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COVID-19 related retinal micro-vasculopathy – a review of current evidence

COVID-19 related retinal micro-vasculopathy
  • Kelvin YC Teo
    Affiliations
    Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore

    Duke-NUS Medical School, National University of Singapore, Singapore

    Save Sight Institute, The University of Sydney, Faculty of Health and Medicine, Sydney, New South Wales, Australia
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  • Alessandro Invernizzi
    Affiliations
    Save Sight Institute, The University of Sydney, Faculty of Health and Medicine, Sydney, New South Wales, Australia

    Eye Clinic, Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Italy
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  • Giovanni Staurenghi
    Affiliations
    Eye Clinic, Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Italy
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  • Chui Ming Gemmy Cheung
    Correspondence
    Correspondence to: Gemmy CM Cheung, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore, T: +65 6322 8335 / F: +65 62263395
    Affiliations
    Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore

    Duke-NUS Medical School, National University of Singapore, Singapore
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Published:September 26, 2021DOI:https://doi.org/10.1016/j.ajo.2021.09.019

      Purpose

      To evaluate the occurrence of retinal micro-vasculopathy in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developed coronavirus disease (COVID-19).

      Design

      Systematic review and meta-analysis.

      Methods

      The Pubmed and Embase databases were comprehensively searched to identify studies that reported retina vascular changes in eyes with COVID-19. Two independent reviewers selected papers and extracted data for analysis. Data of interest were extracted and analysed in RevMan Web versions 3.3. Quality of evidence was assessed using the National institute of health (NIH) quality assessment tool of case-control study.

      Results

      Thirty one studies reporting on 1373 subjects (972 COVID-19 and 401 controls) were included. Only case control studies were included in the pooled analysis. There was a significantly higher likelihood of retinal micro-vasculopathy in subjects with COVID-19 compared to controls. (odds ratio [95% confidence interval], 8.86 [2.54-27.53], p<0.01). Optical coherence tomography angiography (OCTA) reveals reduced vessel density and enlarged foveal avascular zone in subjects with COVID-19 compared to controls.

