key: cord-0748116-ocz40tfa
authors: Ullah, Irfan; Sohail, Aruba; Shah, Mir Umer Farooq Alam; Khurshid, Maman; Diwan, Mufaddal Najmuddin; Qadir, Abdul; Irfan, Muhammad
title: Central Retinal Vein Occlusion in patients with COVID-19 infection: A systematic review
date: 2021-10-08
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2021.102898
sha: 6eacde431900afd517e4ea1f368c794aebc4a8ac
doc_id: 748116
cord_uid: ocz40tfa

This systematic review summarizes the evidence on patients diagnosed with central retinal vein occlusion (CRVO) secondary to COVID-19. We searched PubMed and Google Scholar from its inception till June 2021. From an initial 55 publications, 10 studies provided specific information on COVID-19 patients with CRVO. Studies described 10 patients, 60% were male and the mean age was 39.3 ± 11.6 years. Blurred vision (40%) and decreased vision (50%) were the most common presenting complain. Symptom onset ranged from 5 days to 6 weeks after initial complaint of fever. Laboratory results showed elevated inflammatory markers and D-dimers in 60% of patients included in our review. Common treatment options were intravitreal anti-VEGF injections, steroids, and anticoagulants. Traditional co-morbidities like diabetes mellites, hypertension, and morbid obesity (hyperlipidemia) were observed in only 3/10 patients. The prognosis was excellent as all patients saw improvement in their condition. Our findings highlight the importance of identifying CRVO as an important complication of COVID-19 infection. Thus, physicians should not overlook the likelihood of CRVO in patients with COVID-19 infection and offer prompt treatment.

Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy; CRVO being one of its types [8] . The prevalence of retinal vein occlusions in the developed world has been found to be 5.20 per 1000, and the prevalence of CRVO is 0.8 per 1000 [9] . CRVO is further divided into two categories: non-ischemic (perfused) and ischemic (non-perfused). Non-ischemic CRVO is associated with good visual acuity and mild visual changes; however, ischemic CRVO carries a poorer prognosis [8] . Classic risk factors for the development of CRVO include age (90% of patients older than age 50), hypertension, glaucoma, diabetes mellitus, and hyperlipidemia [9] [10] [11] . Thus, CRVO is generally considered a disease of the elderly. In younger patients, hypercoagulable state has been found to be significantly associated with CRVO; however, diabetes mellitus and hypertension were not significant [12] . Individuals with SARS-CoV-2 infection may have a number of coagulation abnormalities suggesting a hypercoagulable state, which has been called COVID-19 associated coagulopathy [13] . Thus, the hypercoagulable state due to Covid-19 could be associated with CRVO. Only 1/3 rd of older CRVO patients improve without treatment and there is a possibility that non-ischemic CRVO could progress to ischemic CRVO [8] . Hence, early diagnosis and appropriate management is necessary for an improved prognosis. Work up for CRVO should include assessments of visual acuity, Rapid afferent pupillary defect, fundoscopy, optical coherence tomography (OCT) and Fluorescein angiography [14] . Currently, the most common therapy used is by blocking intraocular VEGF by injecting intravitreal anti-VEGF agents such as aflibercept, bevacizumab or ranibizumab. In addition, intraocular and systemic steroids can be used to treat macular oedema as well [15] . A close follow-up is maintained until the visual acuity improves and fluid activity resolves completely. In this review, we discussed the pathophysiological mechanisms leading to CRVO secondary to COVID-19. Also, we conducted a systematic review of case reports to evaluate characteristics and clinical course of patients having CRVO secondary to COVID-19.

Anatomically, the central retinal artery shares a common sheath of adventitia with the central retinal vein, located posterior to the lamina cribrosa at the arteriovenous crossing. Classically, CRVO is induced by compression of the vein by the artery as a result of atherosclerosis of central retinal artery [8] .

The Virchow's triad (hypercoagulability, endothelial damage, and stasis) plays a key role in the development of retinal vein occlusions (RVOs) as it does for other thrombotic conditions; thus, both local and systemic conditions affecting one of the three components should be considered as a risk factor for CRVO [16] . Retinal findings following infection with SARS-CoV-2 virus occur due to complement activated thrombotic microangiopathy and hypercoagulable state [17, 18] . The most typical finding in patients with COVID-19 and coagulopathy is an increased D-dimer concentration, a relatively modest decrease in platelet count, and a prolongation of the prothrombin time [19] . Many different studies have shown a strong association between elevated D-dimer levels vis-à-vis severity and prognosis of disease with specific concerns about thrombotic complications of COVID-19 like pulmonary embolism, stroke, disseminated intravascular coagulation, limb, and digit infarcts. [17, 20] . Thus, the hypercoagulable state of COVID-19 patients has been assessed by an increase in D-dimer levels as it indicates an increased risk of thrombosis [21] [22] [23] . The findings indicate that Covid-19 can induce a DIC-like state, referred to by some authors as "Covid-19 associated coagulopathy (CAC)", which increases the risk of thromboembolic complications such as CRVO. [13, 21, 24] .

