COVID-19 (novel coronavirus infection)-associated retinopathy is a general term for a group of vascular and inflammatory diseases of the posterior segment that occur following SARS-CoV-2 infection.
It mainly manifests as vascular events, and retinal vein occlusion (RVO), retinal artery occlusion (RAO), cotton wool spots, punctate hemorrhages, and paracentral acute middle maculopathy (PAMM) have been reported. 1) Anterior segment findings (such as conjunctivitis) are relatively well known, but posterior segment findings including the retina are less common and more diverse. 1)
The multicenter prospective study SERPICO-19 conducted in Italy is a representative cohort study comparing retinal findings of hospitalized COVID-19 patients with healthy controls. Furthermore, a 2022 systematic review integrated 21 studies, contributing to the understanding of the epidemiology and pathophysiology of retinal lesions. 1)
The SERPICO-19 study confirmed that findings such as hemorrhages, white spots, and venous dilation improved after 6 months. 1) However, if vascular occlusion such as RVO or RAO occurs, visual impact may persist.
Many retinal lesions are asymptomatic or cause only mild symptoms. When vascular occlusion occurs, the following symptoms may appear.
The SERPICO-19 study (COVID-19 inpatients vs. healthy controls) reported the following frequencies of findings. 1)
| Finding | COVID-19 patients | Healthy controls | Significance |
|---|---|---|---|
| Retinal hemorrhage | 9.25% | 1.5% | p=0.01 |
| Cotton wool spots | 7.4% | 0% | Significant |
| Venous dilation | 27.7% | 3.0% | Significant |
The main categories of COVID-19-related retinopathy are shown below.
Vascular occlusive
Retinal vein occlusion (RVO): Relatively young, with a median age of 39 years. Only 36% have cardiovascular risk factors. 1)
Retinal artery occlusion (RAO): Elevated D-dimer is found in 61%, suggesting thrombosis as the main mechanism. 1)
Paracentral acute middle maculopathy (PAMM): Macular lesion due to ischemia of the deep capillary plexus. Confirmed by OCT.
Inflammatory/Other
Cotton wool spots: Ischemic infarction of the nerve fiber layer. Found in 7.4% of COVID-19 patients. 1)
Central serous chorioretinopathy (CSCR): Often resolves spontaneously.
Fungal endophthalmitis: Risk increases with immunosuppression (e.g., high-dose steroids) associated with severe COVID-19.
MIS-C-associated uveitis: Ocular complication in pediatric multisystem inflammatory syndrome associated with COVID-19. 2)
Studies of retinal lesions in COVID-19 have reported that retinal vein diameter shows a positive correlation with COVID-19 severity. 1)
Uveitis has been reported in 5 patients with pediatric multisystem inflammatory syndrome (MIS-C), with 60% having ocular surface abnormalities. 2) If ocular symptoms occur after pediatric COVID-19, ophthalmologic evaluation is necessary.
SARS-CoV-2 uses the ACE2 (angiotensin-converting enzyme 2) receptor and TMPRSS2 (serine protease) for cell entry. 1) In the retina, ACE2 is expressed in the ganglion cell layer, inner nuclear layer (INL), outer nuclear layer (ONL), and capillary endothelial cells, providing an anatomical basis for direct viral invasion and lesion formation. 1)
① Hypercoagulability mechanism: Loss of ACE2 leads to increased angiotensin II (AngII), promoting vasoconstriction, inflammation, and coagulation. 1) Elevated D-dimer and fibrinogen increase thrombotic risk, causing retinal vascular occlusion.
② Cytokine storm: Massive release of inflammatory cytokines such as TNF-α and IL-6 damages retinal vascular endothelium. 1) Endothelial damage and microthrombosis collectively worsen retinal circulation.
Underlying conditions such as hypertension and diabetes may increase the risk of COVID-19-related retinal lesions. 1) However, many young patients with retinal vein occlusion lack these risk factors, and COVID-19 infection itself may be an independent risk factor.
The diagnosis of COVID-19-related retinopathy is made by combining ophthalmic examinations with systemic coagulation and inflammatory markers.
The following examination methods are used for diagnosis.
| Examination | Purpose | Target Lesions |
|---|---|---|
| Fundus examination | Confirmation of hemorrhage, white spots, and occlusion | General |
| OCT | Evaluation of retinal layer structure | PAMM, macular edema |
| Fluorescein angiography (FA) | Vascular occlusion and increased vascular permeability | Retinal vein occlusion, RAO |
Evaluation of coagulation and inflammatory markers is important for understanding the pathophysiology of COVID-19-related retinal vascular occlusion. 1)
Standard treatment for COVID-19-related retinal lesions has not been established, and symptomatic therapy based on the nature of each lesion is the mainstay.
Retinal vein occlusion with macular edema is an indication for anti-VEGF treatment regardless of age. The median age for COVID-19-related retinal vein occlusion is 39 years, which is young, and cases have been reported even in those without cardiovascular risk factors. 1) The need for treatment is determined by the impact on the macula.
SARS-CoV-2 nucleic acid was detected in 21% of retinal tissues from autopsied COVID-19 patients. 1) This is an important finding indicating that the virus can directly invade the retina. ACE2 expression sites in the retina (ganglion cell layer, INL, ONL, capillary endothelium) become targets of the virus. 1)
Histological studies of COVID-19 patients have confirmed damage to retinal capillary endothelium and microthrombi. 1) Endothelial damage is caused by both hypercoagulability and cytokine storm, leading to impaired retinal microcirculation.
Retinal involvement in COVID-19 is conceptualized as the ECOR (Eye as Complement to fOldRs) model. 1) In this model, the pathology progresses in two phases:
Phase 1 (acute phase): Acute vasculitis and endothelial damage due to cytokine storm. Corresponds to the stage where retinal hemorrhages and cotton wool spots occur.
Phase 2 (prolonged/post-acute phase): Persistent hypercoagulability and fibrotic tendency. This is the stage where vascular occlusion events such as retinal vein occlusion and RAO can occur.
① Hypercoagulability: Loss of ACE2 function due to SARS-CoV-2 disrupts the renin-angiotensin system balance, leading to excessive AngII. 1) AngII promotes vascular endothelial activation, tissue factor expression, and platelet activation, measured as elevated D-dimer and fibrinogen.
② Cytokine Storm: Massive release of inflammatory cytokines such as TNF-α, IL-6, and IL-1β increases vascular endothelial permeability. 1) Increased leukocyte adhesion to the vascular endothelium combined with microthrombus formation leads to retinal capillary occlusion and ischemia.
Most current knowledge is based on retrospective studies and small observational studies. 1) Larger prospective cohort studies are needed to clarify the exact prevalence, risk factors, and prognosis of COVID-19-related retinal lesions. 1)
It has been suggested that the mechanisms of COVID-19-related retinal vein occlusion and RAO may differ in their relative contributions. 1) In arterial occlusion, hypercoagulability (elevated D-dimer) is prominent, while venous occlusion is thought to involve endothelial inflammation and blood stasis, but the exact pathophysiological differences remain unclear. 1)
In the 6-month follow-up of the SERPICO-19 study, many of the acute-phase findings such as hemorrhage, cotton-wool spots, and venous dilation improved. 1) However, further data are needed on long-term prognosis beyond the observation period.
Changes in retinal microvasculature have been reported in Long COVID patients, and evaluation using optical coherence tomography angiography (OCTA) is being studied. Whether the retina can serve as a “window” to systemic microcirculatory dysfunction for assessing sequelae is a topic for future research.