      Conclusions

      Our results suggested that COVID-19 related retinal micro-vasculopathy is a significant ocular manifestation of COVID-19 and may herald future retinal complications. These microvascular impairments might occurred antecedent to clinically visible changes and could be detected early by OCTA. These findings are significant due to the large numbers with COVID-19 and needs to be recognized by ophthalmologist as a potential long term sequelea of the disease.
      Introduction
      The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020.1 To date, there are more than 170 million confirmed COVID-19 cases globally. The virus primarily affects the respiratory system and vary from mild constitutional symptoms to pneumonia, sepsis and sometimes severe acute respiratory distress syndrome (ARDS) necessitating hospitalization and intensive care unit (ICU) admission.2  There is increasing evidence of the virus also causing thrombo-embolic complications, with rates reported to be as high as 30%. 3-5 This thrombo-embolic sequalae is linked to thrombo-inflammation and endothelial cell injury thought to be mediated by the over production of inflammatory cytokines. 6
      The eyes are not spared by COVID-19. In fact, anterior segment involvement has been described since early case series, manifesting as conjunctivitis. 7-10 SARS-CoV-2 RNA has been detected in infected patients’ tears as well as in conjunctival tissue. 11, 12 In contrast, posterior segment manifestations are less well understood. Marinho et al first reported 12 cases of patients with mild to moderate COVID-19 infection with retinal signs including retinal hemorrhages and cotton wool spots (CWS) and optical coherence tomography (OCT) abnormalities. 13 However, several authors demonstrated how the OCT abnormalities initially reported were a misinterpretation and could be explained by variation in normal retinal vasculature on OCT b-scans.14-16 In addition, without a comparative control group, the retinal findings such as CWS could have been non-specific and incidental. However, since the initial report by Marinho, several case-control studies have reported retinal features in patients with COVID-19 infection of various severity.17-25
      In addition to clinical features, several OCT angiography (OCTA) studies demonstrated reduction in vessel density (VD) in COVID patients, which corroborated with the possibility of COVID-19 related retinal micro-vasculopathy. 17-20, 23-26 Importantly, these perfusion deficits have been detected in asymptomatic individuals with no significant medical co-morbidities who have recovered from seemingly mild COVID infections. Therefore, understanding of the prevalence and progression pattern of such perfusion deficits may have significant public health implications in the long term.
      In this review, we aim to summarize the evidence and critique the evidence related to COVID-19 related retinal micro-vasculopathy and examine the potential underlying biological mechanisms.
      Methods
      All eligible studies were identified using a 2-level search strategy. Fist, MEDLINE and EMBASE were searched on 26/05/2021 using PubMed. The search terms used were ‘retina’ OR ‘retinal vasculature’ AND ‘COVID’ OR ‘SARS-CoV’. Next, relevant studies were identified by two authors who reviewed the abstract of each article.
      Data extraction
      Potentially relevant studies describing retinal findings, retinal pathology and retinal imaging were retained. Each article was screened individually for reports on the prevalence of retinal signs. Studies excluded were those investigating other ocular associations with COVID infection including uveitis, ocular inflammation, and other anterior segment changes.
      We summarised data separately for 1) case control studies and 2) case series. For case control studies, we planned to analyse data for the prevalence of retinal microangiopathy and quantitative changes indicative of retinal microangiopathy on OCTA. Retinal micro angiopathy was defined by the presence of retinal haemorrhages, cotton wool spots and/or vascular tortuosity on clinical examination or fundus imaging. Parafoveal vascular density (VD) and foveal avascular zone (FAZ) size were assessed as quantitative parameters on OCTA. These data were extracted from each study where available.
      The number of eyes in which retinal hemorrhages or cotton wool spots in cases and controls (where available) were collated. Data regarding the prevalence of retina microangiographic signs (retinal hemorrhages and/or cotton wool spots) were pooled in the case control studies and a subject was defined to have retinal micro-vasculopathy if both or either retinal hemorrhages or cotton wool spots was detected. This data regarding retinal micro-vasculopathy prevalence in both the group with COVID-19 infection and non-infected controls were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs) of presence for retinal micro-vasculopathy versus no retinal micro-vasculopathy.
      In addition, data regarding the mean parafoveal VD and FAZ size (when available) on OCTA was used to generate pooled means and 95% confidence intervals (CI) of each measure respectively. Sensitivity analysis was used to confirm each difference by sequentially omitting each of the included studies and recalculating the summary difference and 95% CI.  The I 2 statistic was used to determine heterogeneity across studies, such that heterogeneity was quantified irrespective of the number of studies.  P value of less than 0.05 was considered to be statistically significant. Forest plots were used to summarise pooled results. Risk of bias assessment was performed on the case control studies using the National institute of health (NIH) quality assessment tool of case-control study. Pooled analysis was performed with RevMan Web versions 3.3. This review has not been registered.
      Results
      We identified 227 articles from our initial search. (Figure 1) After reviewing the abstracts, 179 articles were excluded. The remaining 48 articles were further reviewed with full text examination. For this analysis, we included articles which described retinal signs related to micro-vasculopathy or evaluated retinal vasculature through imaging. Cases describing retinal abnormalities secondary to endophthalmitis, opportunistic infections and uveitis were not included. There were three publications by Guemes-Villahoz.19, 26, 27 Due to overlapping recruitment period, we only included the case-control study in our analysis to avoid duplication. A follow up article by Costa et al28 was also excluded which outlined the longitudinal outcomes of a similar cohort by Pereira et al. 29 We identified ten case-control studies (table 1), nine case series (table 2) and twelve single case reports (supplementary table 1), comprising 944 cases and 401 controls in total. In summary all case control studies were assessed to be of moderate quality when assessed by the National Institutes of Health (NIH) quality assessment tool of case-control studies. Despite the inclusion of control groups in case control studies, we observed that there was still significant heterogeneity in preexisting co-morbidities which may lead to potential selection bias. Reporting bias may affect the quality of conclusions from case series therefore we only performed pooled analysis on data from cases control studies.
      Figure 1:
      Figure 1Search strategy resulting in 226 records from PubMed
      Table 1Case control studies of COVID-19 subjects and associated retina findings
      StudyCohort sizeAge (years) ± SDCOVID confirmation method/ severityexamination time frameRetinal signsDetailed findingsOCT abnormalitiesOCTA protocol/findings
      Zapata et al 25Cases9641-44*RT-PCR

      mild (n=24)

      moderate (n=24)

      severe (n=21)
      60 days after diagnosis

      36 days after discharge
      0.01%retinal haemorrhage (n=1)No abnormalities describedTriton,Topcon, 4.5 × 4.5mm

