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Modjtahedi and colleagues’ access to the large Kaiser Permanente database has revealed an interesting and potentially causal association between COVID-19 infection and the subsequent incidence of retinal vascular occlusions.1 COVID-19 can cause a wide array of systemic complications (arrhythmias, secondary infections, coagulopathies)2 and ocular manifestations (cranial nerve palsies, conjunctivitis, retinal microvascular changes).3 Vascular damage underlies the damage caused by COVID-19 to multiple organs via 2 main mechanisms: disseminated intravascular coagulation–like reaction leading to hypercoagulability and direct viral infection of the endothelial cells leading to a vasculitis-like picture.4 Furthermore, patients with COVID-19 are predisposed to embolism formation due to intravascular coagulation and hypoxia.5 The combination of COVID-19’s vascular damage and higher embolism formation tendencies can hypothetically increase the risk of retinal vascular occlusion. Previous publications reporting retinal vascular occlusion (artery6 or vein7) secondary to COVID-19 infection have been case reports, which lack a study design (eg, case-control or cohort studies) wherein hypothesis testing is used to evaluate this association in a group of individuals.
In order to test for a causal association between exposure (COVID-19) and disease (retinal vascular occlusion), the following 9 aspects (known as the Bradford Hill criteria) should be taken into account: strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy.
In the study by Modjtahedi et al,1 the retrospective cohort study design does assess temporality, as all patients who were diagnosed with COVID-19 were followed up for 6 months to detect the incidence rate of retinal vascular occlusion postinfection. Furthermore, there is support from case studies reporting occurrence of retinal vascular occlusion after infection with COVID-19.6,7
The strength of association was assessed by the incidence rate ratio, which measures the increment of retinal vascular occlusion incidence from pre– to post–COVID-19 infection. None of the previous publications focusing on retinal vascular occlusion secondary to COVID-19 involved a group of individuals; therefore, none had a measure for strength of association.
Biological plausibility exists between the cause and effect. COVID-19 leads to vascular damage through disseminated intravascular coagulation and a vasculitis-like reaction. COVID-19 also leads to a higher tendency of thrombus formation through intravascular coagulation and hypoxia. Vascular damage and thrombus formation are risk factors that can lead to retinal vascular occlusion.
There is consistency in reporting of this association as findings of this retrospective cohort study are consistent with previous published case reports of retinal vascular occlusion attributed to COVID-19.
Experimental evidence is lacking and would require the study of COVID-19 infection in large animal models.
The dose-response association between exposure and disease has not been thoroughly examined. One would expect that a severe COVID-19 infection would lead to more vascular occlusions; however, this may be negated by the anticoagulation regimens initiated in hospitalized patients with severe COVID-19.
In conclusion, the retrospective cohort study by Modjtahedi et al further strengthens the association between COVID-19 and retinal vascular occlusion. However, the strength and consistency of this association would be enhanced by further evaluation including studies that access other large databases now available, to provide a robust basis for causality and help determine recommended strategies for prevention and surveillance.
Corresponding Author: K. Thiran Jayasundera, MD, MS, Retinal Dystrophy Clinic, Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (firstname.lastname@example.org).
Published Online: April 14, 2022. doi:10.1001/jamaophthalmol.2022.0666
Conflict of Interest Disclosures: None reported.
Jayasundera KT, Abuzaitoun RO, Musch DC. COVID-19 Diagnosis and Incidence of Retinal Thromboembolism. JAMA Ophthalmol. 2022;140(5):527–528. doi:10.1001/jamaophthalmol.2022.0666
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