (RT‐PCR) assay. The authors demonstrated that
SARS‐CoV-2 were present in the tears and conjunctival secretions of coronavirus
pneumonia patients with conjunctivitis; however, no virus was detected in the tears
or conjunctival secretions of patients without conjunctivitis. These results could
possibly indicate that tear and conjunctival secretions are not a common route of
coronavirus transmission, given that the majority of COVID-19 patients do not
manifest conjunctivitis. Nevertheless, this route of transmission could not be
completely eliminated in such patients [28]. As ophthalmologists, we should be aware of this finding
because any sign of conjunctivitis in the clinical setting should be considered to be
a possible coronavirus conjunctivitis, especially when accompanied by other
respiratory tract problems or fever.
A study carried out by Loon et al. in 2004 demonstrated the presence of
SARS-CoV RNA in tears [49]. Tear samples
collected from 36 suspected SARS-CoV patients were sent for RT-PCR analysis for the
presence of SARS-CoV; SARS-CoV RNA was identified in three of these patients
[49].
In contrast, there have been studies which have assessed both tears and
conjunctival scrapes from 17 patients with confirmed SARS-CoV infection, with no
positive results from the RT-PCR analysis [50, 51]. The authors
propose three explanations of these results: (1) low sensitivity of RT-PCR on ocular
surface secretions; (2) if there is viral shedding in ocular tissue, the window
period may only last a short period of time; (2) the possibility that SARS-CoV does
not exist in ocular tissues.
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Regarding the severity of the COVID-19 disease, patients with ocular
symptoms are more likely to have higher white blood cell and neutrophil counts and
higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase than
patients without ocular symptoms [31].
Another interesting detail regarding the ocular implication of this
infection is that the human eye actually has its own intraocular renin–angiotensin
system, and ACE2 receptors have been found in the aqueous humor [52]. As previously explained, the main receptor
for SARS-CoV-2 is the ACE2 receptor, which indicates that aqueous humor could be a
target in COVID-19 infection. More studies exploring the hypothesis of SARS-CoV-2
ocular manifestation through the ACE2 receptor need to be performed.
The study of ocular manifestations in animals could improve our current
understanding of eye disease in humans. Therefore, in the following section, ocular
manifestations associated with coronavirus infections in animals are
discussed.
Association of Other Coronaviruses with Ocular Manifestations in Animals
Earlier studies have reported an association between coronaviruses and
ocular problems in animal models. For example, feline infectious peritonitis (FIP) is
caused by a feline coronavirus (FCoV). Vasculitis is a common feature in FIP, and
ocular manifestations include pyogranulomatous anterior uveitis, coroiditis with
retinal detachment and retina vasculitis, with perivascular cuffing by inflammatory
cells [53‐56]. These
manifestations are more common in the non-effusive (dry) form than in the effusive
(wet) form of the disease. Also, it can be present without other systemic signs of
FIP [26]. The treatment of uveitis
associated with FIP has been described: large fibrin clots in the anterior chamber
were treated with intracameral injections of 25 μg tissue plasminogen activator.
However, cats with mild uveitis responded only to topical therapy [26].
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A murine coronavirus, the mouse hepatitis virus (MHV), has shown
involvement of the posterior pole of the eye. The MHV neurotropic strains are of
particular importance in animal model studies in the ophthalmology field. The two
main strains are JHM (JHMV) and A59 (MHV-A59), both of which were isolated from a
paralyzed mouse as a result of extensive demyelination and encephalomyelitis
[57]. JHMV-infected mice were
subsequently utilized for intravitreal inoculation to study the mechanisms of
virus-induced retinal degeneration [58].
This model is known as the experimental CoV retinopathy (ECOR) model, and it is used
to examine genetic and host immune responses that may contribute to retinal disease
[30].
In the ECOR model, the infection has two phases, namely, inflammation
in the early phase and retinal degeneration in the late phase. Following inoculation,
the presence of the virus in the retina and retina pigment epithelium will result in
the infiltration of immune cells and release of proinflammatory mediators. After the
first week of infection, viral clearance is achieved. However, retinal and retinal
pigment epithelial cell autoantibodies are subsequently produced, resulting in
progressive loss of photoreceptors and ganglion cells as well as thinning of the
neuroretina [59]. In this case, the
autoimmune process is the cause of the majority of the retinal damage.
MHV-A59 models, on the other hand, have been used to create
viral-induced optic neuritis. This line of research is based on the increasingly
popular hypothesis that viral-induced inflammation is the likely etiology of multiple
sclerosis. Shindler et al. inoculated MHV-A59 intracranially into mice, inducing
meningitis, focal acute encephalitis and, most importantly, optic neuritis
[60]. Inflammation of the optic nerve
was detected as early as 3 days after inoculation, with the peak incidence at 5 days.
