**4. SARS-CoV-2 related ocular manifestations**

## **4.1 Ocular surface manifestations**

Since ocular surfaces hold the potential for SARS-CoV-2 transmission, clinical research focusing the COVID-19-associated ocular symptoms have attracted great attention. Even though, the incidence of SARS-CoV-2 infection through ocular surfaces is low, ocular manifestations are various. Dry eyes, epiphora, hyperemia were the most prevalent symptoms in COVID-19 patients, while chemosis, photophobia and conjunctivitis are barely seen. Other reported ocular surface symptoms were conjunctival congestion, conjunctival secretions, foreign body sensations, blurred vision, itching/irritation, ocular pain, and eye redness. The prevalence of SARS-CoV-2 and profiling ocular symptoms related to COVID-19 are summarized in **Table 1** by including 2660 patients from 43 independent studies [10–14, 16, 17, 59–61, 69, 78–108].

In a large study, including 535 patients, 5.0% of the patients (27 patients) displayed conjunctival congestion. Conjunctival congestion was in fact, the first symptom in four patients, which explains that ocular manifestations may be observed in early times of SARS-CoV-2 infection. However, SARS-CoV-2 nucleic acid could not be identified in ocular swabs. Other ocular manifestations were dry eye, blurred vision, foreign body sensation, tearing, itching, ocular pain and photophobia. Conjunctival congestion has lasted for 5.9 ± 4.5 days among the patients and ofloxacin, tobramycin and ganciclovir eye drops were supplied for

#### **Table 1.**

*The number of ocular findings observed in a total of 2660 patients with COVID-19 [10–14, 16, 17, 59–61, 69, 78–108].*

#### *Potency of SARS-CoV-2 on Ocular Tissues DOI: http://dx.doi.org/10.5772/intechopen.97055*

treatment. Conjunctival congestion was a more widespread symptom in patients with frequent hand-eye contact [10].

In some studies, the presence of SARS-CoV-2 viral RNA on the ocular surfaces was confirmed. In February 2020, a study including 30 COVID-19 patients has declared SARS-CoV-2 nucleic acid in tear, conjunctival secretion as well as in sputum samples in one patient with conjunctivitis at the third day of the disease. The presence of the virus in the eye allowed speculation that transmission with the aerosols could be possible. However, this was one of the early studies and at that time there was not enough information about the transmission routes of virus [104]. In another study, involving 72 COVID-19 patients, conjunctivitis was detected in two patients (2.8%) and SARS-CoV-2 nucleic acid was identified in ocular discharges of one patient [106]. Detection of virus RNA in the eye suggests that the ocular pathway may be a gateway for viral transmission. In a case study, SARS-CoV-2 RNA was detected on the ocular swab of a woman with conjunctivitis at the third day of the COVID-19 diagnosis. Conjunctival samples were continuously taken on a daily basis and viral RNA was detected, despite in a decreasing curve for 21 days. However, the viral RNA became observable again 5 days after it became unobservable in the ocular swabs. To understand the presence of viral replication in the conjunctiva, researchers have inoculated the first positive viral RNA samples in Vero E6 cells and 5 days later, they have observed cytopathic effect and confirmed viral replication by RT-PCR with RNA purified from Vero E6 cell growth media [83].

On the other hand, SARS-CoV-2 viral RNA was also present in some patients without conjunctivitis. Viral RNA was detected in ocular swabs in two patients among 33 COVID-19 patients (6.1%) without any ocular manifestation [19]. In another study, including 121 patients diagnosed with COVID-19, ocular manifestations such as itching, tearing, redness, foreign body sensation and discharge were obtained in only eight patients (6.6%). Ocular swab was positive for SARS-CoV-2 RNA in one of them and in two patients without ocular manifestations [107]. The presence of SARS-CoV-2 on normal ocular surfaces may indicate that both symptomatic and asymptomatic ocular surface contact also has a risk of virus transmission.

