|Year : 2021 | Volume
| Issue : 2 | Page : 132-138
Retinal manifestations of COVID-19 disease - A review of available information
Kaberi Biswas Feroze
Department of Ophthalmology, King Faisal University, Al Ahsa, Saudi Arabia
|Date of Submission||30-May-2021|
|Date of Decision||02-Jun-2021|
|Date of Acceptance||03-Jun-2021|
|Date of Web Publication||21-Aug-2021|
Dr. Kaberi Biswas Feroze
Department of Ophthalmology, King Faisal University, Al Ahsa
Source of Support: None, Conflict of Interest: None
Ocular signs and symptoms have been reported in COVID-19 patients, and there is a surge of information about corneal, uveal, retinal, and neuro-ophthalmological involvement in COVID-19 infection. This review attempts to determine from various researches published during the time of the pandemic, the retinal manifestations of COVID-19 infection, and its significance and correlation to severity of systemic disease. An extensive search strategy was employed using keywords “novel corona virus”, “COVID-19”, “SARS CoV2,” or “retina,” either singly or variably combined, to retrieve the articles of retinal manifestations of COVID-19 published from January 2020 till date. Retinal manifestations are ubiquitous and include microangiopathy, occlusive vascular conditions, alterations in vascular caliber, and capillary density, among others. They seem to correlate with disease severity and reflect on similar changes in other parts of the body as well. Newer studies are bringing out more and more evidence of hitherto unknown retinal manifestations of COVID-19 disease.
Keywords: COVID-19, novel coronavirus, retina, SARS CoV2
|How to cite this article:|
Feroze KB. Retinal manifestations of COVID-19 disease - A review of available information. Kerala J Ophthalmol 2021;33:132-8
| Introduction|| |
One of the most significant medical events in the present times is the emergence of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS CoV2) causing coronavirus disease 2019 (COVID-19). The first cases, presenting as pneumonia of unknown origin, were identified in Wuhan, the capital city of Hubei province in China. This condition is now recognized as a pandemic, and there are almost 113,467,303 confirmed cases of COVID-19, including 2,520,550 deaths, reported to the WHO. The clinical features of COVID-19 are manifold, ranging from being completely asymptomatic to acute respiratory distress and multiorgan dysfunction. The presenting symptoms range from fever, cough, dyspnea to headaches, fatigue, myalgia, and even conjunctivitis. Ocular signs and symptoms have been reported in COVID-19 patients, and there is increasing recognition of conjunctivitis as a prodromal symptom of this disease. As this is an ongoing pandemic, there is a lot of information accumulating on a regular basis, with newer researches contributing to better understanding of the disease process. Animal studies have shown that coronaviruses can cause a variety of ocular manifestations such as conjunctivitis, anterior uveitis, retinitis, and optic neuritis. The same could be extrapolated to human infections, and recent researches are in fact providing increasing evidence of the same. The SARS CoV2 virus has a high affinity for the ACE2 receptors, and these receptors are seen in retinal vascular endothelial cells and choroid, besides other locations., In a study of retinal biopsies conducted on 14 eyes of patients who died from COVID-19 infection, viral RNA was discovered in three eyes, thus proving beyond doubt that the SARS CoV2 virus can affect the retina. Recent studies show that COVID-19 virus can affect structures such as the cornea, uvea, retina, and the optic nerve, besides the conjunctiva. This review attempts to determine from various researches published during the time of the pandemic, the retinal manifestations of COVID-19 infection, and its significance and correlation to severity of systemic disease, if any. An extensive search was employed to retrieve articles of COVID-19 published from January 2020 to date using the keywords “novel corona virus,” “COVID-19,” “SARS CoV2,” or “retina,” either singly or variably combined.
| Methods|| |
The aim of this study was to review the available data on the retinal signs and symptoms in COVID-19 infection, demographics, its significance, and correlation to severity of systemic disease, if any.
An extensive search was employed to retrieve articles of COVID-19 published from January 2020 to date. The search strategy included the following keywords “novel corona virus,” “COVID-19,” “SARS CoV2,” or “retina,” either singly or variably combined. Databases searched included PubMed, Scopus, Embase, and the Saudi Digital Library.
Inclusion criteria and exclusion criteria
Cross-sectional studies, case series, or case reports of patients with COVID-19 infection having retinal signs on ophthalmoscopy, fundus photography, FFA, OCT, or OCT angiography (OCTA) were included in this review. However, studies of other designs or those not demonstrating retinal signs of COVID-19 infection or studies demonstrating the effect of medications used in COVID-19 treatment on the retina were not included. Similarly, researches not in the English language or in which an English translation could not be obtained were excluded as well.
| Results|| |
After applying the inclusion and exclusion criteria, 19 researches were included in this review. They included 5 cross-sectional studies, 2 case series, and the remaining case reports.