Axonal loss was highlighted by the significant decrease in axonal staining compared
to control optic nerves 30 days after inoculation [60].
It is important to note that in animal models, coronaviruses affect not
only the anterior surface of the eye; thus, we should be careful as ophthalmologists
and prevent any possible ocular transmission of the disease. It is important to learn
more about the transmission mechanism to the eye and try to understand the pathogeny
of the virus in the ocular tissues. We have clear knowledge of retinal and optic
nerve problems related to coronavirus in animals, and the implications thereof;
consequently, we should be meticulous when examining patients who have tested
positive for COVID-19. Nevertheless, to the best of our knowledge, there is no
evidence of human coronaviruses causing intraocular ophthalmic problems, such as
uveitis, retinitis and optic neuritis, as observed in animals.
Ophthalmological Prevention
According to a number of authors, ophthalmologists could have a higher
risk of contracting SARS-CoV-2 infection due to face-to-face communication with
patients, frequent exposure to tears and ocular discharge and the unavoidable use of
equipment, such as slit lamp, tonometer, laser, etc. [29, 61]. Ssome
guidelines have been recently published to minimize the risk of infection.
Before the patient`s visit
The number of patients visiting the clinic should be strictly limited, and
there should be a strict timetable of appointments to prevent any agglomeration of
patients in the clinic waiting room [29, 61]. Online
platforms, such as the hospital`s official website, should be used. Telephone
assistance could be useful in helping the patient distinguish between urgent and
not-urgent ocular problems, recommending treatments for non-urgent diseases,
reminding patients of the use of personal protection equipment (PPE) before coming
to the clinic and answering questions on possible symptoms relative to COVID-19
[61]. A triage system is also
important to identify patients with fever, respiratory symptoms and/or acute
conjunctivitis or who have recently traveled to outbreak areas. Online ordering
and delivery of prescribed medication, especially for chronic medication for
chronic eye diseases, such as glaucoma, is also recommended [61].
During the patient`s visit
The number of accessible entry points to the hospital/clinic should be reduced
and checkpoints set up at the hospital entrance. The temperature of patients
should be controlled and patients should be screening for COVID-19 symptoms and
contact history with confirmed or suspected COVID-19 patients within the past
14 days. Patients should be provided with a mask if they do not bring one from
home and social distancing in the registration and waiting area should be
practiced. Patients with conjunctivitis or other similar infections should be seen
in a separate clinic, and there should be a separate waiting area. Patients should
be tested more than two times for SARS-CoV-2 RNA in the conjunctival sac and
tears. Inside the clinical examination room, the number of people should be
limited (1 doctor and 1 patient per room), with the exception of visually impaired
patients, patients with communication/mobility difficulties or small children. The
room should be well ventilated, and the instruments used should be disinfected
immediately after each patient visit. Infection control training should be
provided to all clinical staff. Installation of protective shields on slit lamps,
frequent disinfection of equipment and provision of eye protection for staff
should be implemented in all clinics. Universal masking, hand hygiene and the
correct use of PPE should be promoted [29]. Direct ophthalmoscope examination is not recommended and
could be replaced by slit light lenses, optical coherence tomography (OCT) or
fundus photography [61].
Inpatient management and surgeries
Preoperative infection screening of the inpatients is recommended, especially
before any surgical procedure. General anesthesia should be avoided, and local
anesthesia is preferable to avoid contamination. Any emergency operation of a
COVID-19–positive patient should be performed in a negative pressure operating
room. If such a surgical area is not available, the patient should be referred to
another qualified hospital equipped with such an operating room. Operations on
healthy patients can be performed in a space with a positive pressure laminar
flow, as is standard practice [61].
Staff management
Infection control training for all staff is necessary. The taking of
temperature and the query-and-questionnaire procedure before entering the hospital
also applies to the staff. Strict hand hygiene is required, and gloves should be
changed regularly; one pair of latex gloves should not be used for long periods of
time [61].
According to current evidence, human coronavirus can remain
infectious on inanimate surfaces for up to 9 days [62]. Therefore, reducing the viral load on surfaces by
disinfection is very important. The World Health Organization recommends cleaning
environmental surfaces with water and detergent and applying commonly used
disinfectants, such as sodium hypochlorite [63]. Bleach is typically used at a dilution of 1:100 of 5%
sodium hypochlorite, resulting in a final concentration of 0.05% [64]. It has also been suggested that a
concentration of 0.1% is effective in 1 min. It therefore seems appropriate to
recommend a dilution 1:50 of standard bleach in the coronavirus setting. In case
of small surface desinfection, ethanol (62–71%) has shown an efficacy against
coronavirus [62, 64]. Other biocidal agents, such as 0.05–0.2%
benzalkonium chloride or 0.02% chlorhexidine digluconate are less effective
[65]. Duan et al. found that
irradiation with ultraviolet light for 60 min on several coronaviruses in culture
medium resulted in undetectable levels of viral infectivity.