      VD reduction
      Controls27390%NANo abnormalities described
      Savastano et al 23Cases7053.7±14RT-PCR

      moderate - severe
      36.1 days after discharge13%CWS (n=9)xCirrus 5000, Zeiss, 3 × 3 mm

      VD not altered
      Controls2244.7±110%NAx
      Guemes-Villahoz et al 19Cases6657.2±7RT-PCR

      case divided into:

      Thrombotic event(n=19)

      no Thrombotic event (n=47)
      88 days after diagnosis0%NAxCirrus 5000, Zeiss, 6 × 6 mm

      VD reduction more in the Thrombotic event group
      Controls2951±11.90%NAx
      Invernizzi et al 21Cases5449.9±15.6RT-PCR

      mild (74%) severe (26%)
      30 days from onset of symptoms31%haemorrhages (n=5)

      CWS (n=4)

      dilated veins (n=15)

      tortuous vessels (n=7)
      xx
      Controls13344.2±12.87%haemorrhages (n=2)

      CWS (n=0)

      dilated veins (n=4)

      tortuous vessels (n=9)
      xx
      Gonzalez-Zamora et al 18Cases2561.3±2.4RT-PCR moderate - severe14 days after discharge20%CWS (n=5)VCIPL thinningTriton,Topcon, 4.5 × 4.5mm

      VD reduction
      Controls2560±2.30%NA
      Hazar et al20Cases5037±5.9RT-PCR mild to moderate30 days after dischargexxxAngiovue, optovue, 3 × 3mm

      VD reduction
      Controls5035.2±6.9xxx
      Oren et al20Cases3548.9±14.7RT-PCR mild14-30 days after onset of symptomsxxincrease CMT reduced GCIPLx
      Controls2551.2±7.6xxx
      Abrishami et al17Cases3140.4±9.2RT-PCRmild (71%) severe (29%)14 days from last symptomsxxxAngiovue, optovue, 3 × 3mm

      VD reduction
      Controls2336.6±7.1xxx
      Turker et al17Cases2738.7±10.7RT-PCR moderatewithin 1 week of dischargexxxAngiovue, optovue, 6 × 6mm

      VD reduction
      Controls2737.4±10xxx
      Cennamo et al 30Cases4049.7±12.6RT-PCR moderate4.1 months0%NANo abnormalities describedAngiovue, optovue, 6 × 6mm

      VD reduction
      Controls4048.6±12.20%NANo abnormalities described
      x finding not part of study protocol
      * only age range of recruited patients presented
      Abbreviations: SD standard deviation; OCT optical coherence tomography; OCTA optical coherence tomography angiography; NA not applicable; VD vessel density; RT-PCR reverse transcriptase polymerase chain reaction; CWS cotton wool spot; GCIPL ganglion cell- inner plexiform layer; CMT central macular thickness
      Table 2Case series of COVID-19 subjects and associated retina findings
      Studycohort sizemean age (years)medical statusCOVID confirmation method /severityRetina signsOCT abnormalitiesDetailed findings
      Sim et al3510836.4not hospitalizedRT-PCR

      Mild
      11.6% combinedMicrohaemorrhages (n=6)

      Vascular tortuosity (n=3)

      Cotton wool spots (n=1)

      GC-IPL hyperreflective plaques (n=10)
      Pirraglia et al344670HospitalizedRT-PCR

      Mild to severe
      0%xNo fundus abnormalities
      Landecho et al322756DischargedPositive antibodies

      Moderate (n=26)

      severe (n=1)
      22% combinedCWS (n=6)
      Lani-Louzada et al332551.2HospitalizedRT-PCR

      Mod to severe
      12%xCWS & micro haemorrhages (n=1)

      flame haemorrhages (n=1)

      microhaemorrhages (n=1)
      Pereira et al291862.5HospitalizedRT-PCR

      Severe
      55.60%xflame haemorrhages (n=4)

      CWS (n=4)

      flame haemorrhages and CWS (n=1)

      peripheral haemorrhages (n=2)
      Marinho et al131225-69not hospitalizedRT-PCR (n=9)

      Antibodies (n=2)

      Mild
      100% combinedGCIPL plaques (n=12)

