Differential COVID-19 Outcomes Across Lysosomal Disorders.

Background: Lysosomal disorders (LDs) are a heterogeneous group of rare inherited disorders characterized by multi-system involvement and high comorbidity burden, which raises concerns about severe COVID-19 outcomes. Conversely, because SARS-CoV-2 relies on endolysosomal pathways for cellular entry and replication, certain LDs may exert a protective effect against viral pathogenesis. Prior clinical evidence investigating LDs and severe SARS-CoV-2 infection has been limited by small sample sizes and inconsistent findings. Therefore, to resolve these conflicting biological hypotheses and estimate population-level outcomes, we conducted a large-scale retrospective cohort study using nationwide U.S. harmonized electronic health record data from the National Clinical Cohort Collaborative (N3C). This design utilized longitudinal records starting January 1, 2018, to evaluate COVID-19 infections captured between January 1, 2020, and July 11, 2024. Results: The study included 16,380 individuals, comprising 5,460 patients with lysosomal disorders and 10,920 matched controls. Patients with LDs had significantly higher odds of COVID-19 hospitalization compared with controls (OR = 1.86, 95% CI: 1.70-2.04). Elevated odds were observed across the evaluated categories, but varied substantially. Notably, neurodegenerative LDs such as neuronal ceroid lipofuscinosis (OR = 9.32) and metachromatic leukodystrophy (OR = 2.33) remained associated with hospitalization after adjustment for comorbidities. Contrarily, the elevated odds for Fabry disease and Gaucher disease were no longer significant after adjustment. Mortality among hospitalized patients with LDs was comparable to that of matched controls (one-year survival: 82.1% vs 82.0%), suggesting that LD status does not independently worsen survival once hospitalization occurs. Conclusions: Patients with LDs were at an increased odds of COVID-19 hospitalization, driven by a combination of elevated comorbidity burden and disorder-specific effects, which vary significantly across LD categories. This study clarifies that excess risk is concentrated in the transition to hospitalization. These patients may thus require personalized clinical care to mitigate the negative consequences of COVID-19.