In a subset of patients most severely affected by COVID-19, a cytokine storm profile can be found, characterized by high concentrations of proinflammatory cytokines and chemokines [25, 26] . The hyperinflammatory profile constitutes significant increases in fibrinogen, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) and ferritin levels [27, 28] . The cytokines storm stimulates the expression of tissue factor on monocytes/macrophages and vascular endothelial cells, on whose surfaces the coagulation cascade is initiated. The thrombus formation at the microvascular level contributes to tissue ischemia and organ dysfunction [29] . Moreover, intermittent hypoxia due to pneumonia can induce endothelial cells release of tissue factor, triggering the extrinsic coagulation pathway [30] . Thus, initiation of coagulation cascade as a result of these factors increases the risk of thrombus formation, consequently increasing the risk of CRVO.

SARS-CoV-2 binds to host cells via the angiotensin converting-enzyme (ACE) 2 receptor (R) -a metallopeptidase. The high expression of ACE2 receptors within endothelial cells raises a question of its vulnerability to SARS-CoV-2 binding, and the pathogen's ability to produce systemic endothelial dysfunction [31] . A pseudo-vasculitis state can result from viral infiltration of the endothelial cells of retinal vessels [32] . COVID-19 may primarily be a vascular disease causing severe endothelial disruption, complement activation, and generalized inflammation, leading to an overall procoagulant state [33] . Thus, disruption of retinal endothelium as a result of viral infiltration increases the risk of thrombus formation and CRVO. Moreover, endothelial cell dysfunction could also lead to breakdown in the inner blood-retinal barrier, resulting in increases capillary permeability and subsequent development of macular oedema [34] .

The work has been reported in line with the PRISMA 2020 criteria [35] . We perused the PubMed and Google scholar databases using the medical subject headings (MeSH) "COVID-19", "covid-19", "SARS-CoV-2", "severe acute respiratory syndrome coronavirus 2", "2019-nCoV", "Coronavirus disease 2019" AND "central retinal vein occlusion", "CRVO". Please see the supplementary file for a detailed search strategy.

The title, abstract and full-text screening was completed in duplicate and independently by two reviewers (AS) and (MUFAS). Duplicate records were excluded, and a third reviewer (MK) was approached to resolve conflicts between authors in study selection. Articles in languages other than English were excluded. Case reports, case series, correspondence articles, and editorials were included in the present review. Studies were excluded if they did not present original empirical data, clinical data, or reported aggregate-level data (i.e., retrospective cohorts) on patients having CRVO secondary to COVID-19. The combined search strategy identified 55 potential publications on CRVO secondary to COVID-19 ( Fig. 1) . After screening and removing duplicate studies (n=37), the full texts of 18 reports were sought to assess for eligibility. Of these, 2 did not report about CRVO secondary to COVID-19, 2 reported aggregate-level data, 1 was in another language and 3 did not have full-text versions available. 

Data extraction was completed in duplicate by two independent reviewers, and discrepancies were resolved through feedback from a third reviewer. Data were extracted on the first author, age and sex, patient characteristics, functional tests, morphological findings, diagnosis, laboratory parameters, treatment, and prognosis.

We conducted the quality assessment of all included studies using Joanna Briggs Institute's critical appraisal tool for case reports [36] . Each qualitative answer was converted to a numeric score. The J o u r n a l P r e -p r o o f assessment was conducted by two independent reviewers and the final score was given after resolving disagreements. A detailed quality assessment is provided in the supplementary file. The quality of our systematic review was assessed using AMSTAR 2 criteria [37] . The level of compliance with AMSTAR 2 came out to be "low". As only case reports were included in the analyses and the number of studies was low, we couldn't conduct a meta-analysis.

Data were extracted and entered on excel sheets. Frequency and percentage were used to report categorical variables whilst continuous variables were reported in mean form.

