key: cord-0733583-7diw0d7e
authors: Hepokur, Mustafa; Gunes, Medine; Durmus, Ebubekir; Aykut, Veysel; Esen, Fehim; Oguz, Halit
title: Long-term follow up of choroidal changes following COVID-19 infection: analysis of choroidal thickness and choroidal vascularity index
date: 2021-07-05
journal: Can J Ophthalmol
DOI: 10.1016/j.jcjo.2021.06.020
sha: fee52ab88f4871b01135043034fb22eb5d74699f
doc_id: 733583
cord_uid: 7diw0d7e

PURPOSE: The aim of this study was to investigate subclinical choroidal involvement in patients with systemic COVID-19 infection and evaluate its long-term course. MATERIALS AND METHODS: This prospective, longitudinal study included 32 eyes of 16 COVID-19 patients and 34 eyes of 17 age-matched healthy control subjects. All of the participants had a detailed ophthalmological including visual acuity assessment, slit lamp examination and indirect ophthalmoscopy. Enhanced depth optical coherence tomography imaging of the posterior pole and peripapillary region was performed at the early (days 15-40) and late (9(th) month) postinfectious periods. Choroidal vascularity index (CVI) was calculated using Image-J software. RESULTS: None of the patients had any examination finding associated with the ocular involvement of COVID-19. Subfoveal choroidal thickness (SFCT) significantly decreased at the early postinfectious period compared to healthy controls (p=0.045). SFCT significantly increased at the late postinfectious period compared to early (p=0.002) and the difference between the patients and controls became statistically insignificant (p=0.362). There was a similar trend for the peripapillary choroidal thickness measurements. CVI remained unchanged (p=0.721) despite the significant decrease in SFCT and total choroidal area (TCA, p=0.042), indicating that this decrease occurred both in choroidal stroma and blood vessels. CVI remained unchanged in the late postinfectious period (p=0.575) compared to the early period, indicating that recovery occurred in the entire choroidal tissue. CONCLUSION: This study demonstrated that choroidal thickness was reduced in all measured areas and this decrease affected all choroidal layers. This choroidopathy was reversible and recovered at the 9(th) postinfectious month.

A new coronavirus strain (severe acute respiratory syndrome -coronavirus -2, SARS-CoV-2) emerged from Wuhan China in December 2019 and caused a new disease called COVID-19, which was later declared as a pandemic by the World Health Organization in March 2020 1 .

COVID-19 is a multisystem disease that can cause respiratory, central nervous system, gastrointestinal, renal, hepatic, olfactory, and ocular involvement 2, 3 . Although respiratory system involvement is the leading cause of mortality, hematological complications of the disease can result in severe morbidity or even mortality 2 . Prolonged prothrombin time, and increased d-dimer levels are relatively common findings in these patients 4 .There is a tendency for hematological complications in critically ill patients and complications such as pulmonary embolism, myocardial infarction, ischemic stroke, deep vein thrombosis, and systemic arterial embolism are encountered in this patient population more commonly 5, 6 . Patients that develop acute respiratory distress syndrome (ARDS) during COVID-19 pneumonia have also a propensity for thrombotic complications compared to ARDS patients without COVID-19 7 . In addition to these systemic complications, this pro-thrombotic status caused by COVID-19 can also result in retinal vascular occlusions and subsequent retinal damage 1 .

SARS-CoV-2 enters human cells using the angiotensin converting enzyme-2 (ACE-2) receptor, and this receptor is expressed on some of the cells in human retina, ciliary body, and choroid 8 . Postmortem evaluation of the retinas of COVID-19 patients reveled that SARS-CoV-2 could be isolated both from the ocular surface and intraocular tissues such as retina 9 . Human choroid consists of blood vessels, melanocytes, fibroblasts, and connective tissue 10 . The choroidal vessels are responsible for the oxygenation and nutrition of the outer third of the retina and photoreceptor cells.

The evaluation of the choroid is relatively hard because it shrinks when systemic circulation stops. Enhanced depth imaging (EDI) mode of the spectral domain optical coherence tomography (SD-OCT) instruments allowed us to evaluate choroidal anatomy with in vivo images that are produced with this non-invasive, inexpensive, reproducible imaging method that delivers high resolution images 11 . Choroidal thickness in different regions of the eye can be evaluated using this high resolution images 12 and structural properties of choroid (such as vascularity) can also be further described with automated software analyses 13 .

Certain antigens of SARS-CoV-2 virus has also molecular similarities with certain retinal structures 14 and can cause thrombotic complications in ocular blood vessels 15 . Therefore, we suspected that there might be a subclinical choroidal involvement in these patients and wanted to study long-term changes in choroidal thickness and structure following COVID-19 infection.

