Pichi and colleagues¹ in this issue of JAMA Ophthalmology describe ocular adverse events after Sinopharm COVID-19 vaccination, including 4 retinal events. Little is known about this vaccine.² Despite the large number of doses of vaccine having been administered worldwide, its adverse systemic events remain uncertain. We will review the evidence regarding associations of COVID-19 infection or COVID-19 vaccination with subsequent ocular adverse events, in particular retinal problems, to consider whether these abnormalities are causally associated or just coincidental. COVID-19 infection causes widespread damage to multiple organs. Proinflammatory cytokines are released and are strong inducers of a procoagulant/prothrombotic reaction,³ resulting in intravascular coagulopathies and endothelial injury. In regard to the retina, COVID-19 infection can be associated with anemia, hypertension or hypotension, hypoxia, and other systemic morbidities, which can contribute to retinal findings such as nerve fiber layer infarcts, hemorrhages, or microaneurysms. Vasculitis and thromboembolism also can contribute to retinal ischemia. Thus, we are not surprised to see reports of retinal hemorrhages, dilated and tortuous retinal veins, central retinal vein occlusion, central retinal artery occlusion, acute macular neuroretinopathy (AMN), paracentral acute middle maculopathy, acute retinal necrosis, endophthalmitis, optic neuritis, and others. These may not be due to the virus, but due to the systemic complications that this virus can cause. In the hundreds of millions of cases of COVID-19 infection seen worldwide, findings supporting direct retinal damage (other than vascular damage) from the virus have not been described. Retinal macro- and microvascular damage⁴ seen in patients with COVID-19 could be related to systemic thromboembolism, other systemic morbidities, or to the effect of the virus on retinal vessels. COVID-19 infection is also associated with a massive dysregulation of the humoral immune system characterized by the appearance of potent autoantibodies reacting against a wide range of soluble and tissue-specific proteins, which also might contribute to ocular disease.

What about COVID-19 vaccination and the retina? There have been anecdotal cases of adverse retinal ischemic events presented at conferences and undoubtedly awaiting publication. For example, we recently saw a middle-aged woman with diabetes and hypertension with a remote branch retinal artery occlusion in the left eye. Optical coherence tomography on the right showed AMN. Two weeks prior, she had received a Johnson & Johnson COVID-19 vaccination. Is the AMN from the vaccination or related to her systemic vasculopathy? When rare retinal findings (eg, AMN) are noted in association with a more common event (in this case COVID-19 vaccination), the findings may be unrelated. However, there are situations where one can suspect the associations have a real cause-and-effect relationship. Post–adenovirus vector vaccination (Johnson & Johnson, AstraZeneca), patients can have potentially life-threatening cerebral venous sinus thrombosis (CVST).⁵ These patients often have thrombocytopenia, which is very rarely associated with thrombosis. While CVST and thrombocytopenia after COVID-19 vaccination are extremely rare, it is much more common than in the general population. In these patients with CVST, the presence of platelet-activating autoantibodies against platelet factor 4 causes multicellular activation of coagulation. It mimics autoimmune heparin-induced thrombocytopenia. This syndrome is now called vaccine-induced immune thrombotic thrombocytopenia. It usually occurs within the first 3 weeks following vaccination, mostly in younger women. Anti–platelet factor 4 antibodies are pathognomonic for vaccine-induced immune thrombotic thrombocytopenia. As of April 4, 2021, 169 cases of CVST were reported in 34 million individuals vaccinated with AstraZeneca in the European Union and UK, corresponding to a reporting rate of 5 cases per million vaccinated adults.⁶ As of April 12, 2021, 6 cases of CVST with thrombocytopenia were reported after 6.86 million Johnson & Johnson doses, corresponding to a reporting rate of 0.87 cases per million doses.⁷ A causal relationship with vector-based vaccination thus is considered plausible by regulatory agencies. In contrast to vector-based vaccines, CVST with thrombocytopenia has not occurred after 183 million messenger RNA (mRNA) COVID-19 vaccine doses administered.

As reviewers for journals and participants in conferences, we are seeing patients presenting who have had COVID-19 vaccination with possible secondary retinal findings (eg, AMN or paracentral acute middle maculopathy). Vaccines have different mechanisms of inducing immunity and different adverse event profiles. COVID-19 vaccines differ in terms of genetic construct (mRNA vs DNA) or vector virus (human replication-incompetent adenovirus [Ad26.COV2S] for Johnson & Johnson vs chimpanzee replication incompetent adenovirus [ChAdOx1] for AstraZeneca). With the adenovirus vector vaccines, DNA encoding the spike protein is delivered and the immune system generates antibodies to this protein. With the Pfizer and Moderna vaccines, the mRNA for the spike protein is encapsulated in liposomes and endocytosed into the muscle cell. The mRNA is translated into S protein in the host cell cytosol. This protein is then expressed on the cell surface where it induces an immune response. In contrast to all other vaccines, the coding sequence SARS-CoV-2 S immunogen in the AstraZeneca vaccine has not been modified to stabilize and to mitigate shedding of the expressed S protein.⁸ Thus, it is possible that expressed S protein in the circulation after AstraZeneca vaccination can induce a proinflammatory/procoagulant response or direct disturbance of endothelial cell integrity.

