Association of Ocular Adverse Events With Inactivated COVID-19 Vaccination in Patients in Abu Dhabi | Macular Diseases | JAMA Ophthalmology | JAMA Network
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Figure 1.  Scleritis Associated With Inactivated COVID-19 Vaccine
Scleritis Associated With Inactivated COVID-19 Vaccine

A and B, Right and left eye of a patient who presented with bilateral anterior scleritis 10 days after receiving the first dose of an inactivated COVID-19 vaccine (Sinopharm). The patient started taking topical steroid drops, and the bilateral episode completely resolved at 2-week follow-up (C and D).

Figure 2.  Acute Macular Neuroretinopathy After Inactivated COVID-19 Vaccine
Acute Macular Neuroretinopathy After Inactivated COVID-19 Vaccine

A patient with an ocular history of central serous chorioretinopathy, in the left eye visible (A) with a serous pigment epithelial detachment and a thick choroid presented with profound loss of central vision 1 week after receiving the inactivated COVID-19 vaccine (Sinopharm). Spectral-domain optical coherence tomography showed hyperreflectivity of the outer plexiform layer, Henle fiber layer, and outer nuclear layer with attenuation of the photoreceptors (B, yellow arrowheads), compatible with acute macular neuroretinopathy. Swept-source optical coherence tomographic angiography at the level of the deep capillary plexus (C) showed a semilunar area of signal absence (pink arrowheads) corresponding with the hyperreflective deep spectral-domain optical coherence tomography lesion that may be a sign of slower deep capillary flow or an artifact from the outer retina changes. The patient was closely observed and at 2-month follow-up the tomographic picture had resolved (D).

Figure 3.  Paracentral Acute Middle Maculopathy in a Patient Receiving Inactivated COVID-19 Vaccine
Paracentral Acute Middle Maculopathy in a Patient Receiving Inactivated COVID-19 Vaccine

One patient developed a sudden paracentral scotoma in the left eye after receiving the inactivated COVID-19 vaccine (Sinopharm). The patient’s fundus examination revealed a dot hemorrhage superior to the fovea (A). Optical coherence tomography angiography revealed a superior enlargement of the foveal avascular zone (B). This fundus and optical coherence tomographic angiography finding corresponded with a round area of hyperreflectivity superior to the fovea on en face swept-source optical coherence tomography (C) that on B-scan swept-source optical coherence tomography presented as an opacification of the inner layers (D). These imaging features may be consistent with paracentral acute middle maculopathy or be secondary to intraretinal hemorrhage.

