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Review Article
Ocular Findings in COVID-19 Patients: A Review of Direct
Manifestations and Indirect Effects on the Eye
Federica Bertoli,
1
,
2
,
3
Daniele Veritti,
1
,
2
Carla Danese,
1
Francesco Samassa,
1
Valentina Sarao,
1
,
2
,
4
Nicol `
oRassu,
1
Tommaso Gambato,
1
and Paolo Lanzetta
1
,
2
,
4
1
Department of Medicine—Ophthalmology, University of Udine, Udine, Italy
2
Clinica Oculistica, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
3
Scientific Institute I.R.C.C.S. “Eugenio Medea”—“La Nostra Famiglia”, Udine, Italy
4
Istituto Europeo di Microchirurgia Oculare (IEMO), Udine, Italy
Correspondence should be addressed to Paolo Lanzetta; paolo.lanzetta@uniud.it
Received 23 May 2020; Accepted 12 August 2020; Published 27 August 2020
Academic Editor: In S. Contreras
Copyright ©2020 Federica Bertoli et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
e novel pandemic coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), has challenged the medical community. While diagnostic and therapeutic efforts have been focused on respiratory
complications of the disease, several ocular implications have also emerged. SARS-CoV-2 RNA has been found in tears of the
infected patients, and reports suggest that the ocular surface could serve as a portal of entry and a reservoir for viral transmission.
Clinically, COVID-19 has been associated with mild conjunctivitis, which can be the first and only symptom of the disease. Subtle
retinal changes like hyperreflective lesions in the inner layers on optical coherence tomography (OCT), cotton-wool spots, and
microhemorrhages have also been reported. In addition, COVID-19 has been associated with an increased incidence of systemic
diseases like diabetes mellitus and Kawasaki disease, which are particularly relevant for ophthalmologists due to their potentially
severe ocular manifestations. Several treatment strategies are currently under investigation for COVID-19, but none of them have
been proved to be safe and effective to date. Intensive care unit patients, due to risk factors like invasive mechanical ventilation,
prone position, and multiresistant bacterial exposure, may develop ocular complications like ocular surface disorders, secondary
infections, and less frequently acute ischemic optic neuropathy and intraocular pressure elevation. Among the array of drugs that
have shown positive results, the use of hydroxychloroquine and chloroquine has raised a concern due to their well-known retinal
toxic effects. However, the risk of retinal toxicity with short-term high-dose use of antimalarials is still unknown. Ocular side
effects have also been reported with other investigational drugs like lopinavir-ritonavir, interferons, and interleukin-1 and
interleukin-6 inhibitors. e aim of this review was to summarize ophthalmological implications of SARS-CoV-2 infection to
serve as a reference for eye care and other physicians for prompt diagnosis and management.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) has led to a global epidemic with more than 4 million
confirmed cases and 280,000 deaths worldwide thus far. e
disease caused by SARS-CoV-2 has been named “COVID-19”
(where “CO” stands for corona, “VI” for virus, “D” for disease,
and “19” indicates the year in which it occurred).
During December 2019, several cases of pneumonia of
unknown origin were reported in Wuhan, the capital of
Hubei Province in China [1]. A young ophthalmologist, Dr.
Li Wenliang, was the first physician to report similarities
with severe acute respiratory syndrome (SARS). Dr. Wen-
liang himself contracted the virus after treating an infected
glaucoma patient and subsequently passed away [2].
A novel RNA betacoronavirus was identified as the
causative pathogen. e phylogenetic analysis suggests that
bats may be the original host of the virus. e first infected
people were exposed to live animals being sold in a wet
market in Wuhan. Transmission of the disease from human
Hindawi
Journal of Ophthalmology
Volume 2020, Article ID 4827304, 9 pages
https://doi.org/10.1155/2020/4827304
to human mainly occurs via direct contact or droplets from
an infected patient through coughing or sneezing [3].
Coronaviruses (CoVs) affect a wide range of birds and
mammals. eir ability to undergo mutations facilitates the
transmission from animals to humans. Beyond SARS-CoV-
2, two human CoVs previously emerged as capable of
causing respiratory failure: SARS-CoV and Middle East
Respiratory Syndrome (MERS)-CoV. ere are no reported
ocular manifestations associated with SARS-CoV infection.
Only one case report describes SARS-CoV positivity of a tear
sample analyzed via polymerase chain reaction (PCR), while
other testing methods resulted negative. As far as MERS-
CoV is concerned, there is no evidence of either ocular
manifestations or viral load in tear samples [4]. CoVs are
single-stranded positive-sense RNA viruses. e genome
codes for both structural and nonstructural proteins.
