Long-term retinal dysfunction following COVID-19 infection: a one-year prospective observational study

Abstract

Background

COVID-19, caused by SARS-CoV-2, may lead to long-term retinal changes. Visual symptoms and retinal alterations have been reported in Long COVID; however, the available evidence remains limited. Swept-source OCT (SS-OCT) and OCT angiography (SS-OCTA) enable non-invasive evaluation of retinal structure and microvasculature. This study aimed to assess retinal alterations before and one year after COVID-19 using SS-OCT and SS-OCTA in a longitudinal design.

Methods

This prospective longitudinal study was conducted at West China Hospital, Sichuan University. All enrolled participants underwent SS-OCT and SS-OCTA before infection, and at 1 month, and 1 year after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Retinal structural and microvascular alterations were quantified using the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, including the thickness of peripheral retinal nerve fiber layer (pRNFL), ganglion cell inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer retina, and the vessel density (VD) of superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP). The foveal avascular zone (FAZ) area was measured in the inner retinal layer.

Results

A total of 44 eyes from 22 participants were analyzed (mean age: 30.59 ± 9.36 years; 17 females and 5 males). Significant reduction in thickness of pRNFL, GCIPL, and outer retina, increased thickness of INL, decreased VD of SVP, and increased VD of ICP and DCP were observed in participants one month after COVID-19 infection (All P < 0.05), which remained persistently altered one year after COVID-19 infection (All P < 0.05).

Conclusions

These findings indicate long-term retinal dysfunction following COVID-19 infection, highlighting the importance of ongoing ophthalmic monitoring. Non-invasive SS-OCT and SS-OCTA could offer valuable tools for detecting and managing retinal alterations associated with long COVID in the post-pandemic era.

Background

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, primarily affects the respiratory system, posing unprecedented challenges to healthcare systems worldwide [1]. Increasing evidence indicates that COVID-19 may lead to multi-organ complications, including significant ocular and retinal manifestations [2–5]. The long-term sequelae of COVID-19, also known as “Long COVID”, brings an increasing burden on global health over time [6]. Various organ-related symptoms have been reported among individuals experiencing Long COVID, affecting the cardiovascular, respiratory, neurological, and visual systems [6–10].

Given the unique capability of the retinal structures to visualize structures and microvasculature directly, ocular manifestations have attracted considerable attention [4, 11, 12]. Ocular symptoms, such as dry eye disease, visual disturbances, convergence insufficiency, neuro-visual deficits, retinal vascular occlusion, uveitis and eye movement dysfunctions, are reported in individuals with Long COVID [8, 13–16]. Additionally, cognitive impairment associated with Long COVID has been shown to contribute to reduced visual function indirectly [17].

Optical coherence tomography (OCT) and angiography (OCTA) have been utilized to evaluate the potential impact of COVID-19 on the visual system, especially the retina and optic nerve [18]. Previous studies have indicated that irreversible retinal alterations may occur following COVID-19 infection [19–21]. For instance, Schlick et al. reported sustained reductions in retinal microvasculature among post-COVID-19 individuals, especially those with chronic fatigue, suggesting a persistent retinal microvascular dysfunction. Significant changes in retinal thickness and vascular density, detected by swept-source OCT (SS-OCT) and OCTA (SS-OCTA), were also reported three months after COVID-19 infection [22–24]. Notably, Cennamo et al. [25] reported a significant reduction in retinal nerve fiber layer (RNFL) thickness and vessel density (VD) in both the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in participants six months after COVID-19 infection compared with healthy controls. However, no significant differences were observed in the thickness of the ganglion cell complex (GCC) [26–28]. This inconsistency may be attributed to the differences in imaging devices, follow-up duration, and the lack of self-comparative longitudinal analyses.

Currently, the long-term implications of COVID-19 on retinal structure and future ocular health require further investigation. Hence, this study aimed to assess the retinal alterations in participants before and after COVID-19 using SS-OCT and SS-OCTA and to detect the potential associations between the alterations in retinal structure and microvasculature.

Methods

Study design

This prospective longitudinal study recruited hospital staff and medical students at West China Hospital, Sichuan University, from January 2022 to January 2024. The study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University, China, and conducted according to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants.

All participants were originally recruited as healthy controls and had comprehensive documented normal ophthalmic examinations and SS-OCT/SS-OCTA imaging at our hospital prior to COVID-19 with complete records available; anyone with retinal/ocular disease was excluded. All participants had confirmed SARS-CoV-2 infection, verified by nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR) testing. The exclusion criteria included a prior history of (1) ocular conditions, such as glaucoma, pathological myopia, and macular disease; (2) systemic conditions, such as diabetes mellitus and hypertension; (3) neurological disorders, such as multiple sclerosis; (4) ocular surgery or ocular trauma, with the exception of cataract extraction and intraocular lens implantation.

All participants underwent ophthalmic evaluations, including slit-lamp biomicroscopy, best-corrected visual acuity (BCVA), intraocular pressure (IOP), axial length, SS-OCT, and SS-OCTA, before COVID-19 infection. Baseline information, including age, sex, and body mass index, were recorded. Follow-up evaluations, including slit-lamp biomicroscopy, SS-OCT, and SS-OCTA, were performed one month and one year following the onset of the initial COVID-19-related symptom. Detailed clinical data, including systemic symptoms over the follow-up period and the frequency of subsequent COVID-19 infections, were collected and analyzed.

SS-OCT and SS-OCTA

SS-OCT and SS-OCTA images were captured using the SS-OCT device (VG200; SVision Imaging), with a tunable laser at a central wavelength of 1050 nm, a scanning speed of 200,000 A-scans/s, a tissue penetration depth of 6 mm, and an axial digital resolution of 1.8 μm. All SS-OCT and SS-OCTA images were automatically segmented and quantified. An experienced ophthalmologist conducted all imaging procedures and was fully masked to clinical status and time point. The scanning modes included 3 mm × 3 mm and 6 mm × 6 mm centered on the macula, as well as 6 mm × 6 mm centered on the optic nerve head (ONH). Images with a signal strength index greater than 8/10 were included.

Outcome measurements

The primary aim was to assess alterations in retinal structure and microvasculature at one month and one year post-COVID-19 infection, including the thickness of the peripapillary RNFL (pRNFL), the ganglion cell inner plexiform layer (GCIPL), the inner nuclear layer (INL) and the outer retina and the VD of the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and DCP. Additionally, the circular index (CI) and VD of foveal avascular zone (FAZ) area on the inner retinal layer were measured within a 3 mm × 3 mm macular region. Relationships between retinal structural and microvascular alterations were also explored. All SS-OCT and SS-OCTA parameters were quantified automatically, and vitreous status was independently assessed by two ophthalmologists (M.K and G.Y).

Statistical analysis

Continuous variables were presented as means (standard deviations), and categorical variables as frequency distributions; baseline characteristics were compared using the χ² test. A generalized estimating equation (GEE) model, adjusted for inter-eye dependency, age, gender, body mass index (BMI), and symptoms, was applied to evaluate longitudinal changes in SS-OCT and SS-OCTA parameters across follow-up visits. Pearson correlation analysis was used to examine associations between the rates of change in SS-OCT and SS-OCTA parameters over the one-year period. A two-tailed P-value < 0.05 after correction was considered statistically significant. To account for multiple comparisons, Bonferroni correction was applied by dividing the significance threshold by the number of tested parameters. All statistical analyses were performed using IBM SPSS Statistics version 29.0 (SPSS Inc.), and figures were generated using R software (version 4.1.2). Post-hoc power calculation was performed using the online tool (Kane SP. Post. ClinCalc: https://clincalc.com/stats/power.aspx. Updated June 23, 2024. Accessed December 1, 2025.) for primary SS-OCT and SS-OCTA parameters to clarify detectable effect sizes at the current sample size.

Results

Study population

A total of 44 eyes of 22 participants were enrolled in this study at baseline (mean age: 30.59 ± 9.36 years; 17 females and 5 males). No participant had pre-existing retinal or ocular disease, as confirmed by prior normal ophthalmic evaluations and imaging. The demographics and clinical characteristics of the participants are summarized in Table 1. During the one-year follow-up period, 14 participants (63.64%) experienced a single COVID-19 infection, 7 participants (31.82%) experienced two infections, and 1 participant (4.54%) experienced three infections. Ocular symptoms were reported in 2 participants (9.01%), described as dry eye (1 participant, 4.53%) and ocular pain (1 participant, 4.53%). Common respiratory symptoms were noted in 18 participants (81.82%), including fever (17 participants, 77.27%) and itchy throat (16 participants, 72.73%). Neurological symptoms were reported in 9 participants (40.91%), including headache (6 participants, 27.27%) and anosmia (4 participants, 18.18%). Additional symptom details are presented in Table 1. All participants had fully recovered from COVID-19 infection at the one-year follow-up, as confirmed by negative oropharyngeal swab results. Besides, post hoc power estimates for all primary outcomes exceeded 80%.

Table 1.

Demographic and clinical characteristics of patients

Characteristic	Total
Number of patients(eyes)	22 (44)
Female (male)	15 (7)
Age, mean (SD, range)	30.59 (9.36, 24–60)
BMI, mean (SD)	21.44 (2.84)
BCVA, mean (SD)	0.00 (0.00)
IOP, mean (SD)	15.56 (1.35)
AL, mean (SD)	24.39 (1.08)
Times of infection	1.41 (0.59)
1	14 (63.64%)
2	7 (31.82%)
3	1 (4.55%)
Duration of symptoms
1–3 days	2 (9.1%)
3–7 days	16 (72.7%)
Over 7 days	4 (18.2%)
Ocular symptoms	2 (9.01%)
Cold symptoms	18 (81.82%)
Respiratory symptoms	1 (4.55%)
Circulatory symptoms	1 (4.55%)
Urinary symptoms	0 (0%)
Digestive System symptoms	1 (4.55%)
Neurological symptoms	9 (40.91%)
Endocrine symptoms	2 (9.01%)
Psychological symptoms	1 (4.55%)

BMI, body mass index; BCVA, best-corrected visual acuity (Snellen chart); COVID‐19, coronavirus disease 2019; IOP, intraocular pressure; AL, axial length

SS-OCT findings

SS-OCT results were shown in Table 2 and Figs. 1 and 2). A significant reduction in the thickness of the pRNFL was observed in both the 0–2 mm and 0–4 mm rings at 1-month and 1-year follow-ups compared with baseline (all P < 0.001). However, no significant differences were shown in the 2–4 mm ring. (P = 0.493; P = 0.320, respectively). Similarly, the GCIPL thickness significantly decreased across all regions (0–1 mm, 1–3 mm, 3–6 mm, and 0–6 mm rings) at both follow-up visits compared with baseline (all P < 0.001). However, the thickness of the INL significantly increased within the 0–1 mm, 3–6 mm, and 0–6 mm rings at the 1-month and 1-year visits compared with baseline (all P < 0.001) but showed no significant difference in the 1–3 mm ring (P = 0.651; P = 0.389, respectively). Significant thinning of the outer retina was only detected in the 0–1 mm ring at both 1-month (P < 0.001) and 1-year (P = 0.010) follow-ups compared with baseline. Overall, no significant changes in any SS-OCT parameters were noted when comparing the 1-month follow-up with the 1-year follow-up (all P > 0.05).

Table 2.

Swept - source optical coherence tomography findings in pre -, 1 - month and 1 year post - COVID-19 patients