The researches involved 260 COVID-19 patients in all. Of the five cross-sectional studies, two were from Italy and one each from Brazil, Spain, and Iran [Table 1].,,,, Both the case series were from Brazil [Table 2]., There were 12 case reports included in this review, which were from various parts of the world, such as Spain, Brazil, France, Italy, and India [Table 3]. Three of the cross-sectional studies focused on the retinal vascular signs of COVID-19, which included reduction in the radial peripapillary capillary plexus (RPCP) density, decrease in foveal and parafoveal superficial and deep capillary plexus (SCP and DCP) density, and increase in retinal arterial and venous caliber.,, In a case series reported from Sao Paulo by Marinho et al., retinal and OCT changes were noted in 12 patients (age group 25–69 years), 11–33 days after developing symptoms of COVID-19. The case reports showed the presence of retinal manifestations such as cotton wool spots and retinal hemorrhages in COVID-19 patients., Vascular changes such as impending CRVO, papillophlebitis, and even bilateral CRVO were reported in five case reports.,,,,, Other retinal manifestations reported include chorioretinitis, outer retinal abnormalities, and panuveitis.,,
|Table 1: Cross-sectional studies of coronavirus disease 2019 patients with retinal manifestation|
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|Table 2: Case series of coronavirus disease 2019 patients with retinal manifestations|
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|Table 3: Case reports of coronavirus disease 2019 patients with retinal manifestations|
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| Discussion|| |
Over the past couple of months, there is increasing evidence of posterior segment involvement in COVID-19 infection. The incidence of retinal involvement ranged from 7% to almost 55% in different studies.,, However, a higher incidence of retinal involvement was noted in studies on more serious/critical patients. Lani-Louzada et al. noted an incidence of 22% retinal involvement in a case series of 47 eyes of severe or critical COVID-19 cases. This points to a correlation between the severity of COVID-19 disease and the incidence of retinal involvement. Some authors consider conjunctivitis to be an association of more severe SARS CoV2 infection and an indicator of the severity of the disease.,,,, Similarly, it is probable that retinal involvement parallels involvement of other organ systems and points to a more severe disease course. Retinal findings associated with COVID-19 infection include retinal hemorrhages and cotton wool spots, which is indicative of a microangiopathy-like picture.,, The retinal changes are thought to be due to the effect of the virus itself or the profound inflammatory response that occurs as part of the disease process. However, some researchers speculate that the retinal changes are unlikely to be due to the direct effect of the virus, due to the associated inflammation and accompanying cytokine storm along with the hypercoagulable state, all of which contribute to the pathogenesis of organ damage., It is now proven conclusively that retinal involvement is a part of COVID 19 disease; thus, retinal examination, either by ophthalmoscopy or retinal imaging, should be a part of the workup of COVID-19 patients complaining of new-onset blurred vision, dyschromatopsia, defective near-vision, or scotomata.
Retinal vascular changes accompanying SARS CoV2 infection were studied in three cross-sectional studies. Using OCT and OCTA, Savastano et al. in a cross-sectional study of 80 Italian subjects 1 month after recovery from COVID-19 noted that there was a reduction in retinal peripapillary capillary plexus (RPCP) density in SARS CoV2 patients compared to controls. Among the COVID patients, lower RPCP density was noted among patients treated with lopinavir and ritonavir, antiplatelet medications, and also in older patients and those with hypertension. All these factors point to microvascular damage in COVID disease, which is aggravated by therapy and preexisting risk factors. In yet another cross-sectional study employing fundus photographs of 54 admitted and swab-positive COVID-19 patients from Italy, retinal arterial and venous diameter was noted to be more in COVID-19 patients as compared to controls. Venous caliber was larger in more serious cases, and the timing of the maximal venous diameter correlated with the peak inflammatory response in the disease process. In a research from Iran conducted using OCTA on 31 COVID-19–recovered patients, the mean SCP and DCP densities in foveal and parafoveal regions were significantly lower in COVID-19 patients compared to cohorts. The OCTA was conducted at least 2 weeks after recovery from COVID-19. The vascular changes were hypothesized to be due to the virus itself or the inflammatory response to the virus. These studies also highlight the susceptibility of the retinal vasculature to the virus and highlight the virus affinity for the ACE2 receptors in the vascular endothelium. Similar vascular changes could probably be existing in blood vessels of other organ systems and ACE2 receptor rich sites, as well, and retinal examination could provide an insight into the effect of virus on the vascular system, in general.
In a case series from Sao Paulo by Marinho et al. published in May 2020, retinal and OCT changes were described in 12 patients seen 11–33 days after the start of COVID-19 symptoms. Four patients showed cotton wool spots and microhemorrhages, and all patients showed hypererflective lesions at the level of the ganglion cell layer and inner plexiform layer, most prominent in the area of the papillomacular bundle. Similar lesions have been noted in animal studies as well. However, there were questions about whether these lesions could be the effect of acute hypoxia or could represent normal retinal vessels., However, Marinho et al. stood by their findings and said that the lesions showed the absence of blood flow (by B scan overlay of OCTA) and thus were unlikely to be normal retinal blood vessels.