Structural proteins permit the viral infection and replication.
Specifically, the surface spike glycoprotein (S-protein) en-
ables the attachment between CoV and host cells [5]. ere
is a structural similarity between the receptor-binding do-
main of SARS-CoV and SARS-CoV-2. e lung epithelial
cells are their primary target. ey bind to the same primary
cellular receptor, which is human angiotensin-converting
enzyme 2 (ACE-2), causing potentially severe infections in
both the upper and lower respiratory tracts [3]. e clinical
manifestations are variable. Patients with mild symptoms
usually recover quickly, while severe cases may develop
progressive respiratory failure, potentially leading to death
[5]. Currently, reverse transcriptase-polymerase chain re-
action PCR (RT-PCR detection of the viral genome in the
upper respiratory tract swabs is the most reliable diagnostic
test [6]. At present, neither a vaccine nor a specific antiviral
treatment is available. e aim of this review is to sum up the
ophthalmological features of the COVID-19 and the effects
that its therapies may have on the ocular tissues.
2. Methods
A thorough literature search was conducted in the PubMed
database (https://pubmed.ncbi.nlm.nih.gov/) using as key-
words “COVID-19” or “SARS-CoV-2” combined with “eye”
or “ophthalmology.” In addition, other appropriate key-
words were used depending on the article section (e.g.,
“COVID-19” AND “Kawasaki,” “Kawasaki” AND “eye,”
“eye” AND “intensive care,” and “eye” AND “chloroquine”).
Considering the peculiarity of the situation and the rapidly
growing body of the literature, a considerable part of the
articles included are of low quality (case reports, letters, and
editorials). Moreover, for the same reasons, non-peer-
reviewed articles have also been included, when appropriate.
3. Results and Discussion
3.1. Eye Complications during the Course of COVID-19
3.1.1. Conjunctivitis. Since SARS-CoV-2 may lead to re-
spiratory failure, most of the diagnostic and therapeutic
efforts are focused on the consequences of the infection in
the respiratory tract. Nevertheless, it is important to be
aware that other manifestations of the disease exist, espe-
cially because they are linked to alternative ways of trans-
mission. During the COVID-19 outbreak, conjunctivitis was
reported as a manifestation of the disease and viral RNA was
found in the patients’ tears.
e first reported case of SARS-CoV-2 conjunctivitis
affected a member of the Chinese panel for pneumonia, who
developed conjunctivitis and COVID-19 after performing
an inspection in the Wuhan Fever Clinic without wearing
eye protection. is case highlights the potential conjunc-
tival transmission route [7].
e exact pathogenetic mechanisms of the conjunctival
infection are still unknown. e ocular surface could po-
tentially serve as a portal of entry through exposure to
aerosolized droplets or hand-eye contact. ACE-2 receptor,
together with cell surface protease enzyme (TMPRSS2), is
the key factor that is responsible for binding with the virus
and allows access of the virus into the host cell. e presence
of these receptors on the ocular surface is controversial. A
study showed, by the means of immunohistochemical
analysis, that there is a distinct presence of the ACE-2 re-
ceptor on the conjunctiva, limbus, and cornea. Conjunctival
specimens also express TMPRSS2 [8].
Other authors did not find evidence of significant
conjunctival ACE-2 expression [9]. A recent study dem-
onstrated that consistent expression of TMPRSS2 cannot be
found in conjunctival samples, while it is present in some
pterygium samples [10]. It has been hypothesized that the
direct viral insult is the basis of the systemic infection, which
is subsequently sustained by a severe immune reaction
leading to potentially massive tissue damage. It is also likely
that the entity of the immune response is not equal in all the
patients, due to variants in the inflammasome genes. e
subsequent life-threatening hyperinflammatory syndrome is
known as macrophage activation syndrome. erefore, both
autoinflammatory and autoimmune response may be in-
volved. Since it is renowned that some forms of conjunc-
tivitis are sustained by an autoimmune mechanism, it may
be possible that macrophage activation syndrome plays a
role also in the pathogenesis of SARS-CoV-2 conjunctivitis
[4].
