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

Jessica G Shantha; Kareem Moussa; Wipada Laovirojjanakul; Steven Yeh; Edmund Tsui; Judy L Chen; Albert T Vitale; Akbar Shakoor; Marissa Larochelle; Katherine Niemeyer; Akshay Mentreddy; Itamar Livnat; Myra Safo; Wendy Ao; Charlene Choo; Daisy Yan; Lina Zhong; Cindi Chen; Kirsten Da Silva; Amit K Reddy; Jennifer Lee; Amol Sura; Eric L Crowell; Ying Qian; Yael Sharon; Armin Hinterwirth; Travis Porco; Benjamin F Arnold; John Gonzales; Nisha R Acharya; Thomas M Lietman; Thuy Doan; OPTICS Study Group

doi:10.1016/j.ajo.2025.07.003

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

Am J Ophthalmol. 2025 Jul 11:S0002-9394(25)00350-2. doi: 10.1016/j.ajo.2025.07.003. Online ahead of print.

Authors

Jessica G Shantha¹, Kareem Moussa², Wipada Laovirojjanakul³, Steven Yeh⁴, Edmund Tsui⁵, Judy L Chen⁵, Albert T Vitale⁶, Akbar Shakoor⁶, Marissa Larochelle⁶, Katherine Niemeyer⁷, Akshay Mentreddy⁸, Itamar Livnat⁹, Myra Safo¹⁰, Wendy Ao¹¹, Charlene Choo⁴, Daisy Yan¹¹, Lina Zhong¹¹, Cindi Chen¹¹, Kirsten Da Silva¹¹, Amit K Reddy¹², Jennifer Lee¹³, Amol Sura¹⁴, Eric L Crowell¹⁵, Ying Qian¹⁶, Yael Sharon¹⁷, Armin Hinterwirth¹¹, Travis Porco¹⁸, Benjamin F Arnold¹⁸, John Gonzales¹⁸, Nisha R Acharya¹⁸, Thomas M Lietman¹⁸, Thuy Doan¹⁸; OPTICS Study Group

Affiliations

¹ Francis I. Proctor Foundation, University of California, San Francisco, California; Department of Ophthalmology, University of California, San Francisco (UCSF), San Francisco, California. Electronic address: jessica.shantha@ucsf.edu.
² Department of Ophthalmology & Vision Science, University of California, Davis, Sacramento, California.
³ Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Thailand.
⁴ University of Nebraska Medical Center, Omaha, Nebraska.
⁵ UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
⁶ University of Utah, Salt Lake City, Utah.
⁷ Kaiser Permanente, San Francisco, California.
⁸ Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina.
⁹ Los Angeles General Medical Center, Los Angeles, California.
¹⁰ Kaiser Permanente, Vallejo, California.
¹¹ Francis I. Proctor Foundation, University of California, San Francisco, California.
¹² Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado.
¹³ Sharp-Rees-Stealy and Rady Children's Hospital, San Diego, California.
¹⁴ Duke University Eye Center, Durham, North Carolina.
¹⁵ Dell Medical School at the University of Texas at Austin, Austin, Texas.
¹⁶ Kaiser Permanente, Oakland Medical Center, Oakland,California.
¹⁷ Rabin Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹⁸ Francis I. Proctor Foundation, University of California, San Francisco, California; Department of Ophthalmology, University of California, San Francisco (UCSF), San Francisco, California.

PMID: 40653257
DOI: 10.1016/j.ajo.2025.07.003

Abstract

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 physicians 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% to 59.1%]; relative risk (RR)=1.35 [95% CI: 1.01 to 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% to 14.0%]; RR= 0.89 [95% CI: 0.68 to 1.15]; P=0.37). There were 3 non-study 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.

Keywords: Uveitis; clinical outcomes; deep sequencing.

Associated data

ClinicalTrials.gov/NCT05286203