1.
Neri  P, Pichi  F.  COVID-19 and the eye immunity: lesson learned from the past and possible new therapeutic insights.   Int Ophthalmol. 2020;40(5):1057-1060.PubMedGoogle ScholarCrossref
2.
Xia  S, Zhang  Y, Wang  Y,  et al.  Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.   Lancet Infect Dis. 2021;21(1):39-51. doi:10.1016/S1473-3099(20)30831-8PubMedGoogle ScholarCrossref
3.
Kempen  JH.  Appropriate use and reporting of uncontrolled case series in the medical literature.   Am J Ophthalmol. 2011;151(1):7-10.e1. doi:10.1016/j.ajo.2010.08.047Google ScholarCrossref
4.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053Google ScholarCrossref
5.
Chen  X, Rahimy  E, Sergott  RC,  et al.  Spectrum of retinal vascular diseases associated with paracentral acute middle maculopathy.   Am J Ophthalmol. 2015;160(1):26-34.e1.PubMedGoogle ScholarCrossref
6.
Liu  JC, Nesper  PL, Fawzi  AA, Gill  MK.  Acute macular neuroretinopathy associated with influenza vaccination with decreased flow at the deep capillary plexus on OCT angiography.   Am J Ophthalmol Case Rep. 2018;10:96-100.PubMedGoogle ScholarCrossref
7.
Virgo  J, Mohamed  M.  Paracentral acute middle maculopathy and acute macular neuroretinopathy following SARS-CoV-2 infection.   Eye (Lond). 2020;34(12):2352-2353.PubMedGoogle ScholarCrossref
8.
Rosen  E.  The significance of ocular complications following vaccination.   Br J Ophthalmol. 1949;33(6):358-368.PubMedGoogle ScholarCrossref
9.
Foster  BS, Agahigian  DD.  Central serous chorioretinopathy associated with anthrax vaccination.   Retina. 2004;24(4):624-625.PubMedGoogle ScholarCrossref
10.
Moorthy  RS, Moorthy  MS, Cunningham  ET  Jr.  Drug-induced uveitis.   Curr Opin Ophthalmol. 2018;29(6):588-603.PubMedGoogle ScholarCrossref
11.
Méndez Mangana  C, Barraquer Kargacin  A, Barraquer  RI.  Episcleritis as an ocular manifestation in a patient with COVID-19.   Acta Ophthalmol. 2020;98(8):e1056-e1057.PubMedGoogle ScholarCrossref
12.
Agarwal  M, Dutta Majumder  P, Babu  K,  et al.  Drug-induced uveitis: a review.   Indian J Ophthalmol. 2020;68(9):1799-1807.PubMedGoogle ScholarCrossref
13.
Cunningham  ET  Jr, Moorthy  RS, Fraunfelder  FW, Zierhut  M.  Vaccine-associated uveitis.   Ocul Immunol Inflamm. 2019;27(4):517-520.PubMedGoogle ScholarCrossref
14.
Cunningham  ET  Jr, Moorthy  RS.  Vaccine-associated posterior uveitis.   Retina. 2020;40(4):595-598. doi:10.1097/IAE.0000000000002816PubMedGoogle ScholarCrossref
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    1 Comment for this article
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    Ocular Adverse Events Following COVID-19 Vaccination - Importance of Postmarketing Safety Surveillance
    William Bloom, BS | Chicago Medical School, Rosalind Franklin University of Medicine and Science
    I read with great interest the article by Pichi and colleagues regarding the association of ocular adverse events with inactivated COVID-19 vaccination (1). In this case series, the authors described ocular manifestations in 9 eyes of 7 patients within 15 days of administration of the inactivated Sinopharm COVID-19 vaccination. While the authors acknowledge a causal relationship cannot be established by this case series, they expect a rise in incidence of ocular adverse events following vaccine administration.

    In the associated commentary, Jampol et al questioned if such cases warrant publication when a causal relationship cannot be established (2). While
    I agree there is inherent difficulty in distinguishing causation from coincidence following widespread vaccination, it is my belief that early publication and dissemination of peer-reviewed case series and case reports represent an important contribution to the body of literature after the introduction of a new product to the general public. Case reports and case series are anecdotal in nature and generally considered “low level” evidence (3). Readers should therefore interpret the findings within the appropriate context when appraising the quality of evidence presented in such reports.

    Clinical trials, including those investigating vaccines, are typically powered to detect a measure of efficacy and may lack adequate power to detect rare adverse events (4, 5). For this reason, some adverse events may not be identified during the clinical trial adverse event surveillance period and are first reported only after many more individuals receive the product of interest. This highlights the importance of postmarketing surveillance systems, such as the U.S. Department of Health and Human Services’ Vaccine Adverse Event Reporting System (VAERS), despite the associated limitations. These unverified reports alone cannot establish a causal relationship to vaccine administration. They do contribute over time to a better understanding of the vaccine safety profile.

    Inclusion of additional information may help to support the authors’ conclusions, but is still unlikely to establish a causal relationship. Did any of the patients have a history of adverse events after prior vaccinations or a history of documented COVID-19 infection? Did any of the patients experience a recurrence of ocular symptoms or additional systemic symptoms following administration of the second dose?