It is likely that SARS-CoV-2 has a low conjunctival
replication. Still, the inoculation of SARS-CoV-2 may
nevertheless happen via infected tears which transport the
virus through the nasolacrimal duct towards the naso-
pharynx. Also, it is possible that the virus infects the con-
junctiva through still unidentified receptors. Sustained
replication in conjunctiva is suggested by a case report of a
patient with persistent positivity of the conjunctival swab,
despite nasopharyngeal tests remaining negative [11].
e signs of COVID-19 conjunctivitis are similar to the
presentation of other viral forms. e patients usually
present mostly bilateral conjunctival hyperemia, chemosis,
follicular reaction of the tarsal conjunctiva, epiphora, watery
discharge, mild eyelid edema, and enlarged preauricular and
submaxillary lymph nodes. At present, there are no reports
of blurred vision or sight-threatening events [12]. In the
literature, there is only one case report that noted a patient
with monolateral keratoconjunctivitis as the first
2Journal of Ophthalmology
manifestation of COVID-19 [13], while another study de-
scribed an unusual bilateral pseudomembranous conjunc-
tivitis in an intubated patient successfully treated with
azithromycin eye drops twice a day, low doses of dexa-
methasone, and mechanical debridement [14].
e exact incidence of conjunctivitis in COVID-19
patients is still unclear, ranging between 0.8% and 31.6%
[1, 12, 15].
In patients affected by conjunctivitis, a conjunctival swab
is usually obtained and analyzed via RT-PCR. However,
there is a low percentage of positive results, confirmed by
different studies. It is possible that, in negative cases, the viral
load is inferior to the threshold of test detection. Also, some
patients had already started systemic antiviral therapy before
the swab. It is possible that there is a low chance of
transmission through tears [15]. Interestingly, a study
revealed that patients with ocular symptoms from COVID-
19, compared with patients with no ocular manifestations,
had higher white blood cells and neutrophil counts and
higher levels of procalcitonin, C-reactive protein, and lactate
dehydrogenase [12]. A meta-analysis concluded that con-
junctivitis in COVID-19 patients is usually associated with a
more severe form of the disease and a worse outcome [16].
ere are reports suggesting that conjunctivitis may
be the first manifestation of the disease, followed by the
onset of systemic symptoms after a variable amount of
time [17]. However, the possibility that conjunctivitis
may be the only manifestation of the disease must also be
taken into account [18]. Interestingly, there are reports of
SARS-CoV-2 RNA being isolated on the normal con-
junctiva of COVID-19 patients without ocular manifes-
tations. is may imply a viral spreading via conjunctival
contact, even in patients without conjunctivitis [19]. e
conjunctival manifestations of COVID-19 appear to be
self-limiting. In some cases, the use of ribavirin and
ganciclovir as topical therapy was followed by im-
provement of signs and symptoms [20].
Together, these results indicate that ocular surface cells
are susceptible to infection by SARS-CoV-2 and could,
therefore, serve as a portal of entry, as well as a reservoir for
person-to-person transmission of this virus. erefore, it is
important to adopt safety practices to prevent infection and
virus spread and to assume an extra caution behavior in
ophthalmology [21, 22].
3.1.2. Kawasaki Disease. Kawasaki disease (KD) is an acute
and usually self-limiting vasculitis of the medium caliber
vessels, which mostly exclusively affects young children, and
it is characterized by fever, oropharyngeal and extremity
changes, polymorphous rash, and unilateral cervical
lymphadenopathy. e cause of KD remains unknown,
despite several decades of investigation. However, earlier
evidence suggests that an infectious agent may trigger a
cascade that causes the illness.
e Bergamo province in Italy, which was extensively
affected by SARS-CoV-2 epidemic, observed a strong as-
sociation between an outbreak of Kawasaki-like disease and
COVID-19. Specifically, some authors reported a 30-fold
increased incidence of a severe form of KD with a percentage
of 80% of children positive for COVID-19 serology [23].
Other studies and news media also report unprecedented
clusters of patients affected by KD in the UK (up to 100
cases, but none tested positive for COVID-19) and New
York state (over 1,000 new cases) [24, 25].
e first described case of KD with concurrent COVID-
19 infection was observed in a 6-month-year-old female in
the setting of fever and minimal respiratory symptoms. e
baby, tested positive for COVID-19, had limbic sparing
conjunctivitis, prominent tongue papilla, a blanching,
polymorphous, maculopapular rash, and swelling of the
hands and lower extremities [25].
e KD has particular relevance for ophthalmologists
due to its potential ocular involvement. Most frequent ocular
manifestations are iridocyclitis, punctate keratitis, vitreous
opacities, papilledema, subconjunctival hemorrhage, and
conjunctival injection. e latter is usually bilateral, painless,
nonexudative, and limbic sparing [26].
As the SARS-CoV-2 epidemic evolves with time, a
similar outbreak of Kawasaki-like disease is expected in
countries around the world. Ophthalmologists should,
therefore, be aware of the potential ocular manifestations
and consider appropriate treatment if needed.
3.1.3. Diabetic Retinopathy. Due to the global coronavirus
outbreak, many countries worldwide have adopted isolation
policies in order to assure social distancing. Physical inac-
tivity and sedentary behavior imposed by lockdown policies
may be deleterious for patients. Daily step reduction from
10,000 to 1,500 steps in healthy adults can lead to impaired
insulin sensitivity and slower lipid metabolism, increasing
visceral fat and decreasing lean body mass and worsening
cardiovascular performances. is may have unforeseen
consequences on public health, such as new onset or
worsening of diabetes mellitus, leading to increased referrals
to ophthalmologists for eye complications related to diabetes
[27].
Future epidemiological studies may reveal a possible
lockdown implication in increased incidence of severe di-
abetic retinopathy cases during COVID-19 pandemic.
3.1.4. Retinal Findings. A recent report analyzing optical
coherence tomography (OCT) findings in 12 patients tested
positive for SARS-CoV-2 infection showed hyperreflective
lesions at the level of the ganglion cell and inner plexiform
layers on OCT. is bilateral finding was present in all
patients and was more prominent at the papillomacular
bundle. Results of OCT angiography and ganglion cell
complex analysis appeared normal. Four patients (33%)
presented subtle cotton-wool spots and microhemorrhages
along the retinal arcade on fundus photography. No signs of
intraocular inflammation, visual acuity alteration, or ab-
normal pupillary reflexes were detected [28]. Recently,
concerns have been raised regarding the possible misin-
terpretation of these findings, suggesting that the hyper-
reflective areas may simply represent normal retinal vessels
[29]. A recent paper by Zhang et al. suggests that the leading
Journal of Ophthalmology 3
factor in the pathogenesis of microcircular damage in
COVID-19 patients is complement-mediated thrombotic
microangiopathy (TMA) [30]. Complement system activa-
tion has been previously described as directly responsible of
ocular vascular damage, with rare cases of atypical hemolytic
uremic syndrome, leading to retinal artery and vein oc-
clusions [31]. It is also worthy of consideration that high
serum levels of C3 complement factor have also been linked
to increased risk of developing diabetic retinopathy, ne-
phropathy, and neuropathy, via endothelial dysfunction and
thrombosis [32]. Immunohistochemical analysis conducted
on the human eye has shown that the ciliary body, choroid,
retina, and retinal pigment epithelium (RPE) express sig-
nificative levels of ACE receptors [33]. Since COVID-19 is
able to target vascular pericytes expressing ACE-2, viral
infection could lead to complement-mediated endothelial
cell dysfunction, microvascular damage, and thus ocular
circulation involvement [34]. COVID-19-associated coa-
gulopathy may predispose to a spectrum of thromboembolic
events. Numerous cases of deep venous thrombosis, pul-
monary embolism, and large-vessel ischemic strokes in
patients with COVID-19 have been described. At the time of
this review, only one case of isolated central retinal artery
occlusion secondary to COVID-19 has been published [35],
while an increase in the incidence of retinal vein occlusions
has not been reported. e role of thrombophilic risk factors
in the pathogenesis of retinal vein occlusions is still con-
troversial, and some authors suggest that cardiovascular risk
factors for artery diseases play a more important role than
coagulation disorders [36]. Future research may disclose a
possible COVID-19 implication in retinal vascular pathol-
ogy and an increased incidence of retinal vascular occlusions
during the COVID-19 pandemic.
3.1.5. Neuro-Ophthalmological Complications.Neurological
complications of COVID-19 include polyneuritis,
Guillain–Barr´
esyndrome (GBS), meningitis, encephalo-
myelitis, and encephalopathy. Reports of patients who were
diagnosed with COVID-19 after presenting with diplopia
and ophthalmoparesis and abnormal perineural or cranial
nerve MRI findings have been described in the literature
[37]. Oculomotor nerve palsy could be triggered by direct
virus invasion or inflammatory factors related to viral in-
fection or could be secondary to neurological complications
such as GBS, acute disseminated encephalomyelitis, or
transverse myelitis [38]. Although animal models suggest
ocular lesions could include optic neuritis, an increase in the
incidence of ischemic or inflammatory optic neuropathies
cases related to COVID-19 has not been reported in the
literature yet [5].