SS-OCT parameters	Pre a	1-month b	1-year c	P Value
				All	Pre vs.1-month	Pre vs.1-year	1-mon vs. 1-year
pRNFL(µm)
0–2	480 (16.26)	439.48 (16.26)	430.72 (16.26)	< 0.001*	< 0.001*	< 0.001*	0.334
2–4	131.62 (5.06)	129.3 (5.06)	128.25 (5.06)	0.596	0.493	0.320	0.758
0–4	218.16 (7.31)	206.35 (7.31)	203.38 (7.31)	< 0.001*	0.004 *	< 0.001*	0.471
GCILP(µm)
0–1	29.3 (2.08)	27.01 (2.08)	27.1 (2.08)	< 0.001*	< 0.001*	< 0.001*	0.875
1–3	90.04 (1.49)	87.85 (1.49)	87.88 (1.49)	< 0.001*	< 0.001*	< 0.001*	0.931
3–6	60.32 (1.34)	57.83 (1.34)	57.82 (1.34)	< 0.001*	< 0.001*	< 0.001*	0.980
0–6	66.11 (1.27)	63.70 (1.27)	63.69 (1.27)	< 0.001*	< 0.001*	< 0.001*	0.979
INL(µm)
0–1	26.85 (0.60)	28.14 (0.60)	28.09 (0.60)	< 0.001*	< 0.001*	< 0.001*	0.890
1–3	43.75 (0.43)	43.68 (0.43)	43.61 (0.43)	0.690	0.651	0.389	0.682
3–6	37.44 (0.33)	38.33 (0.33)	38.24 (0.33)	< 0.001*	< 0.001*	< 0.001*	0.667
0–6	38.56 (0.32)	39.25 (0.32)	39.16 (0.32)	< 0.001*	< 0.001*	< 0.001*	0.631
Outer retina(µm)
0–1	187.59 (2.00)	184.64 (2.00)	185.66 (2.00)	< 0.001*	< 0.001*	0.010*	0.176
1–3	172.16 (1.55)	171.97 (1.55)	172.47 (1.55)	0.624	0.708	0.556	0.336
3–6	148.63 (1.48)	148.26 (1.48)	148.63 (1.48)	0.611	0.391	0.998	0.389
0–6	154.99 (1.44)	154.61 (1.44)	155.01 (1.44)	0.577	0.376	0.966	0.353

COVID-19, coronavirus disease 2019; SS‐OCT, swept‐source optical coherence tomography; pRNFL, peripheral retinal nerve fiber layers; GCIPL, ganglion cell‐inner plexus layer; INL, inner nuclear layer

P-values from χ² tests (categorical) and GEE models (continuous), with Bonferroni correction applied

^a Pre, pre-COVID-19

^b 1- month, one-month post-COVID-19

^c 1- year, one-year post-COVID-19

^*Statistically significant below P < 0.05 or adjusted P < 0.0167 (Bonferroni)

Fig. 1.

Swept-source optical coherence tomography (SS-OCT) images of the ganglion cell inner plexiform layer (GCIPL) of a patient pre-, 1 month, and 1 year after COVID-19. (A), (D), (G) SS-OCT images show the thickness of the GCIPL measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) grid in pre-, 1 month, and 1 year after COVID-19 status. (B), (E), (H), Heat map of the thickness of the GCIPL in pre-, 1 month, and 1 year after COVID-19 status. (C), (F), (I), The B-scan of the macula in pre-, 1 month, and 1 year after COVID-19 status. The automatically segmented GCIPL was marked between the blue lines

Fig. 2.

Line chart of swept-source optical coherence tomography (SS-OCT) parameters during the 1-year follow-up. Thickness changes of the ganglion cell inner plexiform layer (GCIPL) (A), inner nuclear layer (INL) (B), outer retina (C), and peripheral retinal nerve fiber layer (pRNFL) (D) are shown at different time points: before infection,1-month post-infection, and 1-year post-infection. Different colors represent different areas of the detected rings: 0–1 mm(red), 1–3 mm(blue), 3–6 mm(yellow), 0–6 mm(green). Or 0–2 mm(red), 2–4 mm(blue), 0–4 mm(yellow). Asterisk (*** P < 0.001, ** P < 0.01) indicates retinal layers with statistically significant thickness changes according to the GEE analysis