We speculate that some ocular spray disinfectants that contain
hypochlorous acid, usually applied to treat blefaritis in order to reduce
bacterial and viral load on the skin and eyelashes, could be used as a measurement
of prevention for the facial area where many other chemical agents cannot be
applied.
Treatment of Ocular Problems in Patients with COVID-19
Little evidence exists on the treatment of the viral conjunctivitis
associated with COVID-19. Some antiviral systemic drugs have been used during this
outbreak, such as umefenovir, lopinavir, ritonavir [43], but not specifically for the ocular problem. Chen et al.
reported the possibility that ribavirin eye-drops could help the ocular symptom
treatment [43]. Cheema et al. recently
treated one patient who presented with pseudodendritic keratoconjunctivitis with oral
valacyclovir 500 mg orally three times per day and moxifloxacin 1 drop once daily to
the right eye, based on a presumed diagnosis of herpetic keratoconjunctivitis; this
patient, however, turned out to have a positive SARS-CoV-2 conjunctival swab result
[67].
The most common cause of infectious conjunctivitis is human adenovirus
(HAdV), accounting for up to 75% of all conjunctivitis cases and affecting people of
all ages and demographics. As a coronavirus, it can also cause systemic infections in
the form of gastroenteritis and respiratory disease. HAdV causes lytic infection of
the mucoepithelial cells of the conjunctiva and cornea, as well as latent infection
of lymphoid and adenoid cells. Despite it being the most common ophthalmological
viral infection, there is no U.S. Food and Drug Administration-approved antiviral for
treating HAdV keratoconjunctivitis. Therefore, managing viral persistance and
dissemination constitute a challenge. Some treatment modalities have been
investigated, such as systemic and topical antivirals, in-office povidone-iodine
irrigation, immunoglobulin-based therapy, anti-inflammatory therapy and
immunotherapy. Other posible therapeutic options are sialic acid analogs, cold
atmospheric plasma, N-chlorotaurine and
benzalkonium chloride [68].
Although viral conjunctivitis can cause discomfort to patients, it is
not a life-threatening condition. Therefore, all the treatment efforts in patients
testing positive for SARS-CoV-2 are destined to be vital problems rather than serious
threats to the eye itself. Treatment for viral conjunctivitis is mostly supportive,
and the majority of cases are self-limited. Nonetheless, it is important that
ophthalmologists to decrease the possible viral load on the conjunctiva and decrease
the potential of transmission through tear and eye secretions. Some of the general
ophthalmic recommendations for viral conjunctivitis could apply to COVID-19 patients
in terms of reducing both the transmission rate and possible complications; these
include hygienic measures (frequent hand washing, especially when eye drops need to
be applied or contact lens are worn; avoiding touching or rubbing the eyes; changing
pillowcases, sheets, towels, regularly; not sharing personal items, etc.).
More studies should be conducted to establish a specific antiviral
ocular treatment aimed at reducing the viral load, if present, on the conjunctiva of
patients and reducing the transmission rate from the ophthalmological perspective.
However, it is very difficult to determine a treatment when so many doubts still
remain regarding the ophthalmic implications of SARS-CoV-2 infection [69, 70].
Conclusion
Our review of the literature reveal that some studies suggest that ocular
symptoms commonly appear in patients with severe COVID pneumonia and that it is possible
to detect viral RNA from the conjunctival sac of these patients. Apparently,
conjunctivitis is not a frequent manifestation of the coronavirus disease in patients
with non-severe COVID-19. Despite conjunctivitis generally being a self-limited and
benign condition, it is an important route of viral transmission and, therefore,
prevention is the most important aspect to remember as ophthalmologists to protect our
patients and ourselves.
Acknowledgements
Funding
No funding or sponsorship was received for this study or publication of this
article.
Authorship
All named authors meet the International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this article, take responsibility for the
integrity of the work as a whole, and have given their approval for this version to
be published.
Disclosures
María A. Amesty, Jorge L. Alió del Barrio and Jorge L. Alió have
nothing to disclose. Jorge L. Alió is a member of the journal's Editorial
Board.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not
contain any studies with human participants or animals performed by any of the
authors.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or
analyzed during the current study.
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