There are several cases, where ocular manifestations were reported as the first presenting manifestation of COVID-19. A 65-year-old patient applied to ophthalmology department with a complaint of burning sensation and discharge for the last two days was diagnosed with conjunctivitis. After 2 days, the patient was admitted to the hospital with symptoms associated with COVID-19 and SARS-CoV-2 infection was confirmed with positive RT-PCR results of the nasopharyngeal and conjunctival swabs as well as computed tomography (CT) scanning of the lungs [88]. In a study, 12 out of 38 COVID-19 patients (31.6%) presented ocular symptoms, including conjunctivitis, hyperemia, epiphora, chemosis and increased secretions. SARS-CoV-2 nucleic acid was detected in conjunctival swabs of two patients. In these patients, conjunctivitis was the first symptom in one patient [11]. The occurrence of ocular symptoms primarily suggests that ocular surface is the potential transmission site of the virus in these patients.

Conjunctivitis could be seen in both early and late stages in the course of COVID-19. In February 2020, bilateral conjunctivitis, including redness, tearing and foreign body sensation was observed 13 days after the onset of the disease in a COVID-19 patient. Although the presence of SARS-CoV-2 nucleic acid was less in the nasopharyngeal and sputum swabs, it was confirmed in conjunctival swabs by RT-PCR at days 13, 14 and 17 in a gradually decreasing manner. Ribavirin eye drops helped the treatment of the symptoms and the RT-PCR test from ocular swabs turned negative on day 19 [82]. In a COVID-19 patient at intensive care unit, ocular symptoms started on the 17th day of the disease with conjunctival hyperemia and

clear secretions and pseudomembranous. On the 19th day, hemorrhagic conjunctivitis was defined, however, SARS-CoV-2 RNA was not detectable in the patient's conjunctival and tear samples. Azithromycin eyedrop and dexamethasone were used for treatment and ocular manifestations were started to decrease from day 21 [95]. Conjunctivitis, seen in the middle and late phases of the COVID-19, may have developed due to systemic viral infection or auto-inflammatory and autoimmune responses. Considering the nasolacrimal duct forms a connection between the eye and the respiratory tract; it is likely that the virus in the respiratory tract may subsequently infect the eye. The fact that ACE2 receptor is expressed predominantly in the respiratory tract than epithelial cells in the eye surface confirms this theory.

In the first study where keratoconjunctivitis was reported as the main symptom of COVID-19, virus was detected in ocular swabs with much lower titers than respiratory swabs. The corneal findings in this case involved pseudodendrite, subepithelial infiltrate and multiple epithelial defects spreading through the cornea [81]. The first case of COVID-19 related acute anterior uveitis associated with acute follicular conjunctivitis and conjunctival hyperemia was reported in Italy. Acute anterior uveitis was characterized by bilateral eye redness lasting two weeks, unilateral photophobia, lacrimation, miosis, aqueous humour flare and anterior lens opacity causing blurred vision [16].

The low rate of ocular symptoms seen in patients with COVID-19 may be due to the under diagnosis. Particularly, for the diagnosis of conjunctivitis, an ophthalmologist is required. Otherwise, disease can be unnoticed and treated silently during systemic COVID-19 treatment regimen. Besides, since the ocular inoculation of SARS-CoV-2 cannot be fully elucidated, sampling time in the course of disease may also be a factor affecting detection of the presence of the virus on ocular surfaces. Since the virus may have been eliminated by ocular defense mechanisms or may have already entered the respiratory tract, the duration time of the virus on ocular surfaces may be very short. The sensitivity threshold of RT-PCR, which is the conventional method used to confirm the presence of the virus, may also cause false negative results. However, in order to declare that conjunctivitis occurs due to SARS-CoV-2 infection, virus detection through ocular swabs is mandatory since conjunctivitis may be of different viral, bacterial and allergic origin in patients with COVID-19. It should also be taken into account that ocular manifestations may be the only symptoms of the COVID-19.

#### **4.2 Retinal findings in patients with COVID-19**

In viral infections, the cytopathic effect of the viral agent on retinal cells or damage to the retinal vasculature are common pathological findings of the retina. Systemic damage caused by SARS-CoV-2 made it necessary to enlighten additional viral involvement sites in addition to the respiratory system. Presence of ACE2 in aqueous humor [7] and retina [15] has allowed researchers to raise query on the possible injury caused by COVID-19 in the posterior part of the eye.