This prospective, longitudinal study included 32 eyes of 16 healthcare professionals that recovered from COVID-19 (COVID-19 group) and 34 eyes of 17 age-matched healthy control subjects (Control group). All of the COVID-19 patients were followed at the Istanbul Medeniyet University Goztepe Prof. Dr. Suleyman Yalcın City Hospital. Only healthcare professionals who recovered from COVID-19 and did not have ocular symptoms during the disease duration were included to the study. The patients with a history of intraocular surgery, retinal disease, uveitis, retinal laser surgery for any reason, high intraocular pressure or glaucoma were excluded from the study. The statistical analyses were performed using SPSS Statistics for Windows version 21 (IBM Corp., Chicago, IL, USA). The normal distribution of the data was evaluated by performing the Shapiro Wilk test. Data with normal distribution were evaluated with Student's t-test and data without normal distribution were evaluated with the Mann-Whitney U test. Repeated measures were compared with paired-samples t-test for data with normal distribution and a Wilcoxon test for data without normal distribution. P values below <0.05 were accepted as statistically significant. Table 1 .

Choroidal thickness was significantly reduced at the early postinfectious period in the COVID-19 group compared to the controls in all subfoveal locations except for T 500 . There was also a similar trend towards decline in T 500 location. Choroidal thickness was measured in another retinal region to better understand structural changes in the choroid following COVID-19 infection.

Choroidal thickness measurements of the peripapillary region confirmed the above-mentioned observations and was significantly reduced in the superotemporal and temporal regions (p=0.020 and p=0.017, respectively) in the patient group at the early postinfectious period, while there was also an insignificant trend towards decline in the remaining regions for PPCT. The difference in SFCT and PPCT results between the patient and control groups became statistically insignificant at the late postinfectious period, while an insignificant trend towards reduced choroidal thickness remained at most of the studied regions in the patient group. Detailed analysis of choroidal thickness changes between the patients and controls are given at Table 2 .

Longitudinal comparative analysis of the structural changes was also performed to better Cotton wool spots are also believed to be a component of the acute phase of the disease (during which the patients are usually quarantined and don't have access to ocular examination) and around 22% of these patients were reported to have cotton wool spots at the active phase of the disease 23 . Therefore retinal blood vessel involvement is a relatively underdiagnosed and well-established complication of COVID-19. Some researchers even suggest that these lesions might serve as biomarkers to predict patients that have prothrombotic tendencies and will need antiaggregant treatment 23 . The current study suggested that these ocular vascular changes in COVID-19 were not limited to the retina and choroid was also affected by the inflammation and prothrombotic state induced by the disease. Choroidal changes are also observed at the earlier phases of the disease and tend to resolve over time.

COVID-19 can also cause other rare ocular complication including optic neuritis, sudden vision loss, Miller Fisher syndrome, and cranial neuropathies 24 . Optic neuritis secondary to COVID-19 is suggested to be a secondary immune reaction and not a direct vascular pathology 25 . Peripapillary RNFL decreases after optic neuritis attacks in other diseases such as multiple sclerosis 26 This study had certain limitations. The sample size of the study was relatively small but sufficient to demonstrate statistically significant changes in the choroidal structure of these patients.

None of the patients in the study had severe COVID-19 infection, which might cause more vascular damage or prominent ocular involvement. All of the participants were healthcare workers. The exposure of the healthcare workers to the virus might be more and their viral load might have been higher compared to the general population infected with the disease. A strength of this study was that we started this study at the early phase of the pandemic when the role of the antithrombotic prophylaxis was unknown in COVID-19 management. Therefore, none of the participants used anticoagulant / antithrombotic prophylaxis or treatment and we could observe the natural course of the disease for the evaluation of choroidal involvement. Indocyanine green dye is not commercially available in Turkey right now and we were unfortunately unable to evaluate COVID-19 associated choroidopathy in these patients with indocyanine green angiography.

In conclusion, this study demonstrated long term evolution of choroidopathy following 

Retinal findings in hospitalised patients with severe COVID-19

Extra-respiratory manifestations of COVID-19

SARS-CoV-2 Presence in the Saliva, Tears, and Cerumen of COVID-19 Patients

Hematological findings and complications of COVID-19

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Therapeutic targets of reninangiotensin system in ocular disorders

Detection of SARS-CoV-2 in Human Retinal Biopsies of Deceased COVID-19 Patients

The multifunctional choroid

Optical coherence tomography: imaging of the choroid and beyond

Decreased subfoveal choroidal thickness and failure of emmetropisation in patients with oculocutaneous albinism

The effect of optic neuritis attacks on choroidal vascularity index in patients with multiple sclerosis

Using bioinformatic protein sequence similarity to investigate if SARS CoV-2 infection could cause an ocular autoimmune inflammatory reactions?

Pulmonary Thrombosis and Thromboembolism in COVID-19

Evaluation of changes in choroidal vascularity during acute anterior uveitis attack in patients with ankylosing spondylitis by using binarization of EDI-optical coherence tomography images

COVID-19 and its implications for thrombosis and