3.2. Ocular Complications in Intensive Care Unit Patients.
Prevalence of acute respiratory distress syndrome (ARDS)
among COVID-19 patients has been reported to be 17%
[39]. ARDS is a life-threatening condition, which requires
respiratory support in an intensive care unit (ICU). A re-
cently published study on 1,591 COVID-19 patients ad-
mitted to ICUs of the Lombardy Region (Italy) reports an
admission rate of 9%, while other studies report even higher
rates, up to 32% [40, 41]. It must be noted that those patients
who need respiratory support in an ICU have high pro-
pensity to develop ocular complications. e incidence of
eye-related complications in ICU patients in different
studies varies from 3% to 60%. Ocular surface disorders,
intraocular pressure (IOP) elevation, and anterior and
posterior segment disorders are the most frequent mani-
festations [42].
3.2.1. Ocular Surface Disorders. e most common ocular
complications in ICU patients are surface disorders, which
have been reported to occur in up to 60% of critically ill
patients and can range from mild conjunctival irritation to
severe infectious keratitis [42]. ICU patients present several
risk factors for surface disorders, some of which related to
the treatments, while others to the ICU environment itself,
e.g., exposure to many potentially multiresistant bacteria
[43]. In mechanically ventilated patients, the main ocular
surface defense mechanisms are impaired. Muscle relaxants
and sedating agents reduce the tonic contraction of the
orbicularis oculi, thus leading to lagophthalmos. Moreover,
they inhibit the blink reflex and Bell’s phenomenon and
reduce tear production [44]. As a result, an exposure ker-
atopathy of variable severity may develop. Continuous
positive airway pressure (CPAP) and oxygen masks have a
drying effect on the ocular surface. Exposure keratopathy
affects up to 42% of ICU patients and 60% of those sedated
for more than 48 hours [45]. It has been reported that ill-
fitting Venturi masks can cause corneal abrasions by rubbing
on the eye [46]. In addition to the direct damage, exposure
keratopathy can also lead to secondary infections, such as
conjunctivitis and keratitis.
Conjunctival chemosis is commonly seen in ICU pa-
tients and, when particularly severe, may contribute to
lagophthalmos and reduced ocular surface lubrication. Risk
factors for developing conjunctival chemosis include re-
duced venous return from the eye (due to positive pressure
ventilation or tight endotracheal tube taping) and increased
hydrostatic pressure (mainly due to prolonged recumbency,
especially if prone). Prone position has been shown to de-
crease mortality in ARDS patients, and some authors rec-
ommend it for a minimum of 12 hours per day [47, 48].
Since it increases venous pressure in the head, it can the-
oretically also cause subconjunctival hemorrhage, a condi-
tion usually completely benign although it may lead to
surface disorders, if extensive [49, 50]. In mechanically
ventilated patients, the positive end-expiratory pressure may
lead as well to subconjunctival hemorrhage because of an
increase in intrathoracic pressure and consequently in
central venous pressure [51].
Data on the incidence of infectious keratitis and con-
junctivitis in mechanically ventilated patients are not
available. However, a study on 134 patients without pre-
existing ocular surface disorders who underwent sedation
and respiratory support reports that 77% of patients were
colonized by at least one bacterial species other than normal
flora and 40% by multiple species [43]. e most common
4Journal of Ophthalmology
isolates were Pseudomonas aeruginosa,Acinetobacter spp.,
and Staphylococcus epidermidis.
3.2.2. Rare Ocular Complications. It has been reported that
prone position ventilation may rarely lead to acute ischemic
optic neuropathy, which causes permanent vision loss [52].
Ocular perfusion depends on IOP and ocular blood flow,
which in turn depends on arterial and venous pressure and
on vascular resistance [48, 49, 53]. Prone position can
critically reduce ocular perfusion acting on two mechanisms.
On the one hand, it increases venous pressure, and on the
other hand, it also increases the IOP. IOP rises with time, up
to approximately 40 mmHg after 320 minutes in the prone
position [54]. is condition can also be exacerbated by ill-
fitting prone face positioners [55]. In addition, systemic
conditions such as diabetes, arterial hypertension, and
atherosclerosis may determine an increase in vascular re-
sistance, thus further reducing ocular blood flow [50]. It
follows that those patients who are more likely to be ad-
mitted to the ICU for COVID-19 because of their comor-
bidities are also at higher risk to suffer from ocular
hypoperfusion.
Valsalva retinopathy is a condition characterized by
the sudden onset of uni- or bilateral macular preretinal
hemorrhages, resulting from rupture of small superficial
capillaries due to an increased venous pressure [56]. It is
usually associated with activities causing a sudden in-
crease in intrathoracic or intra-abdominal pressure. It has
been reported that valsalva retinopathy can also occur
due to intubation or high positive end-expiratory pres-
sure [51, 57].
