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

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 Doan¹⁹; OPTICS Study Group

Affiliations

¹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA. Electronic address: jessica.shantha@ucsf.edu.
² Department of Ophthalmology & Vision Science (K.M.), University of California, Davis, Sacramento, California, USA.
³ Department of Ophthalmology, Faculty of Medicine (W.L.), Khon Kaen University, Thailand.
⁴ University of Nebraska Medical Center (S.Y., C.C.), Omaha, Nebraska, USA.
⁵ UCLA Stein Eye Institute (E.T., J.L.C.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁶ University of Utah (A.T.V., A.S., M.L.), Salt Lake City, Utah, USA.
⁷ Kaiser Permanente (K.N.), San Francisco, California, USA.
⁸ Atrium Health Wake Forest Baptist (A.M.), Winston-Salem, North Carolina, USA.
⁹ Los Angeles General Medical Center (I.L.), Los Angeles, California, USA.
¹⁰ Kaiser Permanente (M.S.), Vallejo, California, USA.
¹¹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA.
¹² Department of Ophthalmology (M.K.R.), University of Colorado School of Medicine, Aurora, Colorado, USA.
¹³ Sharp-Rees-Stealy and Rady Children's Hospital (J.L.), San Diego, California, USA.
¹⁴ Duke University Eye Center (A.S.), Durham, North Carolina, USA.
¹⁵ Dell Medical School at the University of Texas at Austin (E.L.C.), Austin, Texas, USA.
¹⁶ Kaiser Permanente (Y.Q.), Oakland Medical Center, Oakland, California, USA.
¹⁷ Rabin Medical Center, Faculty of Medicine (Y.S.), Tel Aviv University, Tel Aviv, Israel.
¹⁸ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA.
¹⁹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA. Electronic address: thuy.doan@ucsf.edu.

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

Free article

Randomized Controlled Trial

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

Jessica G Shantha et al. Am J Ophthalmol. 2025 Nov.

Free article

. 2025 Nov:279:100-109.

doi: 10.1016/j.ajo.2025.07.003. Epub 2025 Jul 11.

Authors

Affiliations

¹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA. Electronic address: jessica.shantha@ucsf.edu.
² Department of Ophthalmology & Vision Science (K.M.), University of California, Davis, Sacramento, California, USA.
³ Department of Ophthalmology, Faculty of Medicine (W.L.), Khon Kaen University, Thailand.
⁴ University of Nebraska Medical Center (S.Y., C.C.), Omaha, Nebraska, USA.
⁵ UCLA Stein Eye Institute (E.T., J.L.C.), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁶ University of Utah (A.T.V., A.S., M.L.), Salt Lake City, Utah, USA.
⁷ Kaiser Permanente (K.N.), San Francisco, California, USA.
⁸ Atrium Health Wake Forest Baptist (A.M.), Winston-Salem, North Carolina, USA.
⁹ Los Angeles General Medical Center (I.L.), Los Angeles, California, USA.
¹⁰ Kaiser Permanente (M.S.), Vallejo, California, USA.
¹¹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA.
¹² Department of Ophthalmology (M.K.R.), University of Colorado School of Medicine, Aurora, Colorado, USA.
¹³ Sharp-Rees-Stealy and Rady Children's Hospital (J.L.), San Diego, California, USA.
¹⁴ Duke University Eye Center (A.S.), Durham, North Carolina, USA.
¹⁵ Dell Medical School at the University of Texas at Austin (E.L.C.), Austin, Texas, USA.
¹⁶ Kaiser Permanente (Y.Q.), Oakland Medical Center, Oakland, California, USA.
¹⁷ Rabin Medical Center, Faculty of Medicine (Y.S.), Tel Aviv University, Tel Aviv, Israel.
¹⁸ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA.
¹⁹ From the Francis I. Proctor Foundation (J.G.S., W.A., D.Y., L.Z., C.C., K.D.S., A.H., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco, California, USA; Department of Ophthalmology (J.G.S., T.P., B.F.A., J.G., N.R.A., T.M.L., T.D.), University of California, San Francisco (UCSF), San Francisco, California, USA. Electronic address: thuy.doan@ucsf.edu.

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 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.

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

Affiliations

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous