Among the biggest frustrations in dry eye disease (DED): symptoms and clinical findings don't always match.
Case in point: While patients may report severe burning, irritation and fluctuating vision,standard tests often reveal little or no ocular surface damage. As such, this makes diagnosis and treatment decisions particularly challenging.
So with this in mind … new research suggests that measuring the inflammatory protein lymphotoxin-α (LTA) in tears could help bridge that gap by identifying different dry eye subtypes and disease severity using a single point-of-care (POC) test.
First, let's set the stage.
Dry eye is a multifactorial disease of the ocular surface driven by tear film instability, inflammation and neurosensory abnormalities.
Although clinicians routinely use tests such as tear breakup time (TBUT), corneal staining, and the Schirmer test, these findings often correlate poorly with how patients actually feel—a disconnect that has been recognized for years.
Go on …
Recognizing this disconnect, the recent Tear Film Ocular Society Dry Eye Workshop (TFOS DEWS) III report formally described the pain-without-stain phenotype as neuropathic pain: patients who experience significant dry eye symptoms despite having minimal or no detectable ocular surface staining.
Identifying these patients objectively remains an important unmet clinical need.
And what did the researchers want to find out?
Researchers investigated whether tear LTA concentration could serve as a single biomarker for diagnosing dry eye, grading disease severity, and distinguishing clinically important subgroups—including patients with pain-without-stain.
To note: LTA belongs to the tumor necrosis factor (TNF) superfamily and plays an important role in immune signaling.
- Previous studies suggested that reduced tear LTA levels may be associated with dry eye, but its usefulness as a clinical diagnostic tool has not previously been fully established.
Let’s talk study details: who was included?
The prospective study enrolled 160 adults evaluated at Fudan University in Shanghai, China, between 2020 and 2023.
Participants included:
- 75 patients with clinically diagnosed dry eye
- 55 individuals without dry eye
- 30 patients with pain-without-stain who reported classic dry eye symptoms but did not meet current diagnostic criteria based on clinical signs
All participants underwent a comprehensive dry eye evaluation, including Ocular Surface Disease Index (OSDI), TBUT, Schirmer testing, corneal and conjunctival staining, impression cytology, and measurement of multiple inflammatory tear biomarkers.
Tear LTA was measured using a rapid point-of-care assay requiring only 2.2 µL of tear fluid.
And what was found?
Tear LTA concentrations differed significantly across all three groups.
Patients with dry eye had the lowest average LTA levels, healthy controls had intermediate levels, and patients with pain-without-stain had the highest concentrations.
Using the manufacturer's diagnostic cutoff of 800 pg/mL, the test agreed with expert clinical diagnosis in 83.9% of cases, with:
- 85.3% sensitivity
- 81.8% specificity
Lower LTA concentrations also tracked with increasing disease severity. The researchers identified exploratory thresholds of:
- <105 pg/mL for severe dry eye
- 105–855 pg/mL for mild dry eye
- 855–1,580 pg/mL for non-dry eye
- >1,580 pg/mL for pain-without-stain
Anything of particular interest to note?
Indeed … involving the pain-without-stain group.
Although these patients lacked the clinical staining typically used to diagnose dry eye, they demonstrated markedly elevated LTA concentrations along with significantly increased inflammatory mediators ( MMP-9, IL-1β, IL-6, IL-8, IL-17 and IFN-γ).
What this suggests: Inflammation may already be active before conventional clinical signs become apparent.
Conversely, patients with the lowest LTA concentrations exhibited the greatest ocular surface damage, shortest TBUT, lowest Schirmer scores, fewer conjunctival goblet cells, and the highest inflammatory burden.
This supported LTA's potential role as an objective marker of disease severity.
Now to the study’s limitations.
Among several the authors noted:
- The study was conducted at a single center
- The proposed LTA cutoff values require validation in larger multicenter populations before they can be adopted clinically
- Most participants also had mixed-type dry eye, making it difficult to determine whether LTA behaved differently across individual dry eye subtypes
So, what could this mean for clinicians?
If confirmed in future studies, tear LTA testing could simplify one of the most difficult aspects of dry eye management: objectively identifying patients whose symptoms don't match their examination findings.
Rather than relying solely on combinations of traditional clinical tests, clinicians may eventually have access to a biomarker that helps diagnose disease, estimate severity, and identify biologically distinct patient subgroups using a single rapid assay.
Anything else worth pointing out?
The investigators also suggested that patients with very high LTA concentrations may represent an earlier inflammatory stage of disease rather than a separate condition altogether.
Future studies will need to explore whether identifying these patients earlier could allow treatment before permanent ocular surface damage develops.