      CWS (n=4)

      microhaemorrhages (n=4)
      Costa et al 286446.7 – 55.6HospitalizedRT-PCR

      Mild – moderate (n=7)

      Severe (n=33)

      Critical (n=24)
      17.2%xVascular tortuosity (n=11)
      Bypareddy et al 3113838.5HospitalizedRT-PCR

      Mild - moderate
      0.72%xFlame haemorrhage (n=1)
      Caporossi et al362839-82HospitalizedNot defined- ICU ARDS COVID-19 Severe28.6%xIntraretinal microvascular abnormalities, arterial saccular dilatation, cotton wool spots and micro haemorrhages. (n=8)
      Abbreviations: OCT optical coherence tomography; RT-PCR reverse transcriptase polymerase chain reaction; GC-IPL ganglion cell-inner plexiform layer; CWS cotton wool spot. ARDS adult respiratory distress syndrome
      Summary findings of retinal features related to micro-vasculopathy
      Among cases-control studies and case series, 18 publications (10 case-control studies 17-25, 30 and 9 case series 13, 28, 29, 31-36) reported on the presence or absence of retinal signs related to micro-vasculopathy. Among the 10 case- control studies, retinal signs were reported in 6, with frequency ranging from 0.01% to 20%.
      Retinal features related to micro-vasculopathy in case-control studies
      The largest COVID-19 population was described by Zapata et al in a case-control study including 96 cases and 27 controls. Among the cases, a range of severity were included (24 with mild disease, 24 with moderate disease requiring hospital admission but with no acute respiratory distress and 21 with severe disease who developed ARDS and were admitted in the ICU). Age distribution was similar between cases (mean 41-44 years) and controls (mean 39 years). Eye examination was performed after patients had recovered and have been discharged. The authors reported presence of a small posterior pole retinal hemorrhage in one patient who was under treatment with heparin for presenting a thromboembolic episode during his stay in ICU. In view of the concurrent medical issues, the authors did not attribute the retinal haemorrhage to SARS-CoV-2. However, in the same series, the authors reported cases with moderate or severe infection had significantly reduced vessel density (VD) compared to control and patients with mild infection. 25
      Guemes-Villahoz evaluated macular vessel density in 66 cases with confirmed diagnosis of COVID-19 (mean age 57.1 to 57.3 years) and 29 controls (mean age 51.0 years). The cases were further sub-divided according to presence or absence of thrombotic events (TE). Eye examination was performed 88 days (86-90) after the diagnosis of the infection. Fundus examination of the 66 patients revealed no retinal vascular changes. However, significantly lower VD was detected in COVID-19 patients compared to controls. Within the COVID-19 group, no differences in OCTA parameters were found when considering the history of TE. 19
      Invernizzi et al included 54 cases and 133 controls. Majority of the cases had mild infection (74%), while 26% had severe infection, but no cases requiring previous ICU were included. Fundus examination was performed within 30 days of symptom onset. The cases were older (49.9 vs 44.2 years, p=0.01), had higher BMI (25.8 vs 24.5, p=0.03) but did not differ in other medical history compared to controls. Significantly higher frequency of retinal hemorrhages (9.25% vs 1.5%, p=0.01) and cotton wool spots (7.4% vs 0, p=0.006) were noted in COVID-19 patients compared to controls. In addition, dilated veins were more frequently observed in COVID-19 patients than in controls (27.7% vs 3.0%, p=0.0001). Semi -automatic quantitative measures of mean vein diameter and mean artery diameter further confirmed COVID-19 patients had more dilated retinal vessels. In addition, in multiple regression, mean vein diameter was negatively correlated with the time from symptoms onset and positively correlated with disease severity. 21
      Gonzalez-Zamora et al compared the prevalence of retinal microvascular signs in 25 COVID-19 patients (mean age 61.35 years) requiring hospitalization with 25 age and gender matched controls (mean age 60.03 years). Eye examination was performed 14 days after hospital discharge. CWS were observed in 20% of the COVID-19 group and none of the controls and lower VD and larger FAZ was detected on OCTA in COVID-19 group compared to controls. It was noted that prevalence of hypertension and dyslipidemia was numerically higher in the COVID-19 group. Based on these results, the authors suggested that thrombotic and inflammatory phenomena could be happening in the retina of COVID-19 patients. 18
      After pooling of all reported data from case-control studies which evaluated retinal signs, comprising 494 cases and 401 controls, the frequency of cotton wool spots was significantly higher in COVID-19 patients compared to subjects unexposed to the virus (1.8% vs 0.0%, p<0.01). The frequency of retinal haemorrhages was not significantly different between the two populations (1.2% vs 0.5%, p=0.25).
