Metagenomics May Enhance the Diagnosis of Infectious Keratitis

Christopher J. Rapuano, MD


April 14, 2021

Corneal infiltrates and ulcers are commonly seen in clinical practice. Most are mild and can be successfully managed empirically using frequent broad-spectrum topical antibiotics without obtaining smears and cultures. But there are notable exceptions.

Practicing in a tertiary care referral center, I treat many of these more severe infections. I routinely perform corneal scrapings for smears and cultures to identify the pathologic organism and to determine sensitivity results in order to prescribe the most effective antimicrobial agent. Before I receive the results, though, I treat the infection with broad-spectrum (often fortified) antibiotics. When the culture comes back negative, as it often does, it can be extremely frustrating for both the physician and the patient.

If the infection is improving, I'm not sure which of my antibiotics is working and consequently need to continue both. This increases not only the cost to the patient/healthcare system but also ocular toxicity.

And if the infection is not improving, the lack of a positive culture result leaves me in the dark as to what type of infection I'm treating. I might need to repeat the corneal scraping or perform a more invasive procedure such as a corneal biopsy.

A Metagenomic Solution?

A recent study by Lalitha and colleagues investigated a possible solution for this problem in the form of metagenomic deep sequencing (MDS), which included both RNA sequencing and DNA sequencing. They compared MDS with standard corneal cultures on 46 corneal ulcers.

With standard culture, the result was positive in 52% of eyes, compared with 74% in MDS-assessed eyes. Furthermore, in comparing all the methods (ie, KOH and Gram stain and culture, RNA sequencing, DNA sequencing), they found the highest performance with RNA sequencing, approaching 100% sensitivity and specificity for both fungal and bacterial infections.

Given that this study was conducted in India, it is not surprising that about two thirds of identified infections were fungal and only one third of infections were bacterial. Of note, no viral or parasitic infections were identified in this patient population. Those facts, plus the relatively small sample size, may somewhat limit the generalizability of this study.

Although there is no gold-standard diagnostic test to identify the cause of infectious keratitis, having another option in our toolbox would be most welcome.

How rapidly MDS could become a routine clinical diagnostic test depends on many factors, including local microbiology laboratories' ability to perform the test, the cost of testing, and the turnaround time for results. Currently, the cost is higher and the turnaround time is longer than standard cultures, but both of these factors are expected to improve considerably over time. Another downside of these genetic analyses is their inability to perform sensitivity testing.

I look forward to being able to diagnose infectious keratitis much more accurately and rapidly than we do today. Although MDS may get us closer to that goal, its true value must first be shown in more studies with larger groups of patients.

Christopher J. Rapuano, MD, is a nationally and internationally recognized expert in corneal diseases, chief of the Wills Eye Hospital Cornea Service, and professor of ophthalmology at Sidney Kimmel Medical College at Thomas Jefferson University.

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