    References

    1. Pichi F, Aljneibi S, Neri P, Hay S, Dackiw C, Ghazi NG. Association of Ocular Adverse Events With Inactivated COVID-19 Vaccination in Patients in Abu Dhabi. JAMA Ophthalmol. Published online September 2, 2021. doi:10.1001/jamaophthalmol.2021.3477

    2. Jampol LM, Tauscher R, Schwarz HP. COVID-19, COVID-19 Vaccinations, and Subsequent Abnormalities in the Retina: Causation or Coincidence? JAMA Ophthalmol. Published online September 2, 2021. doi:10.1001/jamaophthalmol.2021.3483

    3. OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Accessed September 13, 2021. http://www.cebm.net/index.aspx?o=5653

    4. Singh S, Loke YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials. 2012;13(1):138. doi:10.1186/1745-6215-13-138

    5. World Health Organization. Design of vaccine efficacy trials to be used during public health emergencies—points of considerations and key principles. Accessed September 13, 2021. https://www.who.int/docs/default-source/blue-print/working-group-for-vaccine-evaluation-(4th-consultation)/ap1-guidelines-online-consultation.pdf

    CONFLICT OF INTEREST: None Reported
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    Brief Report
    September 2, 2021

    Association of Ocular Adverse Events With Inactivated COVID-19 Vaccination in Patients in Abu Dhabi

    Author Affiliations
    • 1Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
    • 2Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
    JAMA Ophthalmol. 2021;139(10):1131-1135. doi:10.1001/jamaophthalmol.2021.3477
    Key Points

    Question  Can ocular adverse events present after inactivated COVID-19 vaccine?

    Findings  In a retrospective case series, 9 patients presented with ocular complaints 5.2 days after administration of an inactivated COVID-19 vaccine. One patient was diagnosed with episcleritis, 2 with anterior scleritis, 2 with acute macular neuroretinopathy, 1 with paracentral acute middle maculopathy, and 1 with subretinal fluid.

    Meaning  Mild, reversible ocular adverse events, both in the anterior and posterior segment, were noted after patients received the inactivated COVID-19 vaccine, although a causal relationship cannot be established from this case series.

    Abstract

    Importance  As vaccinations against COVID-19 continue, potential ocular adverse events should be reported in detail to increase awareness among the medical community, although typically, a causal relationship cannot be established definitively.

    Objective  To describe ocular adverse events that occur soon after receiving an inactivated COVID-19 vaccination (Sinopharm).

    Design, Setting, and Participants  This case series took place from September 2020 to January 2021 at Cleveland Clinic Abu Dhabi, a tertiary referral center. Patients who reported ocular adverse events and presented within 15 days from the first of 2 doses of an inactivated COVID-19 vaccine were analyzed.

    Main Outcomes and Measures  Each patient underwent Snellen best-corrected visual acuity that was then converted to logMAR, applanation tonometry, and biomicroscopic examination with indirect ophthalmoscopy. Color fundus photography was obtained with a conventional 9-field fundus photography camera or with a widefield fundus photography system. Optical coherence tomography and optical coherence tomographic angiography images were obtained. Sex, race, age, and clinical data were self-reported.

    Results  Nine eyes of 7 patients (3 male individuals) presenting with ocular complaints following COVID-19 vaccine were included in the study. The mean (SD) age was 41.4 (9.3) years (range, 30-55 years); the mean best-corrected visual acuity was 0.23 logMAR (range, 0-1 logMAR; approximate Snellen equivalent, 20/32). The mean time of ocular adverse event manifestations was 5.2 days (range, 1-10 days). One patient was diagnosed with episcleritis, 2 with anterior scleritis, 2 with acute macular neuroretinopathy, 1 with paracentral acute middle maculopathy, and 1 with subretinal fluid.

    Conclusions and Relevance  In this case series study of 7 patients, the timing of transient and ocular complications 5.2 days after vaccination with an inactivated COVID-19 vaccine supported an association with the ocular findings, but a causal relationship cannot be established from this study design.