      In addition to the reduction in VD on OCTA reported by Zapata et al, Guemes- Villahoz et al, Gonzalez-Zamora et al and Cennamo et al18, 19, 25, 30, three other case-control studies compared OCTA findings between COVID-19 patients to controls but did not evaluate fundus microvascular signs. 17, 20, 24 Hazar et al compared 50 COVID-19 patients with mild to moderate pneumonia with 50 controls (age 37.00 vs 35.14 years, p=0.147, respectively). Eye examination was performed one month after discharge and recovery. 20 Abrshami et al compared 31 COVID-19 patients with 23 controls. Patients had mean age of 40.4 years and were free of past medical history except two patients who disclosed hypertension. Majority of patients (71%) had mild infection and did not require hospitalization. None of the hospitalized patients required invasive ventilation. 17 Turker et al compared OCTA in 27 COVID-19 patients with moderate pneumonia (hospitalized but not admitted to ICU) and 27 controls. Eye examination was performed within 1 week of discharge. The age distribution of the groups was similar (37.44 years vs 38.74 years, p=0.648). 24 All three studies reported significantly lower VD in the COVID-19 cases compared to controls. In total, 7 case-control studies evaluated retinal microvasculature perfusion using OCTA, comprising 454 cases and 361 controls. Reduction in vessel density in cases was reported in 6 out of 7 studies. 17-20, 23-25
      Oren et al compared retinal changes using OCT quantitative assessment in 35 cases with mild pneumonia not requiring hospitalization and 25 age- and sex-matched controls. Examinations were performed 14-30 days after symptom onset. The authors reported higher central macular thickness and thinner ganglion cell layer and inner nuclear layer in COVID-19 group compared to controls. The authors hypothesized that the GC-IPL changes may represent virus involvement of the retina and/or endothelial cells within the retinal plexus. 22
      Pooled analysis of the presence of COVID-19 related retinal micro-vasculopathy
      Of the 10 case control studies, 6 reported the presence of retinal micro-vasculopathy signs as an outcome. These 6 studies were included in the meta-analysis providing data on a total of 627 subjects (351 COVID-19 infected subjects versus 276 uninfected controls). Pooled analyses of these studies demonstrated statistically significant 8.86-fold increase (OR, 8.86; 95% CI, 2.54–27.53; p< 0.01) retinal micro-vasculopathy prevalence in COVID-19 infected patients relative to non-infected controls. (Figure 2) Sensitivity analysis performed by randomly excluding each study in a sequential manner showed a persistent significant difference between COVID-19 and control subjects with respect to the presence of retinal micro-vasculopathy ( p< 0.01 for all).
      Figure 2:
      Figure 2Forest plot of odds ratios for retina micro-vasculopathy in patients with COVID-19 infection versus non infected controls.
      Pooled analysis of VD and FAZ size in subjects with the COVID-19 infection
      Of the 10 case control studies, 8 studies measured vessel density and FAZ on OCTA. Mean parafoveal VD was pooled in 5 of 8 studies. The remaining 3 studies did not measure the parafoveal VD and hence excluded. The results of a total of 379 subjects (175 COVID-infected versus 204 non-infected controls) were pooled for the measurement of parafoveal VD. The pooled mean parafoveal VD (95% CI) was 2.99% (-3.63 - -1.67) less in the COVID-19 infected subjects compared to non-infected controls (p<0.01). (figure 3) Mean FAZ size was pooled in 7 of the 8 studies. Hazar et al did not performed this measurement in their study cohort. 20 The results of a total of 548 subjects (318 COVID-infected versus 230 non-infected controls) were pooled for the measurement of FAZ size. The pooled mean FAZ (95% CI) was 0.08 mm2 (0.07-0.09) larger in COVID-19 infected patients compared to non-infected controls (p<0.01). (figure 4) Sensitivity analysis performed by randomly excluding each study in a sequential manner showed a persistent significant difference between COVID-19 and control subjects with respect to the VD and FAZ size ( p < 0.05 for all).  Reasons for high heterogeneity in the pooled data for VD and FAZ is likely to be due to the differences in OCTA instruments and differences in measurements methodology.
      Figure 3:
      Figure 3Forest plot of means of para foveal vessel density (%) measured on optical coherence tomography angiography in subjects with COVID-19 infection versus non infected controls.
      Figure 4:
      Figure 4Forest plot of means area of foveal avascular zone (mm2) measured on optical coherence tomography angiography in subjects with COVID-19 infection versus non infected controls.
      From these pooled analyses, the prevalence of retinal micro-vasculopathy is significantly associated with COVID-19 compared to controls. There is a probable association between lower VD and larger FAZ with COVID-19 compared to controls.
      Retinal features related to micro-vasculopathy in case-series
      Nine case series reported retinal features in COVID-19 patients. Among these, the two largest series comprised 138 cases (mean age 38.5 years)31 and 108 cases (36.4 years)35 with mild to moderate infection. Examination in the largest series revealed only 1 patient with a flame hemorrhage (0.72%). Patients in this series were examined at the bedside with a non-mydriatic handheld fundus camera with a mean of 6 days after diagnosis if COVID-19. 31 In contrast, retinal signs observed in the second largest series included micro-haemorrhages (3.7%), CWS (0.93%) and vascular tortuosity (2.8%). Hyper-reflective plaques in the GC-IPL layer were noted on OCT in 5.1%. Fundus imaging and OCT was performed on a Topcon 3D OCT-1 Maestro System (Topcon, Japan). There was no significant difference in the prevalence of retinal signs in symptomatic versus asymptomatic patients. The examination was performed about 16 days after diagnosis of COVID-19 with PCV. 35
      The highest prevalence of retinal microvascular abnormalities was reported by Pereira et al in a series comprising 18 COVID-19 patients with severe infection. Seventeen patients (94.4%) require ICU stay and 77.8% received invasive mechanical ventilation. Dilated eye examination was performed at a median of 11.5 days after COVID-19 diagnosis. 55.6% of patients had abnormalities detected, including flame-shaped haemorrhages (22.2%) or CWS (22.2%). Lani-Louzada et al also evaluated 25 hospitalized patients with severe or critical COVID-19 infection (mean age 51.2 years). ICU monitorization was required in 12 patients and 8 required mechanical ventilation. Ocular examination was performed at the bedside using a handheld digital retinal camera connected with a smartphone (mean 23.9 days after the onset of symptoms). Retinal changes were observed in 12%, including nerve fiber layer infarcts, microhemorrhages, flame-shaped haemorrhage. Landecho et al evaluated a series of 27 patients with retinal fundoscopy, OCT and OCTA with moderate COVID-19 infection at 14 days after hospital discharge and reported the presence of CWS in 22%. 29
      Pirraglia et al examined 46 patients with severe pneumonia (mean age 70 years) during the acute phase. Eye examination was performed after a median of 21.5 days from hospitalization with bedside evaluation using direct and indirect ophthalmoscopy and a handheld fundus camera. The reported ocular findings included one cases of chorioretinitis thought to be due to fungal infection. There were other eyes with retinal findings but the authors had ascribed these to ‘hypertensive retinopathy (9.3%) and diabetic retinopathy (2.3%) but concluded absence of retinal involvement in SARS-CoV-2. 34 Marihno et al reported presence of CWS and microhemorrhages detected on color fundus photography and red free imaging in 4 of 12 patients with mild COVID-19 infection examined 11-33 days after symptom onset. 13 Caporossi et al, described the retinal findings a cohort of patients (n=28 eyes) with adult respiratory distress syndrome (ARDS) managed in an intensive care unit and found that 28.6% had a variety of retinal findings including Intraretinal microvascular abnormalities, arterial saccular dilatation, cotton wool spots and micro haemorrhages.36
      Individual case reports
      Twelve published case reports evaluated fundus and/or OCT findings and reported abnormalities in 10 patients. 37-46 Majority of these cases were symptomatic and presented with blurred vision or scotoma. In 4 cases, COVID-19 diagnosis was made as a result of systemic investigation for the ocular abnormality. 39, 42, 45, 46 There were 4 cases with retinal venous occlusion. 38, 41, 45, 46 Bilateral CWS and corresponding NFL infarct on OCT were reported in 2 cases receiving oxygen therapy. 37, 40 A further case presenting with sudden onset of scotoma was found to have CWS and evidence of paracentral acute middle maculopathy (PAMM) on OCT. 39 In the remaining 4 cases, OCT showed evidence of PAMM (3 cases), acute macular neuroretinopathy (AMN) (1 case) and GCIPL band.43, 44
      Discussion