A potentially sight-threatening complication in ICU
patients is acute angle-closure glaucoma. In the presence of
underlying risk factors, an acute angle closure can be trig-
gered by the prone position, as well as by many local and
systemic drugs, such as anticholinergics (atropine, ipra-
tropium bromide, tricyclic antidepressants, and antihista-
mine), sympathomimetics (adrenaline, noradrenaline,
dopamine, ephedrine, salbutamol, and terbutaline), and
others (sulfonamides derivatives and topiramate) [58, 59].
Horner’s syndrome has been reported as a rare com-
plication of central venous catheterization [60]. Its frequency
was 2% in a sample of 100 patients, prospectively examined.
It was likely caused either by direct trauma to the sympa-
thetic plexus or by an expanding hematoma. A small per-
centage of critically ill COVID-19 patients can develop
typical clinical manifestations of viral sepsis. Endogenous
endophthalmitis should be considered among the possible
rare complications of sepsis related to COVID-19. Till date,
no reports of this condition have been described in the
literature [61].
In conclusion, intensive care, and especially invasive
mechanical ventilation, can be associated with several ocular
complications. ICU staff must be aware of them and refer to
an ophthalmologist when appropriate. Sight-threatening
complications are rare, but it is crucial that they are diag-
nosed and treated before permanent damage occurs. Ocular
surface disorders, on the other hand, are extremely common,
and several studies showed that the application of a proper
protocol can significantly reduce their incidence [62, 63].
3.3. Ocular Side Effects of Drugs Used for the Treatment of
COVID-19. To date, no pharmacological therapies have
been approved for the treatment of COVID-19. However,
several drugs are currently under investigation, such as
chloroquine (CQ) and its derivative hydroxychloroquine
(HCQ), antiviral drugs, and immunomodulators [64].
3.3.1. Antimalarial Drugs. e antimalarial drugs CQ and
HCQ are mainly used to treat malaria, amebiasis, and
rheumatologic conditions, such as systemic lupus eryth-
ematosus, rheumatoid arthritis, Sjogren’s syndrome, and
juvenile idiopathic arthritis. Recent studies have demon-
strated their activity in vitro and in animal models against
SARS-CoV-2, and the FDA has approved an emergency
authorization for use of these drugs for hospitalized
COVID-19 patients [65, 66]. A Chinese study found that CQ
abbreviated the disease course, reduced the exacerbation of
pneumonia, with pulmonary imaging findings improve-
ments, and promoted virus-negative seroconversion [67].
Among patients with COVID-19, the use of HCQ has
been shown to significantly shorten the time to clinical
recovery and promote the resolution of pneumonia [68]. A
recent study by Gautret et al. reported that HCQ treatment
in patients affected by COVID-19 was significantly associ-
ated with viral load reduction/disappearance and that its
effect was reinforced by azithromycin [69]. Further studies
are underway to provide a definitive answer of the value of
CQ and HCQ in patients with severe COVID-19. e an-
tiviral efficacy of CQ and HCQ seems to be explained by (1)
an increase in endosomal pH that inhibits viral fusion and
replication, (2) an interference with the terminal glycosyl-
ation of the ACE-2 receptor for cell entry targeted by SARS-
CoV and SARS-CoV-2, and (3) an immunomodulatory
activity [64]. e dosage of CQ and HCQ is different. Pa-
tients affected by COVID-19 typically received CQ at a dose
of 1,000 mg daily on day 1 and then 500mg daily for 4 or 7
days. e dosage of HCQ is 800 mg daily on day 1, followed
by 400 mg daily for 4 or 7 days.
Side effects of these drugs include QTc interval pro-
longation, hypoglycemia, gastrointestinal disorders, anemia,
extrapyramidal disorders, and ocular complications [65, 66].
e clinical picture of HCQ and CQ ocular toxicity
includes whorl-like corneal intraepithelial deposits, which
are usually reversible, posterior subcapsular lens opacity,
ciliary body dysfunction, and a bilateral maculopathy
characterized by a ring of parafoveal RPE depigmentation
that initially spares the fovea. Advanced cases of CQ and
HCQ maculopathy show widespread photoreceptor loss and
RPE atrophy with foveal involvement and progressive loss of
visual acuity. HCQ and CQ maculopathy is not reversible
and can progress even after interrupting drug assumption,
probably due to a gradual decompensation of retinal cells
that were metabolically injured during drug exposure [70].
e most critical risk factor for the development of
CQ and HCQ toxicity is excessive daily dosage. e
Journal of Ophthalmology 5
American Academy of Ophthalmology recommendations
on screening for CQ and HCQ retinopathy suggest
keeping a daily dosage inferior to 2.3 mg/kg in patients
receiving CQ and less than 5.0 mg/kg in those using HCQ.
erefore, most of the patients treated with CQ and HCQ
for COVID-19 receive potentially retinotoxic doses.
