Age-related macular degeneration and mortality in SARS-CoV-2
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Conditions associated with dysregulated complement were found to be risk factors for SARS-CoV-2-associated morbidity and mortality. History of macular degeneration was an independent risk factor for morbidity and mortality in SARS-CoV-2-infected patients. This association was attributed to dysfunction in the complement system, which is known to account for the risk for age-related macular degeneration (AMD), and which might also contribute to SARS-CoV-2-mediated disease. The hazard ratio (HR) of death associated with SARS-CoV-2 in patients with macular degeneration was 3.0 in univariate analysis, and 1.5 when age and sex-corrected.

It is true that several molecular pathways have been implicated in AMD and that the focus of current research is on modulating the complement cascade. Importantly, it should be acknowledged the other obvious risk factors these patients have and the proposed vasculature–lung tissue interface pathophysiology in SARS-CoV-2 disease. In a previous study, we found a positive association between mortality and the number of anti-VEGF injections – a proxy for disease severity (Blasiak et al. 2019). Furthermore, we found a significantly elevated mortality ratio in wet AMD patients in comparison with controls. Researchers observed decreased serum levels of microRNAs (miRNAs): miR-34-5p, miR-126-3p, miR-145-5p, and miR-205-5p in wet AMD patients when compared with controls. These miRNAs have been linked with oxidative stress, cytokine secretion during hypoxia, VEGF expression, and extracellular matrix remodeling. Greater mortality in patients with macular degeneration was also reported by Hanhart et al.; during their follow-up (up to 73 months), 19.7% of individuals with wet macular degeneration treated with bevacizumab died compared with 12.1% in the control group (OR = 1.69; 95% CI: 1.54–1.84) (Hanhart et al. 2017). These results were seen prior to the current COVID-19 pandemic. Together, these show that patients with AMD, and especially with advanced disease, are at higher risk of mortality regardless of the cause.

The potential association between macular degeneration and the risk for morbidity and mortality in SARS-CoV-2-infected patients should not be, however, taken lightly. Patients with advanced disease commonly visit the hospital for repeated anti-VEGF injections, exposing them to contacts in proximity with health workers, and other patient populations. While other elderly patients practiced social distancing, especially from medical facilities, patients with wet AMD have no choice other than to frequent hospitals repeatedly. This is especially notable as a recent study has shown that SARS-CoV-2 may continue to circulate among human populations despite herd immunity due to natural infection or vaccination (To et al. 2020).

The emerging associations of SARS-CoV-2 morbidity and mortality with complement dysfunction are intriguing. They might be a basis for management decisions and possible treatment avenues. However, macular degeneration is a complex disease and should not be considered a straightforward marker of complement dysfunction, especially as patients with macular degeneration have other evident risk factors that can be attributed to increased susceptibility to this pandemic. Research into ways to modulate the complement cascade should nonetheless be encouraged, as this could hopefully be found to be beneficial to patients with macular degeneration, and perhaps eventually to patients infected with SARS-CoV-2 as well.