SS-OCTA findings

SS-OCTA results were shown in Table 3 and Fig. 3. The VD of SVP in the 0–1 and 1–3 mm ring was significantly decreased at the 1-month follow-up (P = 0.011; P = 0.015, respectively), and the decrease remained at 1-year follow-up in the 1–3 mm ring (P = 0.010); however, VD in the 0–1 mm ring recovered by the 1-year follow-up (P = 0.073). The VD of ICP and DCP were significantly increased during follow-up (all P < 0.001), except in the 0–1 mm ring of ICP, where no significant difference was noted during both follow-ups (P = 0.288; P = 0.487, respectively). As for the FAZ, no significant difference was found during the follow-ups when considering the area (P = 0.987; P = 0.616, respectively) or the perimeter (P = 0.245; P = 0.872, respectively). The CI of the FAZ showed no significant difference at the follow-ups (P = 0.024; P = 0.080, respectively) with Bonferroni correction applied. In contrast, the VD of FAZ demonstrated a significant reduction across follow-ups (P < 0.001; P = 0.009, respectively).

Table 3.

Swept - source optical coherence tomography angiography findings in pre -, 1 month and 1 year post - COVID-19 patients

SS-OCTA parameters	Pre a	1-month b	1-year c	P Value
				All	Pre vs.1-month	Pre vs.1-year	1-mon vs. 1-year
SVP (%)
0–1	11.99 (0.98)	10.91 (0.98)	11.23 (0.98)	0.032*	0.011*	0.073	0.450
1–3	45.09 (0.81)	43.76 (0.81)	43.68 (0.81)	0.015*	0.015*	0.010*	0.891
3–6	37.87 (0.59)	37.81 (0.59)	37.57 (0.59)	0.761	0.899	0.488	0.570
0–6	38.76 (0.57)	38.39 (0.57)	38.2 (0.57)	0.410	0.387	0.189	0.654
ICP (%)
0–1	19.98 (1.25)	20.68 (1.25)	20.44 (1.25)	0.559	0.288	0.487	0.714
1–3	34.96 (0.61)	39.79 (0.61)	39.19 (0.61)	< 0.001*	< 0.001*	< 0.001*	0.315
3–6	25.31 (0.72)	34.01 (0.72)	33.46 (0.72)	< 0.001*	< 0.001*	< 0.001*	0.443
0–6	27.32 (0.61)	34.93 (0.61)	34.37 (0.61)	< 0.001*	< 0.001*	< 0.001*	0.383
DCP (%)
0–1	1.71 (0.52)	2.98 (0.52)	2.80 (0.52)	< 0.001*	< 0.001*	< 0.001*	0.576
1–3	6.25 (0.86)	12.07 (0.86)	11.14 (0.86)	< 0.001*	< 0.001*	< 0.001*	0.095
3–6	11.27 (0.78)	21.63 (0.78)	20.38 (0.78)	< 0.001*	< 0.001*	< 0.001*	0.076
0–6	9.88 (0.74)	18.96 (0.74)	17.81 (0.74)	< 0.001*	< 0.001*	< 0.001*	0.064
FAZ
Area(mm2)	0.32 (0.02)	0.32 (0.02)	0.31 (0.02)	0.850	0.987	0.616	0.628
Perim(mm)	2.25 (0.08)	2.31 (0.08)	2.26 (0.08)	0.453	0.245	0.872	0.317
CI	0.76 (0.01)	0.73 (0.01)	0.74 (0.01)	0.061	0.024	0.080	0.614
VD	42.13 (0.64)	39.93 (0.64)	40.49 (0.64)	< 0.001*	< 0.001*	0.009*	0.363

COVID-19, coronavirus disease 2019; SS-OCTA, swept‐source optical coherence tomography angiography; SVP, superficial vascular plexus; ICP, intermediate capillary plexus; DCP, deep capillary plexus; FAZ, foveal avascular zone; CI, circularity index; VD, vessel density

P-values from χ² tests (categorical) and GEE models (continuous), with Bonferroni correction applied

^a Pre, pre-COVID-19

^b 1- month, one-month post-COVID-19

^c 1- year, one-year post-COVID-19

^*Statistically significant below P < 0.05 or adjusted P < 0.0167 (Bonferroni)

Fig. 3.