    Introduction

    As of March 2021, the COVID-19 pandemic has caused 35 million infections and more than 1 million deaths worldwide, leading to the urgent demand for a vaccine.1 To date, 2 inactivated vaccine candidates have been reported to protect against SARS-CoV-2. The inactivated COVID-19 vaccine by Sinopharm’s China National Biotec Group is mixed with aluminum-based adjuvant and has been found tolerable and immunogenic in healthy people with 2 doses administered 21 days apart.2 As of March 2021, the United Arab Emirates Ministry of Health and Prevention announced that the United Arab Emirates had crossed 2 million doses of the Sinopharm inactivated vaccine (20% of the population). We hereby present a case series of ocular adverse events presenting at Cleveland Clinic Abu Dhabi in the United Arab Emirates after receiving the Sinopharm COVID-19 vaccine.

    Methods

    Retrospective consecutive case series, adherent to the reporting guidelines,3 of patients presenting at the retina and uveitis service from September 2020 to January 2021 were performed in accordance with the ethical standards of the Declaration of Helsinki.4 The institutional review board of Cleveland Clinic Abu Dhabi waived the need for approval of a case series of fewer than 10 patients. Written informed consent was obtained from all enrolled individuals.

    The main inclusion criterion was the development of ocular symptoms within 15 days from the first dose of the COVID-19 vaccine. Each patient underwent Snellen best-corrected visual acuity (BCVA) that was then converted to logMAR and biomicroscopic examination. Color fundus photography was obtained with a 9-field fundus photography (Carl Zeiss Meditec) camera. Optical coherence tomography (OCT) was obtained with a spectral-domain machine (Spectralis HRA OCT; Heidelberg Engineering) and swept-source PLEX Elite 9000 (Carl Zeiss Meditec) was used for OCT angiography images.

    Sex, race, age, and clinical data were self-reported and collected, and patient data were deidentified. None of the included patients were previously reported in any other publication.

    Results

    Nine eyes of 7 patients (3 male individuals) presenting with ocular complaints following COVID-19 vaccine were included in the study. The mean (SD) age was 41.4 (9.3) years (range, 30-55 years); the mean BCVA was 0.23 logMAR (approximate Snellen equivalent, 20/32) with a range of 0 to 1 (20/20 to 20/200). The mean time of ocular adverse events was 5.2 days (range, 1-10 days).

    Patients were diagnosed with episcleritis (case 1), anterior scleritis (case 2 and case 5), acute macular neuroretinopathy (AMN) (case 3 and case 4), paracentral acute middle maculopathy (PAMM) (case 7), and subretinal fluid (case 6).

    Selected Cases
    Case 2

    Patient 2 presented to our uveitis clinic with redness and pain in both eyes 1 week after receiving an inactivated COVID-19 vaccine. The patient’s medical history was remarkable for rheumatoid arthritis, well controlled with sulfasalazine. Visual acuity at baseline was 20/20 OU with an intraocular pressure of 18 mm Hg. Slitlamp examination showed more than 2 diffuse scleral hyperemia (Figure 1A and B) with positive phenylephrine test results. No cells and flare were noticed in the anterior chamber and no further signs of inflammation were seen. The patient started receiving a tapering dose of topical steroid to control the episode; on 1-week follow-up, the scleritis had resolved (Figure 1C and D).