The first report published in May 2020 declaring COVID-19 related retinal alterations has paved the way for further studies. Retinal cotton wool spots and microhemorrhages in four patients as well as hyperreflective lesions at ganglion cell layer and inner plexiform layer in 12 patients was reported. Of the 12 patients, three had high blood pressure, one had diabetes and one had dyslipidemia. Examination was performed on 11–33 days after the onset of COVID-19 symptoms using optical coherence tomography (OCT). Intraocular inflammation was not noticed in any of the patients, however the presence of SARS-CoV-2 in the intraocular fluids was not tested in this study [14]. Similarly, in another study, 10 out of 18 intensive care unit patients had retinal abnormalities characterized by cotton wool spots, flame-shaped

#### *Potency of SARS-CoV-2 on Ocular Tissues DOI: http://dx.doi.org/10.5772/intechopen.97055*

hemorrhages, peripheral retinal hemorrhages, macular hemorrhages, retinal pigment epithelium hyperplasia and choroidal naevus. Nine of them had a history of diabetes and 12 of them had high blood pressure [96]. In another study of 25 patients, 3 patients (12%) displayed retinal changes including microhemorrhages, flame-shaped hemorrhage and nerve fiber layer infarcts (**Figure 3**). Retinal examinations were performed at 12–59 days after the onset of symptoms and only one patient had a medical history of hypertension. Another patient had hypotension, severe anemia, kidney and peripheral nervous system damage, which may explain microhemorrhages and nerve fiber layer infarcts [89]. These findings suggest that retinal alterations may occur depending on the patients' medical histories, yet it may also be due to the cytokine storm, which is developed as a result of immune response induced by COVID-19 and reaches to the retina by passing through the blood retina barrier.

In the fundus examination of a COVID-19 patient who was admitted to the hospital with the complaint of scotoma and decreased vision in one eye, fern-like retinal whitening, hyperreflective inner layers, increased venular tortuosity and retinal hemorrhages were found in the right eye and the patient was diagnosed with impending central retinal vein occlusion (iCRVO). After 10 days of treatment with steroids, patient's retinal changes and blood flow in central retinal vein almost returned to normal [87]. The iCRVO in this patient is thought to be due to the systemic response of COVID-19, as it can be treated with steroid therapy and the patient has no risk-bearing medical history. In the examination of a patient with lower leg pain and blurred vision in addition to common COVID-19 symptoms, deep venous thrombosis in the leg, bilateral CRVO, intraretinal hemorrhages, optic disk swelling, and cotton wool spots were detected. After 2 weeks of anticoagulant treatment, the patient's complaints returned to normal [12]. Similar to this, vascular occlusions may occur in the cases of hypertension, obesity and high cholesterol. In another study, bilateral cotton wool spots were detected on fundus examination during the late stage of COVID-19 in one patient, suffering an arcuate visual field defect in one eye. It was the first study to report COVID-19 induced vision loss. Retinal microvascular ischemia in the superficial plexus, which corresponded to the arcuate scotoma was detected by optical coherence tomography (OCT) angiography

#### **Figure 3.**

*Retinal photograph of a patient with COVID-19. (A) Nerve fiber layer infarct above the optic nerve head, and microhemorrhages in the papillomacular bundle close to the optic disc was present in the right eye. (B) Nerve fiber layer infarcts at the inferior temporal vascular arcade, approximately 1.5-disc diameters inferior to the macula was present in the left eye. Reproduced from Reference [89] (CC BY 4.0).*

[17]. These retinal changes can be related to microangiopathy and ischemia that are characterized in different anatomic parts in COVID-19 pathogenesis [109, 110].

In a study involving 54 COVID-19 patients, 15 patients had dilated veins, tortuous vessels was observed in seven patients, retinal hemorrhages in five patients, cotton wools spots in four patients and drusen in six patients were reported during fundus examination. Both mean artery diameters for severe cases and mean vein diameters for severe or non-severe cases were significantly higher in 54 COVID-19 patients, compared to 133 unexposed subjects [13]. Retinal vessel diameters and retinal circulation are parallel to the systemic circulation. Alterations in the retinal vessels can provide an insight into alterations in other organs. Enlargement of the vessels can be explained by the increased blood supply and effect of inflammatory mediators together with the inflammatory response to COVID-19 or a direct effect of the SARS-CoV-2 to endothelium. Moreover, two patients with COVID-19 had paracentral acute middle maculopathy and acute macular neuroretinopathy accompanied by scotoma [60]. In another study, scotoma, acute vision loss and several retinal hemorrhages related with acute macular neuroretinopathy and paracentral acute middle maculopathy were reported in one patient [61]. It has been reported that paracentral acute middle maculopathy is associated with the reduced blood supply to intermediate, deep, superficial capillary plexuses and acute macular neuroretinopathy is associated with the reduced blood supply to deep capillary plexus [111].