There were three case reports of COVID-19 patients presenting with scotomata in patients recovering from COVID-19 infections, ranging from 8 to 17 days postinfection. Virgo and Mohamed described two Caucasian patients in their thirties who recovered from COVID-19. In the first patient, there was a focal area of hyperreflective change in inner and outer plexiform layers with inner nuclear layer volume loss on OCT, leading to a diagnosis of paracentral acute middle maculopathy (PAMM). The OCT of the other patient showed a focal zone of faint outer plexiform layer hyperreflective change and disruption of the interdigitation zone, making a diagnosis of acute macular neuroretinopathy (AMN). Gascon et al. reported a case of a 53-year-old Frenchman whose fundus showed retinal hemorrhages and Roth's spots and OCT showed a picture resembling AMN and PAMM. Gonzalez-Lopez et al. reported a case of a 50-year-old patient with fundus findings of peripapillary cotton wool spots in both eyes. OCT showed Retinal nerve fibre layer (RNFL) edema and disruption of the normal reflectivity of the nuclear and plexiform layers in the largest lesion. OCTA showed decreased SCP flow, and automated perimetry showed an arcuate scotoma corresponding to the largest lesion. All these reports again highlight the microvascular damage seen in COVID-19 disease, which may also be seen in other organ systems.
There were six case reports of involvement of the retinal venous system in COVID infection. The first report was that of a 40-year-old man presenting after 6 weeks of COVID infection with decreased vision sensitivity in one eye. Ocular examination revealed a picture resembling papillophlebitis with dilated and tortuous retinal blood vessels, disc edema, macular edema, and hemorrhages, which responded to intravitreal dexamethasone injection. Invernizzi et al. reported a case of a 54-year-old man presenting 10 days post-COVID with a unilateral scotoma and defective vision. Fundoscopy and imaging showed retinal hemorrhages and whitening and a fernlike pattern was seen on autofluorescence, which was typical of impending CRVO. There were two case reports of venous occlusion in COVID-19 patients from India, one of which was an inferior hemi-RVO with a superonasal BRVO and the other patient had a CRVO., Both cases had associated macular edema and responded to intravitreal anti-VEGF injections. There were two case reports of a bilateral CRVO like picture. The retinal findings improved with improvement of the patients' general condition. In all these cases, it is thought that the inflammation and hypercoagulability as part of COVID-19 disease could play a role in pathogenesis of the vasocclusive events. The COVID-19 associated cytokine storm and hyperinflammatory response could result in a cascade of events which can lead to vascular occlusions. Especially in patients with preexisting risk factors and severe COVID-19 disease, it may be prudent to start early anticoagulation to prevent end-organ, including retinal damage., There were three case reports of unique posterior segment manifestations in COVID-19 patients. Ortiz-Seller et al. reported a case of multifocal chorioretinitis and bilateral Adie's pupil in a COVID-19 patient presenting with retroocular pain and defective reading 2 days after COVID onset. There were multiple bilateral white-yellowish placoid lesions in the mid-peripheral and posterior retina, which improved with oral prednisolone. The virus was presumed to be responsible for the denervation of the postganglionic pupillary and ciliary muscle nerve supply, resulting in Adie's pupil and providing evidence for the neurotropism of the SARS CoV2 virus. Zago Filho et al. described a case of a 57-year-old woman with bilateral red eyes seen 12 days after a COVID 19 symptom onset and diagnosis. A diagnosis of vitritis and outer retinal inflammation was made. The authors hypothesized that these lesions were due to COVID-19 infection and anticipated more reports as the pandemic progresses. Benito-Pascual et al. reported a case of a patient who presented with ocular pain, blurred vision and redness in one eye with a 2-week past history of respiratory infection and sinusitis. The patient had a 2-week history of follicular conjunctivitis followed by panuveitis. Other causes of panuveitis were ruled out. Ocular symptoms improved as the patient's systemic condition improved; however, disc pallor was noted. The authors postulated that the choroid has ACE2 receptors which could present a site for virus dwelling and replication.
| Conclusion|| |
It has been proven beyond doubt that the SARS CoV2 virus can affect the retina. Increasing amounts of evidence to the same have been accumulating as the pandemic progresses. Retinal manifestations are ubiquitous, but microangiopathy and vascular occlusions are among the most common. They probably are a reflection of the severity of the disease and may serve as an indicator of similar events in other organs. Retinal involvement in COVID can affect vision permanently, and it is therefore very important to safely examine the retina of any COVID-19 patient presenting with new onset visual symptoms by either ophthalmoscopy or retinal imaging. It is anticipated that with time, newer retinal manifestations of COVID-19 disease will be discovered, and there will also be more information about the ones we already know. The ophthalmologist during the time of the pandemic should keep thus his eyes open to the possibility of the SARS CoV2 virus affecting every part of the eye and identifying unknown and hitherto undiscovered manifestations of the disease. As the vaccine is now within reach and with increasing knowledge about the virus, the sense of panic and fear among populations may abate. However, it is best to take care, stay safe, and practice hand hygiene and social distancing to face this challenging situation.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]