Swept-source optical coherence tomography angiography (SS-OCTA) images of the superficial vascular plexus (SVP) of a patient pre-, 1 month, and 1 year after COVID-19. (A), (D), (G) SS-OCTA images show the pre-, 1-month, and 1-year after COVID-19 status. (B), (E), (H), Heat map of vessel density of the SVP measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) grid in pre-, 1-month, and 1-year after COVID-19 status. (C), (F), (I), The B-scan of the macula in pre-, 1-month, and 1-year after COVID-19 status. The automatically segmented SVP was marked between the blue lines

Correlation analysis

Correlation analyses were conducted to evaluate associations between the rates of change in SS-OCT and SS-OCTA parameters at the 1-month and 1-year follow-ups (Table 4; Fig. 4). Significant positive correlations were identified between the rate of change in the VD of SVP and GCIPL thickness within the 0–1 mm and 3–6 mm rings at the 1-year follow-up (r = 0.664, P < 0.001; r = 0.383, P = 0.010, respectively) (Fig. 4). No significant correlations were found between the GCIPL thickness and the VD of ICP and between the INL thickness and the VD in ICP or DCP (all P > 0.05).

Table 4.

Correlations between SSOCT and SSOCTA parameters

Change rates	1-month		1-year
	r	P Value	r	P Value
T-GCIPL and VD-SVP
0–1	0.585	< 0.001*	0.664	< 0.001*
1–3	-0.027	0.863	-0.097	0.530
3–6	0.373	0.013	0.383	0.010*
0–6	0.266	0.081	0.272	0.074
T-GCIPL and VD-ICP
0–1	0.019	0.905	0.080	0.607
1–3	-0.174	0.257	-0.181	0.240
3–6	-0.090	0.563	-0.031	0.841
0–6	-0.108	0.484	-0.067	0.664
T-INL and VD-ICP
0–1	0.183	0.234	0.122	0.432
1–3	0.014	0.930	0.015	0.924
3–6	0.080	0.605	0.144	0.350
0–6	0.025	0.873	0.096	0.536
T-INL and VD-DCP
0–1	-0.206	0.202	-0.308	0.053
1–3	-0.021	0.890	-0.053	0.733
3–6	0.128	0.408	0.203	0.187
0–6	0.060	0.697	0.102	0.511

SS-OCT, swept‐source optical coherence tomography; SS‐OCTA, swept‐source optical coherence tomography angiography; GCIPL, ganglion cell‐inner plexus layer; SVP, superficial vascular plexus; ICP, intermediate capillary; DCP, deep capillary plexus

P-values from Pearson correlation analysis, with Bonferroni correction applied

^*Statistically significant below P < 0.05 or adjusted P < 0.0167 (Bonferroni)

Fig. 4.

Scattered map showing correlations between the change rates of the thickness of ganglion cell inner plexiform layer (GCIPL) and vessel density (VD) of superficial vascular plexus (SVP) at different time-points in different areas of detected rings: 1 month post-infection (A) and 1 year post-infection (B)

Discussion

In this study, we identified the long-term impact of COVID-19 infection on retinal structure and microvasculature using SS-OCT and SS-OCTA. Our findings revealed significant and persistent retinal structure and microvasculature alterations one year after COVID-19 infection. To our knowledge, this is the first study to investigate the long-term alterations in retinal structure and microvasculature within individuals before and after COVID-19 infection, providing valuable insights into the ocular manifestations associated with long COVID in the post-pandemic period.

The significant thinning of the pRNFL and GCIPL layer observed in this study aligns with previous findings [19, 29–32]. Jeong et al. demonstrated the presence of SARS-CoV-2 spike protein in retinal ganglion cells in mouse models, suggesting direct viral involvement leading to GCIPL thinning [33]. In addition, previous study has confirmed that SARS-CoV-2 RNA remains in the retina long after infection, indicating long-term damage incuded by infection of the virus [34]. Regarding RNFL thinning, Jevnikar et al. proposed that the thinning of RNFL might predominantly reflect reactive regeneration rather than progressive atrophy due to SARS-CoV-2 infection [24]. Given that the RNFL is composed of axons of ganglion cells, the loss of ganglion cells might directly contribute to the thinning of RNFL. However, some studies have reported increased RNFL thickness in participants after COVID infection. For instance, Burgos-Blasco found increases in global RNFL thickness in participants after COVID-19 infection, potentially due to neuroinflammation [19, 31]. Similar alterations have also been reported in retinal diseases, such as diabetic retinopathy and glaucoma [35, 36].

