The characteristics of white dot syndromes following COVID-19 Vaccines: a systematic review

Purpose To review all studies reporting the onset of white dot syndromes following COVID-19 vaccines. Methods Our protocol was registered prospectively on PROSPERO [registration number: CRD42023426012]. We searched five different databases including PubMed, Scopus, Web of Science, Google Scholar, and Science Direct up to May 2023. All the studies that reported the occurrence of white dot syndrome following COVID-19 vaccines were included. All statistical tests were conducted with a 95% confidence interval and a 5% error margin. A p value of less than 0.05 was considered statistically significant. The methodological quality of included studies was performed using the IHE Quality Appraisal Checklist for Case Series studies and JBI Critical Appraisal Checklist for Case Reports. Results Fifty studies involving seventy-one subjects were included. Multiple evanescent white dot syndrome (MEWDS) was the most common disease (n = 25, 35.2% %), followed by acute macular neuroretinopathy (AMN) (n = 22, 31.0%) and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 4, 5.6%). They were mostly unilateral (n = 50, 70.4%). The presenting symptoms were blurred vision (n = 26, 36.6%), paracentral scotoma (n = 19, 26.8%), visual field disturbance, and photopsia (n = 7, 9.9%). The mean duration for follow-up was 10.15 ± 14.04 weeks. Nineteen subjects (29.69%) received steroids with improvement reported in 68.4%. Eleven subjects (17.19%) were managed by observation only with reported full recovery and improvement. Conclusion White dot syndromes are very rare entities. Our findings highlight a possible association between COVID-19 vaccines and the occurrence of white dot syndromes. However, larger studies with good quality should be implemented to confirm these findings. Supplementary Information The online version contains supplementary material available at 10.1007/s10792-024-03119-4.


Introduction
The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic has significant health consequences.Seven million fatalities have been reported from the 768 million confirmed cases of COVID-19 worldwide [1].Nearly all the body's organs may be affected by the illness, which has the potential to cause respiratory issues ranging from those with no symptoms to those that are seriously uncomfortable or even fatal [2].To control the COVID-19 pandemic, reliable and safe vaccines are crucial [3,4].As of the time of this writing, More than 13.4 billion doses of vaccines have been distributed [1] including messenger RNA vaccines (Pfizer-BioNTech and Moderna), inactivated vaccines (Sinopharm, Bharat Biotech, Sinovac), vector vaccines (Johnson & Johnson, AstraZeneca, Sputnik V), and protein subunit vaccinations (Novavax) [5].Even though these vaccines were effective in halting the disease's spread and lowering the incidence of severe forms of SARS-CoV-2, many potential adverse events were reported worldwide.[6,7] Until now, numerous unfavorable side effects, particularly those affecting the eyes, were reported [8].For instance, some studies have reported that the Pfizer-BioNTech vaccine may cause about eye swelling, ocular hyperemia, conjunctivitis, blurred vision, uveitis, and visual impairment [6,9].Pfizer-BioNTech and AstraZeneca vaccines have been reported to result in ocular vascular events including vitreous hemorrhage, central/branch retinal vein occlusion, and ischemic optic neuropathy [10].Mahendradas et al. [1] have reported anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, episcleritis, scleritis, sclerouveitis, sclerokeratouveitis, and keratouveitis following COVID-19 vaccines in their tertiary center.
The development of WDS following COVID-19 vaccination should therefore receive more attention.The importance of this recent possible association has been emphasized in several recent studies that have been published in this field but are solely based on case reports.As a result, we conducted a systematic review with a focus on the data regarding the vaccines (type, dose, duration), the patient's characteristics (sociodemographic and clinical), and the outcomes of the disease (origin, type, location, presentation, management, and outcomes) to summarize the current evidence on COVID-19 vaccineassociated WDS.This is the first systematic review that, to our knowledge, addresses WDS that develops following COVID-19 vaccination.Page 3 of 49 189 Vol.: (0123456789)

Study protocol and database search
This research was carried out in accordance with the Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA) recommendations [30,31].The study adhered to the tenets of the Declaration of Helsinki and the necessity for institutional review board (IRB) approval was not required since it did not involve human subjects.In May 2023, our protocol was registered prospectively on PROSPERO [registration number: CRD42023426012].
Meanwhile, on May 25, 2023, we searched five electronic databases [PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar] to retrieve all studies that reported the onset of any type of WDS following COVID-19 vaccines within 8 weeks using the following keywords: (Pfizer-BioNTech OR BTN162b2 OR Sinopharm OR Sinovac OR Moderna OR AstraZeneca OR ChAdOx1 OR AZD1222 OR Janssen OR "Johnson & Johnson" OR Novavax OR CoronaVac OR Covaxin OR Convidecia OR Sputnik OR Zifivax OR Corbevax OR COVIran OR SCB-2019 OR vaccin* OR "COVID- 19 Vaccines"[Mesh]) AND (("white dot syndrome" OR "multiple evanescent white dot syndrome" OR "acute idiopathic blind spot enlargement syndrome" OR "punctate inner chorioretinop*" OR "acute macular neuroretinopath*" OR "acute posterior multifocal placoid pigment epitheliopathy" OR "diffuse subretinal fibrosis uveitis" OR "serpiginous choroid*" OR "birdshot chorioretinopathy*" OR "acute zonal occult outer retinopathy"))).Medical Subject Headings (MeSH) terms were also added whenever applicable to retrieve all relevant studies based on their indexed terms in included databases.In addition, only the first 200 records from Google Scholar were retrieved and screened as per the recent recommendations [30].Noteworthy, an updated database search was carried out just before the analysis to include any newly published studies before the official synthesis of collected data which didn't yield any new results.
Furthermore, after finishing the screening process, we conducted a manual search of references to identify any relevant studies that we could not identify through the original database search.This search was conducted by (1) searching similar articles of the finally included articles in our review through the "similar articles" option on PubMed, (2) searching the reference list of finally included articles in our review, and (3) searching through Google with the keywords used in the original database search.