Venous thromboembolism is also a reported condition in COVID-19 patients; however, it is not known whether this is caused by the direct effect of the virus or the inflammatory response of the COVID-19. Cotton wool spots are characterized by disruption of axoplasmic flow in nerve tissue layer due to microvascular occlusion, and retina is extremely sensitive to ischemic events in the body. Considering the thrombotic conditions caused in COVID-19 patients, it can be thought that cotton wool spots in the retina are a result of the occlusion of terminal retinal arterioles.

The fact that the SARS-CoV-2 affects the central nervous system [112, 113] and the presence of its nucleic acid in retina [114] suggests that as a part of central nervous system, retina may be directly affected by the virus. Considering that the effect of SARS-CoV-2 on the central nervous system also effects the vital organ brain, non-invasive retinal examinations could be a prediction of the scope of COVID-19 in other organs like brain and heart, which has been implemented before for different diseases such as stroke, Alzheimer disease, multiple sclerosis and Parkinson disease [115].

In some studies, there was no link between retinal findings and ocular surface changes suggesting that retinal findings may be a marker of systemic alterations, and thus the importance of fundus examination should not be underestimated even in patients without any ocular complaints during the COVID-19 pandemic.

#### **4.3 COVID-19 related expected long-term effects on eye**

Ocular manifestations of COVID-19 range from redness to acute anterior uveitis on the anterior segment of the eye and from microhemorrhages to retinal microvascular ischemia on the retina. Some of these manifestations may cause vision loss and blurred vision.

Retinal changes such as damage of retinal cells or retinal vasculature may be the precursor of a long-term retinal disease. When the peripapillary vascular impairment is compared between the control group and patients recovered from COVID-19, lower radial peripapillary capillary plexus perfusion density and reduced blood supply to peripapillary retinal nerve fiber layer were present in

#### *Potency of SARS-CoV-2 on Ocular Tissues DOI: http://dx.doi.org/10.5772/intechopen.97055*

post COVID-19 patients [98]. Older and systemic hypertensive patients were more prone to this microvascular damage. The radial peripapillary capillary plexus is very important for function of the retinal ganglion cells and axons and it is related to nerve fiber layer thickness and visual field loss in glaucoma [116]. Decrease in radial peripapillary capillary plexus density and nerve fiber layer thinning have been characterized in patients with early stage of glaucoma [117, 118]. Besides, it is more prominent in patients with glaucoma for more than ten years than in patients with glaucoma less than ten years [119]. However, whether the peripapillary capillary changes in patients with COVID-19 are reversible will be seen in further studies. Although these patients are at risk of developing glaucoma in the future, it should be kept in mind that there are several effective physiological parameters for disease development.

Looking at MERS and SARS outbreaks, it is difficult to predict the long-term ocular effect of COVID-19, due to the insufficient ocular findings and limited number of patients. Although different mechanisms cause the ocular effects of coronaviruses in animals, studies in animal models and understanding these mechanisms could give an idea about the long-term ocular effects of coronavirus in humans. Investigation of the effect of the coronavirus-related immune responses in retinal disease using experimental coronavirus retinopathy (ECOR) model indicated that levels of some cytokine molecules (TNF-α, TNF receptors) and signaling molecules (nitric oxide) increased in mice infected with murine coronavirus (mouse hepatitis virus) [120]. It was stated that TNF-α induction of nitric oxide may cause retina degeneration and loss of photoreceptor cells. In addition to that, following the primary immune response to virus, increased TNF receptor molecules and T cell reactivity may trigger autoimmunity.

The RAS system and its component ACE2 have important regulatory functions in the eye. ACE2 activation is known to reduce intraocular pressure [36]. Decreased expression of ACE2 to prevent viral spread can lead to misbalance of ACE-Angiotensin II/ACE-Angiotensin (1–7) balance, increase in intraocular pressure, vasoconstriction [61] and subsequently cause glaucoma. Hypothetically, in the light of this information, it is difficult to say that COVID-19 can cause a medium- or long-term serious ocular diseases such as glaucoma. However, ocular follow-up of COVID-19 patients with retinal symptoms may present whether these assumptions are justified as well as may benefit understanding virus tropism and immune responses to the virus.
