Persistent ocular symptoms following mild COVID-19 may be associated with objective abnormalities detectable only through specialized ophthalmic testing and tear proteomics, according to a study published in Nature Communications. The findings suggest that patients with ongoing visual complaints following SARS-CoV-2 infection may require evaluation beyond routine eye examinations.
Researchers prospectively studied 100 patients in Sweden who developed persistent ocular symptoms for at least 12 weeks following nonhospitalized COVID-19 and compared them with 32 patients who recovered without ocular symptoms. Symptoms persisted from 3 months to as long as 3 years following infection, with 78 percent of affected patients reporting symptoms lasting at least 1 year. Only 39 percent had received a formal diagnosis of long COVID.
Patients with persistent ocular symptoms reported significantly greater vision-related disability than controls. The most common symptoms were light sensitivity (43 percent), eye pain (30 percent), eye fatigue (26 percent), and reduced focusing ability (23 percent), with most patients experiencing multiple symptoms simultaneously.
Routine ophthalmic examinations identified few abnormalities. In contrast, specialized testing detected deficits in near visual acuity, ocular alignment, and fusional reserves, along with reduced corneal nerve density, diminished corneal sensitivity, abnormal pupillary responses, and increased densities of mature dendritic and T cells in the corneal subbasal nerve plexus. These findings pointed to peripheral corneal neuropathy, ocular dysautonomia, and chronic immune activation that would not typically be identified during standard eye examinations.
Tear proteomic analysis identified 178 dysregulated proteins in patients with persistent ocular symptoms. Five proteins remained statistically significant after multiple-comparison adjustment: integrin beta-6 (ITGB6), neurofascin (NFASC), connective tissue growth factor (CTGF/CCN2), tryptase alpha/beta-1 (TPSAB1), and mitochondrial creatine kinase (CKMT1A/CKMT1B). Several protein changes also correlated with clinical findings, including associations between JUN and pupillary dysfunction and between ANGPTL2, SKAP2, and DAPP1 and corneal inflammatory cell changes.
The researchers also developed diagnostic models to distinguish patients with persistent ocular symptoms from controls. A model using five clinical parameters – including corneal nerve density, corneal sensitivity, pupillary function, and inflammatory cell density – achieved approximately 77 percent cross-validated diagnostic accuracy. Adding six tear protein biomarkers increased accuracy to approximately 91 percent, suggesting that integrating molecular biomarkers with specialized clinical testing may improve identification of post-COVID ocular sequelae.
The researchers noted that the study was limited by its modest sample size, recruitment strategy, and lack of a control group without prior SARS-CoV-2 infection. They also did not estimate the prevalence of persistent ocular symptoms following COVID-19.
The findings highlight tear proteomics as a potential adjunct to specialized ophthalmic testing and identify candidate biomarkers for future validation as objective diagnostic tools.
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