      Ocular involvement associated with SARS-CoV-2 infection in the anterior segment has been well recognized. However, evidence regarding posterior segment involvement has been inconsistently reported. Marinho et al first reported retinal micro-haemorrhages and CWS and hyper-reflective plaques in the GC-ILP layers in a series of 12 healthcare workers with COVID-19 infection.13 However, multiple authors have highlighted how the OCT features initially described as COVID-19-related were simply reflections from normal retinal vasculature.14-16 Nonetheless, a number of subsequent reports of retinal micro-vasculopathy have been published and are summarized in this review. The most common retinal features described include CWS, micro-haemorrhages and venous tortuosity. (Figure 5) The pooled analysis of the literature to date show that COVID-19 infection is associated with an 8.86 fold retinal micro-vasculopathy prevalence. This is further supported the pooled analysis showing reduced parafoveal VD and increase FAZ in eyes of subjects with COVID-19 infection compared to non-infected controls. Taken together, our findings suggest that COVID-19 infection appear to result in sub clinical microvascular damage which manifest in the retina micro circulation (detected on OCTA) and is a continuation of a spectrum that can result in clinically detectable features of micro-vasculopathy (as seen as retinal hemorrhages and cotton wool spots).
      Figure 5:
      Figure 5flame haemorrhage (white arrows) and cotton wool spots (white circle) noted on color fundus photograph of a patient with COVID-19
      A significant challenge in the interpretation of these findings is the potential imbalance between preexisting medical conditions in patients with COVID-19 infections and controls. Patients tend to be older and had significantly more co-morbidities such as hypertension and diabetes. Nonetheless, the inclusion of controls has significantly improved the validity of retina micro-vasculopathy as an ocular feature of COVID-19. Among the 263 controls included in published studies, none had CWS and only 2 had micro-haemorrhages. In our pooled analysis, although it was still not possible to fully adjust for differences in patient demographics, the frequency of CWS was significantly higher in cases than in controls. The frequency of micro-haemorrhages was numerically higher but did not achieve statistically significant.
      Based on the current evidence that COVID-19 may manifest as retinal micro-vasculopathy in a subgroup of infected persons, we suggest that in addition to clinical examination, OCTA, with its ability to assess the retina micro-vasculature to a high degree of accuracy, be considered the imaging modality of choice when assessing the posterior segment in this condition. However, there is currently a lack of standardized OCTA-based parameters for comparative studies. We suggest that future studies related to this condition report on two aspects of OCTA. First, perfusion characteristics such as perfused pixel area density (also known as vessel density). This metric is calculated by dividing the area of perfused pixels (often denoted as white pixels) by the area of the region of interest (ROI). Other metrics for perfusion may include perfused pixel length density (also known as skeletonized vessel density). This metric is derived by converting all vessels to a single pixel width and dividing the length of the pixels by the ROI. Non-perfusion characteristics should also be assessed. This may be an assessment of the foveal avascular zone (FAZ) in terms of its area, circularity, or diameter. In subtle cases of micro-vasculopathy, the FAZ may remain relatively intact, hence other metrics of non-perfusion like assessing spaces between vessels may be used. These include intercapillary areas quantified by the areas of non-perfusion (black pixels) or percent area of nonperfusion, which essentially is the ration of areas of non-perfusion to area of ROI.47, 48
      Inconsistency in reported findings among COVID-19 patients may also be related to variations in the time of eye examination, severity of infection, and method of detection. 29, 34 The timing of eye examination varied considerably between published studies, with some reporting as early as 2 weeks after diagnosis of COVID-19, while others were performed at 30- 88 days after diagnosis. For hospitalized patients, eye examination were carried out much later after recovery and discharge. These differences may explain in part some of the inconsistencies in the frequency of abnormal findings. The variable severity of COVID-19 is another potential confounder. Several studies suggested patients with moderate or severe disease had more retinal vasculature changes than controls or patients with mild infection. Patients with severe COVID-19 are known to have more marked disturbance in blood parameters and are therefore at higher risk of systemic complications, including hypertension and thrombotic events.49 These patients are also more likely to require invasive ventilation and anticoagulant therapy. The microvascular changes in the retina may be, at least in part, a result of these treatments rather than COVID-19 itself. Conversely, changes in the retinal vasculature were also seen in cases with mild symptoms who did not require hospitalization and might have been considered fully recovered in the conventional sense. 17, 21, 35 Finally, cases who were severely ill were more likely to have been examined at the bedside with handheld devices. It is possible that detection rate could have been affected due to suboptimal examination conditions. 33, 34