    Case 3

    Patient 3 had an ocular history of central serous chorioretinopathy in both eyes with a chronic serous pigment epithelial detachment in the left eye (Figure 2A) and a BCVA of 20/25 at previous visits. The patient presented to our emergency department with an acute vision loss in the left eye 5 days after receiving the inactivated COVID-19 vaccine (Sinopharm). Vital parameters were within normal limits, but the BCVA in the left eye had dropped to 20/400. Spectral-domain OCT showed hyperreflectivity of the outer plexiform layer, Henle fiber layer, and outer nuclear layer (Figure 2B, yellow arrowheads) nasal to the unchanged pigment epithelium detachment. Ellipsoid and interdigitation zones were attenuated. The tomographic picture was consistent with AMN. Swept-source OCT angiography at the level of the deep capillary plexus showed a semilunar area of flow void (Figure 2D, pink arrowheads) corresponding with the hyperreflective deep spectral-domain OCT lesion. The patient was closely observed, and at 2-month follow-up, the tomographic picture had resolved (Figure 2C) and BCVA was back to 20/30.

    Case 7

    Patient 7 presented to the retina clinic in January 2021 with blurry vision in the left eye and headache. Ocular and medical history were unremarkable. However, the patient reported that 20 minutes after receiving COVID-19 vaccine (Sinopharm), they developed persistent tachycardia and raised systolic blood pressure, recorded at 210 mm Hg, and was nonresponsive to treatment for 3 weeks. Simultaneously, the patient started noticing an inferior scotoma in the left eye. BCVA at presentation was 20/30 OS, and dilated fundus examination revealed a dot hemorrhage superior to the fovea (Figure 3A). OCT angiography revealed a superior enlargement of the foveal avascular zone (Figure 3B). This fundus and OCT angiography finding corresponded with a round area of hyperreflectivity superior to the fovea on en face SS-OCT (Figure 3C) that on B-scan SS-OCT presented as an opacification of the inner layer (Figure 3D).

    Discussion

    In the current case series, we report 9 eyes presenting with ocular adverse events after the first inoculation of inactivated COVID-19 vaccine (Sinopharm), although a causal relationship cannot be established from this study design. Only 1 patient (case 7) presented associated systemic signs of vaccine reaction in the form of uncontrollable hypertension.

    At a mean of 6 days after the first inoculation, 2 of 9 eyes in the present series presented with acute unilateral vision loss associated with AMN and 1 of 9 eyes with PAMM. PAMM5 and AMN6 have been reported after H1N1 vaccination. Furthermore, Virgo and Mohamed7 reported 2 patients with new paracentral scotoma secondary to AMN and PAMM 16 days after confirmed COVID-19 infections.

    One patient presented with bilateral, shallow areas of subretinal fluid with no thickening of the underlying choroid and an associated hypertrophy of the photoreceptor overlying the fluid. This picture was suggestive of a forme fruste of central serous chorioretinopathy that has previously been documented after smallpox8 and anthrax vaccination.9

    Scleritis and episcleritis was reported in 4 of 9 cases at a mean of 5 days after the first dose of the vaccine. Although uncommon, there are few reports of episcleritis and scleritis following administration of live, attenuated viruses.10 Consistent with the reported literature, the present cases of scleritis noted soon after vaccination were mild. Of note, Méndez Mangana et al11 reported a patient with episcleritis 7 days after confirmation of COVID-19 infection.

    The theoretic pathogenesis of an inactivated COVID-19–associated ocular inflammation is not known. Commonly proposed mechanisms have included both molecular mimicry and antigen-specific cell and antibody-mediated hypersensitivity reactions.12-14

    Limitations

    The timing of complications 5.2 days after vaccination points toward an association between inactivated COVID-19 vaccination (Sinopharm) and the ocular findings. During the study period, no additional cases of AMN or PAMM were identified in our tertiary center, while cases of scleritis, episcleritis, and subretinal fluid were common.

    Conclusions

    As the urge for a vaccine against COVID-19 continues, we expect to see an increasing number of ocular adverse events from the various candidates.

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    Article Information

    Corresponding Author: Francesco Pichi, MD, Eye Institute, Cleveland Clinic Abu Dhabi, PO Box 112412, Al Maryah Island, Abu Dhabi, United Arab Emirates (ilmiticopicchio@gmail.com).