Eligibility criteria
We included all original research papers that reported the onset of any type of WDSs following any type of COVID-19 vaccine within 8 weeks of vaccine administration following the PICO framework (Population: subjects with any type of WDS, Intervention: COVID-19 vaccines, Comparator: none, Outcome: presentation, management, and prognostic factors.We included all of the following study designs: randomized controlled clinical trials (RCT), retrospective and observational studies, case series, and case reports.Of note, studies were included regardless of the language of publication.Meanwhile, studies were excluded if they were (1) non-original research (i.e., reviews, commentaries, guidelines, editorials, correspondence, letters to editors, opinions etc.), (2) unavailable full-texts, (3) duplicated records or records with overlapping datasets, (4) studies reporting WDSs following SARS-CoV-2 infection (5) studies with irrelevant data (lack of primary outcome data) (6) studies reporting WDSs following COVID-19 vaccines within > 8 weeks.

Screening and study selection
Retrieved records from the database search were exported into EndNote software for duplicate removal before the beginning of the screening phase.Records were then imported into an Excel (Microsoft, USA) sheet for screening.The screening was divided into two steps: title and abstract screening followed by full-text screening.The full texts of eligible articles were then retrieved for screening before being finally included in the review.Both steps were carried out by three reviewers [AKH, ARH, AS].Any differences between reviewers were solved through group discussions, and the senior authors [HAS, AGE] were consulted if reviewers could not reach an agreement.

Data extraction and assessment of methodological quality and risk of bias
The data extraction was performed by three reviewers

Data synthesis
No modifications have been made to the pre-defined analysis plan in the study protocol.We performed qualitative analysis after organizing the acquired data.Qualitative analysis was done using the Statistical Package for Social Sciences (SPSS) version 27 (IBM SPSS Corp, SPSS Statistics ver.27, USA).Descriptive analysis was used to display categorical variables as percentages and frequencies while presenting numerical variables as a mean and standard deviation.We tried to run time-to-event analysis for better understanding of relation of theWDS to the vaccines.The significance of the data was determined using a categorical Chi-square test.All statistical tests were conducted with a 95% confidence interval and a 5% error margin.A p-value of less than 0.05 was considered statistically significant.Visual acuity (VA) was commonly reported as an Early Treatment Diabetic Retinopathy Study letter scores.We standardized VA scores using the minimum angle of resolution (log-MAR) chart scores, the score was converted to log-MAR scores using Gregori et al. method.[34]
Regarding the patients' previous ophthalmological history, six (9.38%) patients reported a previous history of ophthalmological issues.Myopia was present in five patients (83.33%), previous ocular surgeries/ treatments reported in three patients (50%), and specific eye conditions (central serous chorioretinopathy with chronic serous pigment epithelial detachment and a previous episode of MEWDS) were found in two patients (33.33%).The mean baseline visual acuity (LogMAR) was 1.02 ± 0.43.(Table 1).

