Abstract
Purpose
This study investigated changes in retinal vessel density in macular and papillary regions in post-SARS-CoV-2 pneumonia patients by means of optical coherence tomography angiography (OCTA).
Design
Prospective, observational, cohort study.
Methods
Forty eyes of 40 patients (mean age: 49.7 ± 12.6 years old) post-SARS-CoV-2 infection and 40 healthy subjects were enrolled in this study. COVID-19 patients had to be fully recovered from COVID-19 pneumonia and were evaluated 6 months after COVID-19 infection. The primary outcome resulted from OCTA studies of the following vascular structures: vessel density (VD) in the retinal superficial capillary plexus (SCP), deep capillary plexus (DCP), and radial peripapillary capillaries (RPC) compared to those of controls. Structural spectral domain (SD)-OCT parameters were also evaluated: ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL).
Results
The patients showed a significant reduction in VD of the SCP in whole images and in the DCP in all sectors compared to those in healthy subjects ( P <.05). COVID-19 patients featured a reduced VD of the RPC compared to that in controls ( P <.001). No differences were found in the GCC, whereas the RNFL was reduced in the COVID-19 group compared to that in controls ( P = .012). Significant correlations were found between the RNFL and VD of the SCP, DCP, RPC, and FAZ area in the COVID-19 group ( P <.05).
Conclusions
OCTA showed retinal vascular changes in subjects fully recovered from COVID-19 pneumonia. These findings could be a consequence of a thrombotic microangiopathy that affected retinal structures as well as other systemic organs. OCTA could represent a valid, noninvasive biomarker of early vascular dysfunction after SARS-CoV-2 infection.
S ince December 2019, the SARS-CoV-2 outbreak has been a dramatic issue all over the world. On March 11, 2020, the World Health Organization declared a pandemic. All countries have been tremendously affected, and all health care systems have been overwhelmed by this calamity. To date, no effective therapy has been developed, and there is no clue as to whether a future vaccine will be able to stop it.
This infection can be completely asymptomatic or it can involve several organs and tissues, eyes included. A hypercoagulable state leading to thromboembolic events and disseminated intravascular coagulation has been observed in many critical patients. , Recent research has demonstrated diffuse endothelial damage that causes ischemic injury to different regions of the body. Such an impairment of the microcirculatory system may lead to functional disorders in multiple organs. ,
Ocular implications have not been fully studied. Non specific retinal signs, such as microhemorrhages, vein dilation, cotton-wool spots, and flame-shaped hemorrhages, have been reported in many recent studies. However, it has not been possible to clearly establish whether these signs were secondary to COVID-19 infection or just incidental findings, given the high presence of comorbidities in the general population. Optical coherence tomography angiography (OCTA), a new non invasive imaging technique, may provide qualitative and quantitative features of retinal and choroidal vascularization and could monitor the changes of vascular perfusion in patients with COVID-19 infection. ,
This pilot study evaluated retinal vessel densities (VD) in patients who fully recovered from COVID-19 pneumonia and compared those findings with densities in healthy controls.
METHODS
The present study was a prospective, observational, cohort study. The study protocol was registered on clinicaltrial.gov (OCTA Study: Retinal Vascular Changes in Patients With SARS-CoV-2 Infection; NCT04601012). The study adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board. Written informed consent was obtained from all subjects enrolled in the study.
