The Effect of Metagenomic Sequencing on Patient Clinical Outcomes for Intraocular Infections: A Multicenter Randomized Controlled Trial

Objective: To determine whether the addition of an unbiased test, metagenomic sequencing of intraocular fluid, compared to standard-of-care diagnostics alone, leads to better patient outcomes in presumed infectious intraocular inflammatory eye diseases. Design: A randomized controlled trial was conducted from May 2022 through February 2024. Participants: Eligible participants had intraocular inflammation concerning for an infectious etiology, were 18 years or older, and had vision better than no light perception (NLP). This study enrolled participants at 6 tertiary referral eye centers in the United States (5 sites) and Thailand (1 site). Interventions: Participants were randomized to have their physician have access to deep sequencing results or not. Main Outcomes and Measures: The main outcomes were (1) clinical improvement on examination at 4 weeks after randomization and (2) appropriate therapy administered by the treating physician as determined by an independent expert panel. Results: Among the 100 participants enrolled (median [IQR] age, 62.0 [47.5-71.0] years; 57 [57.0%] were women), 92 participants completed the study. Forty-one (41.0%) participants had resolution of inflammation at their 2-week follow-up and 23 (23.0%) participants had a pathogen identified with routine diagnostics and exited the study. Twenty-one (21.0%) participants met the criteria for randomization. At the primary endpoint, 8 (88.9%) patients in the metagenomic sequencing group had clinical improvement compared to 7 (63.6%) patients in the no metagenomic sequencing group (risk difference, 30% [95% CI: 0.6%-59.1%]; relative risk [RR] = 1.35 [95% CI: 1.01-1.81]; P = 0.045). Eight (88.9%) patients were considered to receive the appropriate therapy in the metagenomic sequencing group compared to 11 (100%) patients in the no metagenomic sequencing group (risk difference, −12.0% [95% CI: −38.0%-14.0%]; RR = 0.89 [95% CI: 0.68-1.15]; P = .37). There were 3 nonstudy related adverse events. Conclusions: Having access to metagenomic sequencing results modestly improved clinical outcomes in a subset of patients with suspected intraocular infections. Larger studies are needed to determine the long-term impact on management and clinical outcomes. Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05286203.