The search found 10 studies [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] that met our inclusion criteria and were included in the systematic review (Table 1) . All these 10 studies were case reports and reported single cases. Joanna Briggs Institute critical appraisal tools assessments score ranged from 4 to 7, with a mean score of 5.8 out of a total score of 8 (Table S1 ). A total of 10 cases were retrieved, comprising 6 males and 4 females [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] . The mean age of the patients was 39.3 ± 11.6 years ranging from ages 17 to 56. Notably, patients having CRVO secondary to COVID-19 were younger than the usual age of onset of the disease. Only 3 of the 10 patients had traditional risk factors of CRVO: diabetes mellites, hypertension, and morbid obesity (hyperlipidemia) [40, 42, 43] . The time of presentation after the first onset of fever ranged from 5 days to 6 weeks. Associated macular edema was seen in 4/10 patients [38, 42, 44, 45] . The two patients with diabetes mellites also had superimposed diabetic retinopathy [42, 43] . A staggering 60% of the patients had elevated inflammatory markers and D-dimers [39] [40] [41] [42] [43] 47] The prognosis was good as all the patients improved after treatment. The treatment options included intravitreal anti-VEGF injections, steroids, and anticoagulants. Although the patient reported by Venkatesh et al. was only treated with low-dose aspirin 150 mg/day, improvement was reported at follow-up [42] . As aspirin is an anti-platelet agent, it prevents the formation of new blood clots. This reduction in hypercoagulability could favor the anti-coagulant mechanisms to dissolve clots that led to CRVO; resulting in restoration of blood flow in the retinal vessels. The findings of the literature review are depicted in Table 1 . 

The studies in the review describe ophthalmic exam findings and patient outcomes of CRVO secondary to COVID-19. We also attempted to evaluate the pathophysiological mechanisms that could lead to CRVO secondary to COVID-19. Classically, the patients having CRVO present with significantly reduced vision. They may exhibit an afferent pupillary defect in the affected eye and/or a reduction in visual acuity; Ophthalmic examination findings include cotton wool spots, swelling of the optic disc, extensive 4-quadrant hemorrhage, tortuosity and dilation of the retinal veins [8] . These findings have also been reported in patients having CRVO secondary to COVID-19. Thus, the findings and presenting symptoms in patients with CRVO secondary to COVID-19 are similar to those in patients having CRVO as a result of other etiologies.

Classically, the risk factors for CRVO include age (90% of patients older than age 50), hypertension, glaucoma, diabetes mellites and hyperlipidemia [9] [10] [11] . However, in this study, the mean age of the patients was 39.3 years which shows that patients having CRVO secondary to COVID-19 were younger than the usual age of onset of the disease. Moreover, only 3 of the 10 patients had traditional risk factors of CRVO: diabetes mellites, hypertension, and morbid obesity (hyperlipidemia). The key takeaway is clear: the risk of acquiring CRVO secondary to COVID-19 persists irrespective of the age or J o u r n a l P r e -p r o o f presence of classic risk factors. In these patients, the hypercoagulable state as a result of COVID-19 associated coagulopathy (CAC) lends a helping hand to the development of CRVO. We have described the pathophysiological mechanisms that could lead to CRVO secondary to COVID-19. These mechanisms are more significant than classic risk factors associated with CRVO in these patients.

The patient reported by Venkatesh et al. [42] improved at follow-up despite being only treated with lowdose aspirin 150 mg/day. As aspirin is an anti-platelet agent, it prevents the formation of new blood clots. This reduction in hypercoagulability could favor the anti-coagulant mechanisms to dissolve clots that lead to CRVO, resulting in restoration of blood flow in the retinal vessels. As treatment with Aspirin resulted in good clinical outcomes, early anticoagulant prophylaxis should be considered in patients with systemic comorbidities and severe COVID-19 infection as they could be more susceptible to CRVO. Venous thromboembolism (VTE) prophylaxis has been recommended for hospitalized and critically ill patients [48] . As COVID-19 associated coagulopathy (CAC) could play a significant role in CRVO, anticoagulant prophylaxis could significantly decrease the risk of CRVO. Moreover, as the thromboembolic complications of COVID-19 are well established [17, 20] , there is a need to devise anticoagulant prophylaxis regimens bearing in mind the ophthalmic implications as well.

Diabetic retinopathy superimposed on CRVO was also reported in diabetic COVID-19 patients; thus, further studies are warranted to establish the correlation between COVID-19 and diabetic retinopathy. Given these evolving challenges, it is essential that large scale trials are devised -not just to discern the interplay between COVID-19 and CRVO, but also other thromboembolic conditions that can cause significant morbidity and mortality.

Our study has some limitations. Most of the studies in our review are case reports in which a limited number of patients are assessed. Larger scale studies with greater number of cases and longer followups are needed to reliably draw the correlation between COVID-19 and CRVO. Nevertheless, there is a conspicuous correlation between the two that cannot be discounted. Moreover, studies in languages other than English were excluded. As CRVO is not a well-known complication of COVID-19, it is likely that many cases go unreported which further limits the literature available. Our study has some limitations.

Most of the studies in our review are case reports in which a limited number of patients are assessed. Larger scale studies with greater number of cases and longer follow-ups are needed to reliably draw the correlation between COVID-19 and CRVO. Nevertheless, there is a conspicuous correlation between the two that cannot be discounted. Moreover, studies in languages other than English were excluded. As CRVO is not a well-known complication of COVID-19, it is likely that many cases go unreported which further limits the literature available.

Our review has comprehensively summarized all published CRVO cases reported to date secondary to COVID-19 disease since the beginning of the pandemic. Although the literature is limited, this review has been successful in establishing the causality between COVID-19 and CRVO. Irrespective of the traditional risk factors, hypercoagulability associated with COVID-19 can be a factor in the development of CRVO. Clinicians must be aware of this plausible complication of COVID-19 in case they come across patients displaying signs and symptoms of CRVO. Along with necessary clinical investigations, linking these signs and symptoms with the history of COVID-19 infection could provide an aide in prompt diagnosis of CRVO. As our review reported a good prognosis, timely initiation of appropriate treatment could bring about complete resolution of the disease.

Weekly epidemiological update on COVID-19 -10

Coronavirus disease 2019 (COVID-19): A literature review

Outcomes of in-hospital cardiac arrest in COVID-19 patients: A proportional prevalence meta-analysis

Hematological findings and complications of COVID-19

Coronavirus disease 2019 (COVID-19): Multisystem review of pathophysiology

COVID-19 and Eye: A Review of Ophthalmic Manifestations of COVID-19

The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study

Central Retinal Vein Occlusion

The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study

Retinal vein occlusion and traditional risk factors for atherosclerosis

Central retinal vein occlusion: review of management

Risk factors for central retinal vein occlusion in young adults

COVID-19 and its implications for thrombosis and anticoagulation

Central Retinal Vein Occlusion

Management of macular edema due to central retinal vein occlusion -The role of aflibercept

Retinal vein thrombosis: pathogenesis and management

Covid-19 Cases: Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

COVID-19, coagulopathy and venous thromboembolism: more questions than answers

Coagulation abnormalities and thrombosis in patients with COVID

Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

D-dimer is Associated with Severity of Coronavirus Disease 2019: A Pooled Analysis

How I treat disseminated intravascular coagulation

COVID-19: consider cytokine storm syndromes and immunosuppression

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

Clinical and immunological features of severe and moderate coronavirus disease 2019

Clinical and immunological features of severe and moderate coronavirus disease 2019

COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimmun Rev

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

Retinal vein thrombosis: The Internist's role in the etiologic and therapeutic management

COVID-19 update: Covid-19-associated coagulopathy

Endothelial cell infection and endotheliitis in COVID-19

COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure

Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Joanna Briggs Institute Reviewer's Manual. The Joanna Briggs Institute

AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or nonrandomised studies of healthcare interventions, or both

Central retinal vein occlusion with COVID-19 infection as the presumptive etiology

Impending Central Retinal Vein Occlusion in a Patient with Coronavirus Disease 2019 (COVID-19)

Bilateral Central Retinal Vein Occlusion in a 40-Year-Old Man with Severe Coronavirus Disease 2019 (COVID-19) Pneumonia. Am J Case Rep

Central retinal vein occlusion in a young healthy COVID-19 patient: A case report

COVID-19-associated central retinal vein occlusion treated with oral aspirin

Bilateral retinal vein occlusion and diabetic retinopathy after COVID-19

Central retinal vein occlusion in the setting of COVID-19 infection

Retinal vein occlusion in COVID-19: A novel entity

Hemi-retinal vein occlusion in a young patient with COVID-19

Papillophlebitis in a COVID-19 patient: Inflammation and hypercoagulable state

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

The authors declare that there is no conflict of interests

Not commissioned, externally peer reviewedReferences

 All published CRVO cases reported to date secondary to COVID-19 disease since the beginning of the pandemic has comprehensively been summarized  Timely initiation of appropriate treatment could bring about complete resolution of the disease  Treatment with aspirin resulted in good clinical outcomes, early anticoagulant prophylaxis could be considered in patients with systemic comorbidities and severe COVID-19 infection as they could be more susceptible to CRVO J o u r n a l P r e -p r o o f

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