Consecutive patients who had been hospitalized with COVID-19 pneumonia and had fully recovered from the infection were referred after 6 months from discharge to the Eye Clinic of the University of Naples “Federico II” in October 2020 and were assessed for eligibility. The following inclusion criteria had to be satisfied to be enrolled: a) a history of hospital admission for COVID-19 pneumonia, classified as moderate illness, not requiring supplemental oxygen; b) a full recovery; c) 2 consecutive upper respiratory tract samples negative for viral nucleic acid. Moderate illness was defined as evidence of disease affecting the lower respiratory tract with an Sp o 2 ≥94%, not requiring administration of supplemental oxygen. Exclusion criteria were congenital eye disease, high myopia and high hyperopia (greater than 6 diopters), retinal vascular diseases, macular diseases, previous ocular surgery except uneventful cataract surgery, history of other ocular disorders, or significant lens opacity to avoid low-quality OCTA images. All subjects with a history of stroke, blood disorders, diabetes, uncontrolled hypertension, and neurodegenerative disease were also excluded. Each patient enrolled in the COVID-19 group was age and sex matched with a healthy control. Each subject underwent a complete ocular assessment including best-corrected visual acuity (BCVA) measurement, slit-lamp biomicroscopy, Goldmann applanation tonometry, and dilated fundus examination. Snellen BCVA measurements were based on the Early Treatment Diabetic Retinopathy Study (ETDRS) charts (converted into logMAR for statistical analysis). Spectral domain-OCT (SD-OCT) and OCTA were performed by 2 independent observers (G.C. and D.M.) who carefully reviewed the OCTA and SD-OCT scans to confirm accurate retinal layer segmentation. Only 1 eye was randomly selected for each participant and included in the analysis.
The primary outcome of this study was the vessel density of macular and papillary regions on OCTA in the COVID-19 group compared with those in the control group. Foveal avascular zone, SD-OCT parameters, such as ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL), were considered secondary outcome measurements, as well as clinical variables, including BCVA and retinal findings.
Spectral Domain Optical Coherence Tomography
All patients were examined using SD-OCT (software RTVue XR version 2017.1.0.151, Optovue Inc., Fremont, California, USA). The optic nerve head (ONH) analysis measurements of the disc area, the rim area, and the cup-to-disc ratio were used to assess the RNFL thickness, calculated along a 3.45-mm diameter circle around the optic disc. The GCC thickness was obtained from a 7 × 7-mm grid of the macula centered 1 mm temporal to the fovea. The GCC thickness is the distance from the internal limiting membrane to the outer boundary of the inner plexiform layer.
Optical Coherence Tomography Angiography
All subjects underwent OCTA scanning. (Optovue Angiovue System, software ReVue XR version 2017.1.0.151, Optovue Inc., Fremont, California, USA). The system is based on a split-spectrum amplitude decorrelation algorithm. The OCTA analysis divided the macular region into whole image, fovea, and parafovea in each vascular network of the retina, according to the ETDRS classification of diabetic retinopathy. The software (AngioAnalytic) automatically calculated the vessel density in different retinal vascular networks: superficial capillary plexus (SCP) and deep capillary plexus (DCP) in a 6 × 6-mm quadrant scan centered on the fovea. Moreover, the software automatically calculated the foveal avascular zone (FAZ) area in the full retinal plexus. The VD of the radial peripapillary capillary plexus (RPC), analyzing the whole papillary region, inside the disc and peripapillary region with an area scan of 4.5 × 4.5-mm, was automatically calculated by the AngioVue disc mode.
The OCTA device included the 3-dimensional (3D) projection artifact removal (PAR) algorithm to remove projection artifacts for improving depth resolution on an OCTA signal and then distinguishing vascular plexus-specific features. Each OCTA scan underwent automatic scan quality (1~10), values ≥6 were accepted. OCTA images with a signal strength index (SSI) less than 80, and residual motion artifacts were excluded from the analysis.
Statistical Analysis
Statistical analysis was performed using Statistical Package for Social Sciences version 25 software (SPSS, Chicago, Illinois, USA) for Windows (Microsoft, Redmond, Washington, USA). The χ 2 test was used to determine differences in terms of sex. Student t -test analysis for independent samples was used to compare structural SD-OCT with OCTA parameters between patients and controls. The multiple linear regression model was used to evaluate the relationship between OCT and OCTA parameters in the post-COVID-19 group. The agreement between 2 observers in the measurement of SD-OCT and OCTA parameters was assessed using the intraclass correlation coefficient. A P value of <.05 was considered statistically significant.