    Accepted for Publication: May 24, 2021.

    Published Online: September 2, 2021. doi:10.1001/jamaophthalmol.2021.3477

    Author Contributions: Drs Pichi and Ghazi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Pichi, Neri, Ghazi.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Pichi, Aljneibi, Neri, Hay.

    Critical revision of the manuscript for important intellectual content: Neri, Dackiw, Ghazi.

    Statistical analysis: Pichi, Neri.

    Administrative, technical, or material support: Aljneibi, Hay, Dackiw.

    Supervision: Pichi, Neri, Ghazi.

    Conflict of Interest Disclosures: None reported.

    References
    1.
    Neri  P, Pichi  F.  COVID-19 and the eye immunity: lesson learned from the past and possible new therapeutic insights.   Int Ophthalmol. 2020;40(5):1057-1060.PubMedGoogle ScholarCrossref
    2.
    Xia  S, Zhang  Y, Wang  Y,  et al.  Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.   Lancet Infect Dis. 2021;21(1):39-51. doi:10.1016/S1473-3099(20)30831-8PubMedGoogle ScholarCrossref
    3.
    Kempen  JH.  Appropriate use and reporting of uncontrolled case series in the medical literature.   Am J Ophthalmol. 2011;151(1):7-10.e1. doi:10.1016/j.ajo.2010.08.047Google ScholarCrossref
    4.
    World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053Google ScholarCrossref
    5.
    Chen  X, Rahimy  E, Sergott  RC,  et al.  Spectrum of retinal vascular diseases associated with paracentral acute middle maculopathy.   Am J Ophthalmol. 2015;160(1):26-34.e1.PubMedGoogle ScholarCrossref
    6.
    Liu  JC, Nesper  PL, Fawzi  AA, Gill  MK.  Acute macular neuroretinopathy associated with influenza vaccination with decreased flow at the deep capillary plexus on OCT angiography.   Am J Ophthalmol Case Rep. 2018;10:96-100.PubMedGoogle ScholarCrossref
    7.
    Virgo  J, Mohamed  M.  Paracentral acute middle maculopathy and acute macular neuroretinopathy following SARS-CoV-2 infection.   Eye (Lond). 2020;34(12):2352-2353.PubMedGoogle ScholarCrossref
    8.
    Rosen  E.  The significance of ocular complications following vaccination.   Br J Ophthalmol. 1949;33(6):358-368.PubMedGoogle ScholarCrossref
    9.
    Foster  BS, Agahigian  DD.  Central serous chorioretinopathy associated with anthrax vaccination.   Retina. 2004;24(4):624-625.PubMedGoogle ScholarCrossref
    10.
    Moorthy  RS, Moorthy  MS, Cunningham  ET  Jr.  Drug-induced uveitis.   Curr Opin Ophthalmol. 2018;29(6):588-603.PubMedGoogle ScholarCrossref
    11.
    Méndez Mangana  C, Barraquer Kargacin  A, Barraquer  RI.  Episcleritis as an ocular manifestation in a patient with COVID-19.   Acta Ophthalmol. 2020;98(8):e1056-e1057.PubMedGoogle ScholarCrossref
    12.
    Agarwal  M, Dutta Majumder  P, Babu  K,  et al.  Drug-induced uveitis: a review.   Indian J Ophthalmol. 2020;68(9):1799-1807.PubMedGoogle ScholarCrossref
    13.
    Cunningham  ET  Jr, Moorthy  RS, Fraunfelder  FW, Zierhut  M.  Vaccine-associated uveitis.   Ocul Immunol Inflamm. 2019;27(4):517-520.PubMedGoogle ScholarCrossref
    14.
    Cunningham  ET  Jr, Moorthy  RS.  Vaccine-associated posterior uveitis.   Retina. 2020;40(4):595-598. doi:10.1097/IAE.0000000000002816PubMedGoogle ScholarCrossref
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