Our study also found significantly increased INL thickness in individuals one year after COVID-19 infection, which is consistent with our previous findings at 1-month follow-up [22]. The INL contains the cell bodies of retinal neurons. Additionally, the deep retinal capillary network is situated within the INL, highlighting the crucial role of INL in maintaining the integrity of the retinal microvasculature. The thickening of INL may result from Müller cell activation and gliosis, as seen in diabetic retinopathy [37]. Moreover, increased INL thickness was also reported in multiple sclerosis patients with a history of optic neuritis [38, 39], suggesting potential subclinical inflammation in the retina.

The outer retina, which primarily consists of photoreceptor cells and retinal pigment epithelium (RPE) cells, is particularly susceptible to ischemia and oxidative stress due to the high metabolic activity of photoreceptors [26]. Thinning of the outer retina has been reported in previous studies. Recently, Talebnejad et al. found that severe COVID-19 patients, especially those needing respiratory support, may develop ischemia and atrophy of outer plexiform layer (OPL) [27]. SARS-CoV-2 has also been shown to disrupt RPE barrier function and phagocytic activity in animal models [28]. These findings indicate that long-term photoreceptor and RPE dysfunction may result from post-acute viral sequelae, which is consistent with the thinning of the outer retina one year post-infection in our study.

Increasing evidence suggests COVID-19 is primarily a microvascular disease, highlighting endothelial and perivascular cells’ involvement. However, previous findings regarding COVID-19-associated alterations in retinal microvasculature remain inconsistent [25, 30, 40, 41]. A previous study comparing individuals six months after SARS-CoV-2 infection to healthy controls, reported a significant reduction in VD of the SCP and DCP [25]. In contrast, Savastano et al. found no significant difference in VD of SCP and DCP [40] in individuals 1 month after COVID-19 infection, when compared with healthy controls. Our findings suggest significantly decreased VD of SVP and increased VD of ICP and DCP, consistent with our previous research at 3-month follow-up [22]. We hypothesized that these retinal vascular alterations may be attributed to two primary mechanisms. First, both endothelial and perivascular cells express high levels of angiotensin-converting enzyme (ACE)-2, a receptor of SARS-CoV-2. Hence, direct viral invasion may compromise vascular integrity, leading to impaired retinal microcirculation in individuals after COVID-19 infection [42]. Second, retinal blood flow is closely regulated by oxygen availability. SARS-CoV-2 infection can cause chronic inflammation, oxidative stress, and endothelial dysfunction, leading to decreased vascular density in SVP and potentially resulting in ganglion cell loss [43]. This observation is also supported by our study, which demonstrates an association between GCIPL thinning with decreased VD of SVP. Similar microvascular alterations have also been observed in patients with diabetes and glaucoma [44–46], where ischemia and hypoxia contribute to retinal degeneration.

The above retinal changes suggest a more prolonged impact of COVID-19 on ocular health than previously anticipated. Moreover, none of the participants in our cohort experienced vision loss or reported other ocular symptoms related to vision, and standard ophthalmic examinations did not identify significant clinical abnormalities. These findings may indicate that COVID-19 infection may induce widespread subclinical retinal microvascular damage, as previously reported [25]. However, these findings should be interpreted with caution because subtle segmentation errors and other subtle artifacts may have introduced variability into the quantitative measurements [47].

Our longitudinal analysis revealed significant changes in both retinal structure and microvasculature at 1 month and 1 year post-infection compared to pre-infection baselines. However, no significant differences were found between the two follow-up time points (All P > 0.05), suggesting that these alterations are sustained over time. Notably, the similar retinal changes observed at both time points may be driven by different underlying pathophysiological mechanisms. Based on our findings and existing literature, we attempt to interpret the structural effects of SARS-CoV-2 infection on the retina as follows:

Following SARS-CoV-2 infection, retinal changes appear to evolve progressively rather than in distinct phases. Early on, the virus may directly invade retinal vascular endothelial cells via ACE2 receptors, causing microvascular and ganglion cell damage [33]. This triggers Müller glial cell activation and the release of pro-inflammatory cytokines (e.g., IL-6, TNF-α), initiating a neuroinflammatory response that likely underlies GCIPL thinning and reactive INL thickening due to immune cell infiltration [37]. As inflammation deepens, endothelial injury would be expected to reduce vascular density (VD) globally; however, we observed a selective reduction in SVP VD alongside paradoxical increases in ICP and DCP VD. This suggests localized hemodynamic adaptations, possibly driven by the metabolic demands of immune and glial cells. Over time, as viral activity wanes, the retina appears to shift from acute inflammation to low-grade chronic inflammation with persistent hypoxia. Upregulation of GFAP and VEGF points to ongoing vascular remodeling, though retinal thickness and VD only partially recover within the observation period, indicating that full restoration may require longer follow-up.

Our study has several strengths. First, we conducted within-subject comparisons in individuals before and after SARS-CoV-2 infection, which provides a more accurate assessment of the potential impact of the infection on individuals. Additionally, we performed long-term follow-ups on individuals recovering from COVID-19 infection, helping us better understand the possible long-term effects of SARS-CoV-2 infection on the retina.

Our study has several limitations. First, the sample size was relatively small and consisted predominantly of young healthcare workers and medical students. Although the post hoc power values exceeded 80% for the primary SS-OCT and SS-OCTA parameters, the restricted age distribution still limits the generalizability of the findings. Therefore, the results should be interpreted with caution. Second, subgroup analyses based on the severity of SARS-CoV-2 infection or the burden of post-infection symptoms were not feasible, as nearly all participants experienced mild disease and the sample size was limited. Third, although rigorous quality control procedures were applied to all included images, we acknowledge that subtle artifacts may have influenced the interpretation of the quantitative measurements. In addition, comprehensive functional assessments—such as visual field testing or electrophysiological measurements—were not performed, which limits our ability to evaluate potential functional correlates of the observed structural changes.

Future studies with larger and more diverse cohorts are warranted to enable meaningful subgroup analyses and to further elucidate the potential differences across disease severity, symptom burden, and the number of SARS-CoV-2 infections. In addition, incorporating contemporaneous uninfected control groups, multicenter recruitment, and extended longitudinal follow-up will be important for improving generalizability and distinguishing COVID-19–related retinal changes from normal physiological variation.

Conclusion

In conclusion, our study indicates that retinal alterations can persist for one year following COVID-19 recovery, highlighting the long-term impact of COVID-19 infection on the retina. Noninvasive SS-OCT and SS-OCTA could help detect subclinical retinal changes associated with Long COVID-19.

Abbreviations

COVID-19

Coronavirus disease 2019

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

SS‐OCT

Swept‐source optical coherence tomography

SS‐OCTA

Swept‐source optical coherence tomography angiography

pRNFL

Peripheral retinal nerve fiber layers

GCIPL

Ganglion cell‐inner plexus layer

INL

Inner nuclear layer

VD

Vessel density

GCC

Ganglion cell complex

BCVA

Best-corrected visual acuity

IOP

Intraocular pressure

ONH

Optic nerve head

SVP

Superficial vascular plexus

ICP

Intermediate capillary plexus

DCP

Deep capillary plexus

FAZ

Foveal avascular zone

CI

Circularity index

GEE

Eneralized estimating equation

BMI

Body mass index

Author contributions

K.F.M. and Y.Z.G. designed the study, collected the participants, conducted the examination, contributed to the discussion, and drafted the initial version of the manuscript. M.Z. reviewed and revised the manuscript for intellectual content. Y.C., Y.F.Z., S.L.M., H.Y.X., and Q.C. contributed to the participants’ follow-ups and participated in manuscript review and revision. All authors approved the final version of the manuscript. M.Z. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was supported by the 1·3·5 project for disciplines of excellence–Clinical Research Fund, West China Hospital, Sichuan University (2023HXFH043).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University, China, and conducted according to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Commercial relationships disclosure

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.

Competing interests

The authors declare no competing interests.