RESULTS
A total of 40 eyes of 40 patients were included in the COVID-19 group (mean age: 49.7 ± 12.6; 11 females and 29 males) and a total of 40 eyes of 40 age- and sex-matched healthy subjects in the control group (mean age: 48.6 ± 12.2). Demographic and ocular characteristics of enrolled patients are reported in Table 1 . Mean BCVA was 0.06 ± 0.06 logMAR (Snellen: 20/23) and 0.05 ± 0.05 logMAR (Snellen: 20/22) in the COVID-19 group and the control group, respectively. All patients included in the COVID-19 group presented unremarkable ocular examinations on the slit lamp as well as normal fundus examination. None of the patients complained of eye symptoms at the time of enrollment, and no participant had a history of eye symptoms during hospital admission for COVID-19 pneumonia. All patients were phakic in both the COVID-19 and the control groups. Recovery time from SARS-CoV-2 infection, confirmed by 2 consecutive negative oropharyngeal swabs, was 4.1 ± 1.3 months. There was no significant correlation between OCTA parameters and recovery time after SARS-CoV-2 infection ( P = .732).
| COVID-19 Group | Control Group | |
|---|---|---|
| Number of eyes | 40.0 | 40.0 |
| Males/females | 29.0/11.0 | .029/11.0 |
| Age, yrs | 49.7 ± 12.6 | 48.6 ± 12.2 |
| BCVA, logMAR (Snellen) | 0.06 ± 0.06 (20/23) | 0.05 ± 0.05 (20/22) |
| Axial length, mm | 23.3 ± 0.3 | 23.2 ± 0.5 |
| IOP, mm Hg | 13.9 ± 2.2 | 13.6 ± 2.3 |
| SSI | 83.5 ± 2.2 | 84.1 ± 2.1 |
| Recovery time from SARS-CoV-2 infection, months | 4.1 ± 1.3 | – |
On OCTA imaging, SSI values were comparable between the 2 groups ( P = .921). SCP vascular density was decreased in the COVID-19 group compared to that in the control group only in the whole image ( P = .038). DCP vascular density showed a significant reduction in all macular sectors in the COVID-19 group compared to that in the control group ( P = .029; P = .016; and P = .027 in the whole image, parafovea, and fovea, respectively). A significant reduction of the RCP vessel density in the whole image was found in the COVID-19 group compared to that in the control group ( P <.001) ( Table 2 , Figure 1 ). The FAZ area did not show any significant changes between the 2 study groups ( P >.05) ( Table 2 , Figure 1 ). The structural SD-OCT showed no significant differences in GCC averages ( P = .309), whereas the RNFL averages were decreased ( P = .012) in the COVID-19 group compared to those in the control group ( Table 2 , Figure 1 ).
| Post COVID-19 Group | Healthy Subjects | P Value | |
|---|---|---|---|
| OCTA parameters | |||
| SCP, % | |||
| Whole image | 48.86 ± 4.32 | 50.94 ± 4.49 | .038 |
| Parafovea | 52.34 ± 5.29 | 52.59 ± 6.72 | .858 |
| Fovea | 25.21 ± 5.28 | 25.30 ± 4.22 | .929 |
| DCP, % | |||
| Whole image | 52.42 ± 7.18 | 55.79 ± 6.35 | .029 |
| Parafovea | 56.27 ± 6.31 | 59.72 ± 6.20 | .016 |
| Fovea | 44.08 ± 7.16 | 47.80 ± 7.57 | .027 |
| RPC, % | |||
| Whole image | 46.43 ± 4.01 | 50.44 ± 4.67 | <.001 |
| Inside disc | 52.40 ± 3.42 | 53.61 ± 4.34 | .171 |
| Peripapillary | 48.02 ± 4.80 | 50.02 ± 5.03 | .073 |
| FAZ area, mm 2 | 0.225 ± 0.07 | 0.223 ± 0.07 | .883 |
| SD-OCT parameters | |||
| GCC average, µm | 99.17 ± 6.81 | 100.77 ± 7.15 | .309 |
| RNFL average, µm | 98.27 ± 6.64 | 101.92 ± 6.06 | .012 |
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