Discussion
Since the emergence of COVID-19 vaccines, many adverse events have been recognized globally.Of these adverse events, different types of WDS had been reported in the literature.Our results reviewed 82 cases received different COVID-19 vaccines.The most reported vaccine used was Pfizer (n = 23, 28%) in which showed a predominance of MEWDS (n = 15, 65.2%) and the rest of cases (n = 4, 17%) were diagnosed as AMPPE.AstraZeneca was seen in a total of 12 cases (14.6%), 10 cases of them diagnosed with AMN.Finally, Sinovac was administered in 16 cases (19%) of which 10 of them were associated with MEWDS and three of them were associated with AMN.Therefore, our data showed that Pfizer and AstraZeneca vaccine are associated mainly with MEWDS, and AMN, respectively.This could be explained by the fact that MEWDS is believed to be of an autoimmune nature given its autoimmune associations [11].Pfizer-BioNTech vaccine produces an additional CD8 T-cell immune response triggering autoimmune reactions.[77] Nevertheless, this finding could also be explained by the dominance of the Pfizer-BioNTech vaccine over other COVID-19 vaccine types in the number of given doses worldwide [78].Furthermore, AMN is hypothesized to be a systemic autoimmune disease that causes small-vessel occlusion due to micro-thrombi production, leading to ischemic retinopathy [79].It has been reported that AstraZeneca vaccine provides protection against SARS-CoV-2 infection through immune-mediated mechanisms which are believed to cause thrombosis through an activation of platelets, immune cells, and hypercoagulability factors [10].
Our review included subjects with a mean age of 32.79 ± 14.81 years which is the typical age of WDS reported in the literature [82].Because of the autoimmunity nature of WDS, it tends to occur more frequently in females [83].Although it's unclear what's causing this trend, there is growing evidence that sex hormones affect the immune response, with estrogen enhancing and androgens suppressing it [84].Moreover, it has been hypothesized that estrogen is crucial for the development and function of Th17 cells in addition to IL-17 generation [85].Our results coincide with this trend, showing that COVID-19 vaccine-associated WDS were more likely to occur in females than in males (77.5% vs. 21.1%).
The mean of the duration from taking the vaccine till the onset of symptoms was 10.06 ± 11.37 days (mean ± SD).In the literature, ocular adverse effects of COVID-19 vaccines, in general, happened in the first 10 days after administration of vaccines [86] .This temporal association could be explained by the fact that vaccine-related antibodies, that promote immune response including hypercoagulability, appear maximally within the first 5-10 days after vaccination, and disappear within 100 days [87].In addition, 58.3% of WDS after AstraZeneca vaccine administration occurred within the first week, and all of them were AMN.Pfizer-BioNTech vaccine cases also were seen most frequently in the first week (46.1%) and second week (30.8%).On the other hand, Covishield and mRNA Spikvax-associated WDS were observed within 2 months of administration.(Supplementary Table 4).
Regarding OCT, VF and FAF findings in our study, the results were consistent with previously reported literature.The SD-OCT appearance of MEWDS is that of disruption mainly of the ellipsoid zone and interdigitation zone complex in the fovea and it is sometimes associated with reflective focal lesions that crossed the external limiting membrane line [80] and FA reveals early punctate hyperfluorescence in a wreath-like pattern and late staining, in areas corresponding to the white dots.This hyperfluorescence may be due to dilated retinal microcirculation in the middle or deep retinal capillary plexus [81].
Regarding VF complications, a total of nine patients (9.7%) reported complications of VF ch were mainly associated with AMN (n = 5, 62.5%) in the form of the typical VF defects (paracentral and temporal scotoma).Other 2 cases (n = 2, 25%) were associated with MEWDS in the form of enlarged blind spot and paracentral scotoma.Lastly, one case (n = 1, 12.5%) was associated with neuroretinitis in the form of superior scotoma and generalized field defect.Our results showed further analysis of the types of vaccine causing VF defect.Four cases of paracentral scotoma were found.Two of them were associated with Astra-Zeneca vaccine, one case was associated with MVC COVID-19 and Sinopharm vaccines, respectively.Enlarged blind spots and inferotemporal scotomas were seen in only one case, respectively, due to Spikevax vaccine.Interestingly, Pfizer-BioNTech vaccine has not been reported to cause VF defects.
Overall, the etiology of WDS is still uncertain and the emergence of cases under COVID-19 vaccines may shed some light on the exact pathogenesis of these syndromes.According to the WHO, as of the 21st of September 2023, 13.5 billion COVID-19 vaccine doses have been administered globally, and 27,338 are now administered each day [1].Therefore, this possible association between COVID-19 vaccines and WDS might be a coincidence.In addition, the nature of case reports and series may introduce bias and limit the generalizability of our findings raising questionable associations.Further research is recommended to investigate these possible associations.The large number of studies included increases the discrepancy in reporting between different studies, hence a large group study could mitigate this effect and unify the reporting criteria for these syndromes.

Conclusion
Our review summarizes the occurrence of COVID-19 vaccination-associated WDS, which is more likely to occur among middle-aged females.Our findings indicate a possible association between COVID-19 vaccines and WDS, but this association is limited by the quality and number of available studies.The clinicians should be aware enough of this possible association and report them immediately upon the identification of similar cases for better implementation of the evidence.Further studies are needed for better determination of the incidence, risk factors, characteristics, and management of these syndromes.

Fig. 1
Fig. 1 Shows PRISMA chart for selection of included articles

Fig. 2
Fig.2shows the mean duration from administration the vaccine till the onset of WDS symptoms [AKH, ARH, AS] through a data extraction sheet that [33]fourth part included a thorough assessment of the reported event in terms of presenting symptoms, diagnostic methods, examination findings, initial and final best-corrected visual acuity (BCVA), investigations (blood and eye investigations), management (either medical or surgical), the follow-up period, and management outcomes and associated complications if present.The fifth part included the quality assessment of the included studies.Methodological quality and risk of bias were assessed using the IHE Quality Appraisal Checklist for Case Series studies[32]and the JBI Critical Appraisal Checklist for Case Reports.[33]

Table 2
Clinical description of included articles and related management and outcomes Author (ID) Vol.: (0123456789)