Duration of therapy is an additional critical factor.
Prolonged use of HCQ at recommended doses increases
the risk of ocular toxicity, rising from less than 2% after
10 years to almost 20% after 20 years [71]. However, it is
also reported that high CQ and HCQ dosages can lead to
retinopathy even with shorter therapy duration. Two
recent studies on patients receiving 800–1,000 mg/day of
HCQ showed a 25% to 40% incidence of retinopathy
within 1-2 years [72, 73]. No reports of retinal toxicity
under 2 weeks of CQ or HCQ administration have been
described. us, to date, evidence suggests that high doses
of these drugs can accelerate retinal toxicity over a period
of weeks to years [74].
3.3.2. Antiviral Drugs. e second-generation antiretroviral
drugs, lopinavir and ritonavir, are widely used for the
treatment of HIV, and some reports have drawn attention to
the use of these drugs as a possible treatment for patients
with COVID-19 infection. Ritonavir inhibits the cyto-
chrome P450 3A4 increasing the half-life of lopinavir;
therefore, these two drugs are formulated in combination.
Lopinavir/ritonavir inhibits viral protease and seems to
reduce the viral load in COVID-19 patients. However, the
clinical evidence for this therapy remains limited, and
several clinical trials are currently ongoing. Common side
effects of lopinavir/ritonavir include gastrointestinal dis-
turbance, insomnia, dyslipidemia, diabetes mellitus, pan-
creatitis, hepatic disorders, and numerous drug interactions
[75].
Several authors reported the adverse effects of ritonavir
on the human retina. Roe et al. first described a bilateral
macular retinal pigment epitheliopathy with parafoveal
telangiectasias and intraretinal crystal deposits in three HIV-
positive patients on a long-term therapy with ritonavir [76].
e most common clinical findings are pigmentary changes
of the macula that can present with a granular pattern, a
bull’s eye shape, or less specific patterns and can lead to
severe vision loss. Bone spicule-like pigment changes in the
midperipheral retina and crystalline intraretinal deposits can
also occur. OCT features include macular thinning with
outer retinal layers atrophy and loss of the ellipsoid zone,
which also shows an abnormal hyperreflectivity. Ritonavir-
associated retinal toxicity has been reported only with
chronic use. e shortest time before diagnosis described in
the literature is 19 months [76]. As for HIV cases, the
suggested dosage of lopinavir/ritonavir for COVID-19 pa-
tients is 400/100 mg twice daily. In most COVID-19 cases,
the duration of treatment is 5 to 7 days [75]. erefore, a
retinal toxicity caused by a short-term use of lopinavir/
ritonavir seems unlikely in COVID-19 patients.
3.3.3. Immunomodulatory Drugs. Interferons (IFN), a
family of cytokines with antiviral properties, have been
suggested as a potential treatment for COVID-19 due to
their antiviral, antiproliferative, and immunomodulatory
activities.
Among IFN subtypes, IFN-beta-1 may account for a safe
and easy-to-upscale treatment against COVID-19 in the
early stages of infection [64].
Interferon-associated retinopathy often presents with
cotton-wool spots, retinal hemorrhages, and other retinal
microvascular irregularities. ese changes occur most
notably around the optic nerve head and in the posterior
pole [77]. e retinopathy typically presents 3 to 5 months
after treatment begins; however, it can present as early as 2 to
6 weeks into the treatment [78]. Fortunately, the ocular
findings of interferon-associated retinopathy appear to re-
verse with cessation of treatment.
Interleukin-1 inhibitors (e.g., anakinra) and inter-
leukin-6 inhibitors (e.g., sarilumab, siltuximab, and
tocilizumab) are also under evaluation for the treatment
of COVID-19. Endogenous IL-1 and IL-6 are elevated in
patients with SARS-CoV-2 infection, and they could be
important mediators of severe systemic inflammatory
responses in these patients. To date, no studies on the use
of IL-1 and IL-6 inhibitors in patients with COVID-19 are
published, although several clinical trials are underway
[64].
Some studies reported an association between high dose
of anakinra and nystagmus. A case report described some
ocular adverse events related to tocilizumab, such as bilateral
retinopathy with multifocal cotton-wool spots and retinal
hemorrhages, bilateral papilledema, HTLV-1 uveitis, viral
conjunctivitis, and ophthalmic herpes zoster infection
[79, 80].