Pichi和他的同事¹在这个问题上JAMA眼科描述国药COVID-19疫苗接种后的眼部不良反应事件，其中包括4个视网膜事件。人们对这种疫苗知之甚少。²尽管世界范围内接种了大量疫苗，但其全身不良事件仍不确定。我们将审查关于 COVID-19 感染或 COVID-19 疫苗接种与随后的眼部不良事件（尤其是视网膜问题）之间关联的证据，以考虑这些异常是因果关系还是巧合。COVID-19 感染对多个器官造成广泛损害。促炎细胞因子被释放并且是促凝/促血栓形成反应的强诱导剂，³导致血管内凝血病和内皮损伤。在视网膜方面，COVID-19 感染可能与贫血、高血压或低血压、缺氧和其他全身性疾病有关，这可能导致视网膜发现，如神经纤维层梗塞、出血或微动脉瘤。血管炎和血栓栓塞也会导致视网膜缺血。因此，我们对视网膜出血、扩张和扭曲的视网膜静脉、视网膜中央静脉阻塞、视网膜中央动脉阻塞、急性黄斑神经视网膜病变 (AMN)、中央旁急性中间黄斑病变、急性视网膜坏死、眼内炎、视神经炎、和别的。这些可能不是由于病毒，而是由于该病毒可能引起的全身并发症。在全球数亿例 COVID-19 感染病例中，尚未描述支持该病毒对视网膜造成直接损伤（血管损伤除外）的发现。视网膜大血管和微血管损伤在 COVID-19 患者中观察到的⁴可能与全身性血栓栓塞、其他全身性疾病或病毒对视网膜血管的影响有关。COVID-19 感染还与体液免疫系统的大规模失调有关，其特征是出现针对多种可溶性和组织特异性蛋白质的强效自身抗体，这也可能导致眼部疾病。

COVID-19疫苗接种和视网膜怎么样？在会议上有一些不良视网膜缺血事件的轶事案例，毫无疑问有待发表。例如，我们最近看到一位患有糖尿病和高血压的中年妇女左眼视网膜远端动脉阻塞。右侧的光学相干断层扫描显示 AMN。两周前，她接种了强生公司的 COVID-19 疫苗。AMN 是来自接种疫苗还是与她的全身血管病变有关？当罕见的视网膜发现（例如 AMN）与更常见的事件（在这种情况下为 COVID-19 疫苗接种）相关时，这些发现可能是无关的。然而，在某些情况下，人们可以怀疑这些关联具有真正的因果关系。腺病毒载体疫苗接种后（强生公司，⁵这些患者通常有血小板减少症，这很少与血栓形成有关。尽管 COVID-19 疫苗接种后的 CVST 和血小板减少症极为罕见，但比普通人群更为常见。在这些 CVST 患者中，针对血小板因子 4 的血小板激活自身抗体的存在导致凝血的多细胞激活。它模拟自身免疫性肝素诱导的血小板减少症。这种综合征现在称为疫苗诱导的免疫血栓性血小板减少症。它通常发生在接种疫苗后的前 3 周内，主要发生在年轻女性中。抗血小板因子 4 抗体是疫苗诱导的免疫血栓性血小板减少症的特征性抗体。截至 2021 年 4 月 4 日，在欧盟和英国接种阿斯利康疫苗的 3400 万人中报告了 169 例 CVST，⁶截至 2021 年 4 月 12 日，强生注射了 686 万剂后报告了 6 例 CVST 伴血小板减少症，对应的报告率为每百万剂 0.87 例。⁷因此，监管机构认为与基于载体的疫苗接种存在因果关系是合理的。与基于载体的疫苗相比，在施用 1.83 亿次信使 RNA (mRNA) COVID-19 疫苗剂量后，尚未发生血小板减少症的 CVST。

作为期刊审稿人和会议参与者，我们看到接受过 COVID-19 疫苗接种的患者可能出现继发性视网膜发现（例如，AMN 或中央旁急性中段黄斑病变）。疫苗具有不同的诱导免疫机制和不同的不良事件特征。COVID-19 疫苗在基因结构（mRNA 与 DNA）或载体病毒（强生公司的人类复制无功能腺病毒 [Ad26.COV2S] 与阿斯利康的黑猩猩复制无功能腺病毒 [ChAdOx1]）方面有所不同。使用腺病毒载体疫苗，编码刺突蛋白的 DNA 被传递，免疫系统产生针对该蛋白的抗体。对于辉瑞和 Moderna 疫苗，刺突蛋白的 mRNA 被包裹在脂质体中并被内吞到肌肉细胞中。mRNA在宿主细胞胞质溶胶中被翻译成S蛋白。然后这种蛋白质在细胞表面表达，在那里它诱导免疫反应。与所有其他疫苗相比，阿斯利康疫苗中的编码序列 SARS-CoV-2 S 免疫原没有经过修饰以稳定和减轻表达的 S 蛋白的脱落。⁸因此，阿斯利康疫苗接种后在循环中表达的 S 蛋白可能会诱导促炎/促凝反应或直接干扰内皮细胞完整性。