      The mechanism through which SARS-CoV-2 may affect the retinal vasculature remains poorly understood. It is recognized that ACE-2 receptors which are involved in transmission of SARS-CoV-2 are abundant in the retina and choroid. 50 In keeping with the reduction in vessel density in in vivo studies, severely reduced microvascular density has also been reported in retina flat mount from donor eyes from COVID subjects compared to controls, which has led some investigators to propose direct effect of virus infection on endothelial cell damage. 51, 52 However, the detection of virus within the retina in post-mortem studies has been inconsistent. In addition to direct effects, hypercoagulation and vasculopathy may also lead to the observed retinal findings. 53-56 In fact, fibrin microthrombi, inflammatory cells were identified in the retinal and choroidal vessels and the choriocapillaris of eyes from patients who died from COVID-19.52
      The main limitation in the analysis is the use of only case-control studies. While cohort studies would the ideal method to determine cause or effect, in the context of the COVID-19 pandemic, it would be virtually impossible for such a prospective study to be conducted. Sampling bias, confounders such as severity of the COVID-19 infection and preexisting conditions and patient characteristics such as age, hypertension, diabetes and hyperlipidemia may still be present despite best efforts to control them.
      In summary, there are cumulating evidence suggesting possible retinal microvascular sequelae in patients infected with SARS-CoV-2. While it is important to acknowledge the potential confounders mentioned above, the scale of the potential issue warrants further investigations. At the time of writing (June 2021), there are 170 million infected individuals worldwide. Assuming retinal micro-vasculopathy develops in 10% of infected persons, this will translate into a substantial cohort. While majority of infected persons with mild symptoms may appear to have fully recovered, the longitudinal course of the retinal changes is still unknown. However, if these retinal signs persist or progress, coupled with aging and co-existence of further common systemic co-morbidities such as hypertension, hyperlipidemia and diabetes, could place these subjects at higher risk of retinal complications and visual loss. Further prospectively designed studies with large cohorts that adjust for significant confounders should be carried out to ascertain the risk of micro vasculopathy and whether these are associated with longitudinal functional deficits.
      Financial Support: “National Medical Research Council Singapore Open Fund Large Collaborative Grant: NMRC/LCG/004/2018.”
      COVID_REVIEW_precis
      This review summarises the currently available evidence on the prevalence of retina retinal micro-vasculopathy due to coronavirus disease (COVID-19). Due to the large numbers affected by COVID -19, we conclude that COVID-19 retina retinal micro-vasculopathy is significant and needs to be recognized by ophthalmologist as a potential long term sequelea of the disease.
      Conflict of interest:
      Dr. Teo reports consultancy fees, honorarium, travel support and speaker fees from Bayer and Novartis outside the submitted work.
      Dr Staurenghi reports consultation fee from Heidelberg Engineering,Centervue, Carl Zeiss Apellis, Allergan, Bayer, Boheringer, Genentech, Novartis, Roche, Chengdu Kanghong Biotechnology Co; grant support from Heidelberg Engineering, Optos, Optovue, Quantel Medical, Centervue, Carl Zeiss Meditec, Nidek, Topcon; lecture fee from Heidelberg Engineering, Carl Zeiss Meditec, Nidek, Bayer, Novartis, Roche outside the submitted work.
      Dr. Invernizzi reports consultancy fees, grants, travel support and speaker fees from Bayer, Allergan and Novartis outside the submitted work.
      Dr. Cheung reports non-financial support from Bayer during the conduct of the study; grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Novartis, grants from Roche, grants from GlaxoSmith Kline, non-financial support from Allergan, non-financial support from Topcon, outside the submitted work.
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      Appendix. Supplementary materials