4. Conclusions
e rapid progression of the COVID-19 pandemic has
created significant challenges for the public, as well as
healthcare professionals around the world. Knowledge re-
garding virus incubation, transmission, and shedding is
crucial for the reduction of new cases and protection of
healthcare professionals. Patient management has surely
changed, also from an ophthalmological point of view. ere
have been several reports of eye redness and irritation in
COVID-19 patients, both anecdotal and published, sug-
gesting that conjunctivitis may be an ocular manifestation of
SARS-CoV-2 infection. As conjunctivitis is a common eye
condition, ophthalmologists may be the first medical pro-
fessionals to evaluate a patient with COVID-19. e real
incidence of conjunctivitis in COVID-19 patients is not
certain yet, and this may be the only manifestation of in-
fection from SARS-CoV-2. erefore, special care must be
taken when examining patients with signs and symptoms of
viral conjunctivitis. It is mandatory to investigate the
presence of respiratory symptoms or any element that, from
an epidemiological point of view, suggests a potential in-
fection from SARS-CoV-2. Conjunctival swabs may repre-
sent a help in clinical practice, even though a negative
analysis via RT-PCR does not exclude the infection.
6Journal of Ophthalmology
Other patients are going to require ophthalmological
attention.
Many people throughout the world are having a more
sedentary lifestyle and less healthy diet, due to restrictions
and economic difficulties. is may lead to poor diabetes
control, and it potentially increases the risk of developing
more severe forms of diabetic retinopathy. In addition,
diabetic patients are receiving less strict medical controls,
due to lockdown.
Implications of therapies used to treat COVID-19 pa-
tients are likely to be of ophthalmological interest too. Since
a targeted therapy against SARS-CoV-2 is lacking, many
drugs have been used synergically, usually at high dosage.
Most of them may develop retinopathies as side effects.
When the pandemic is over, ophthalmologists may be called
to assess the extent of the retinal and visual damage exerted
by these life-saving therapies.
Most patients requiring mechanical ventilation may
experience disorders of the eye surface, with a variable
degree of severity. It may be difficult to treat these occur-
rences while the patient remains in the ICU; however, they
may lead to sight-threatening complications, like bacterial
superinfection and corneal abrasions. Also, optic neuritis
and acute angle-closure glaucoma are a rare complication of
prone positioning, which has proven itself efficient in
treating cases of severe COVID-19 pneumonia. To sum up,
the health care professionals are nowadays facing an un-
precedented global health issue, which is affecting each
medical specialty. It is important to exert the maximum
effort on reducing the contagion rate and to treat patients to
the best of our abilities, despite the pandemic.
Disclosure
Federica Bertoli, Carla Danese, Francesco Samassa, Nicol`
o
Rassu, Tommaso Gambato: no financial interest to disclose.
Daniele Veritti: consultant for Bayer, Novartis, Roche,
outside the submitted work. Valentina Sarao: consultant for
Centervue, Roche, outside the submitted work. Paolo
Lanzetta: consultant for Allergan, Alcon, Bayer, Bausch &
Lomb, Novartis, Centervue, Roche, Topcon, outside the
submitted work.
Conflicts of Interest
Daniele Veritti is a consultant for Bayer, Novartis, and
Roche. Valentina Sarao is a consultant for Centervue and
Roche. Paolo Lanzetta is a consultant for Allergan, Alcon,
Bayer, Bausch & Lomb, Novartis, Centervue, Roche, and
Topcon. Federica Bertoli, Carla Danese, Francesco Samassa,
Nicol`
o Rassu, and Tommaso Gambato have no financial
interest to disclose.
Authors’ Contributions
Federica Bertoli and Daniele Veritti contributed equally to
this manuscript and share the first authorship on this work.
Lanzetta Paolo had full access to all the data in the study and
takes responsibility for the integrity of the data and the
accuracy of the data analysis. D. Veritti and V. Sarao were
responsible for the study concept and design. All authors
were involved in acquisition, analysis, or interpretation of
data. Drafting of the manuscript was performed by
F. Bertoli, D. Veritti, C. Danese, F. Samassa, V. Sarao,
N. Rassu, and T. Gambato. Critical revision of the manu-
script for important intellectual content was conducted by
F. Bertoli, D. Veritti, V. Sarao, and P. Lanzetta. Adminis-
trative, technical, or material support was provided by
P. Lanzetta. Study supervision was conducted by D. Veritti
and P. Lanzetta.
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