Ocular surface epithelial immune cells and corneal nerves in dry eye disease - A systematic review and meta-analysis of in vivo confocal microscopy data
Soumen Sadhu, Isabelle Jalbert, Luz Palacios-Derflingher, Ali Saad Thafeed AlGhamdi, Blanka Golebiowski, Fiona Stapleton
Abstract
Purpose To examine ocular surface epithelial immune cell (EIC) density and corneal nerve parameters between patients with dry eye disease (DED) compared to healthy controls with further comparisons between auto-immune - Sjӧgren Syndrome DED (SS-DED) and non-autoimmune – non-Sjӧgren Syndrome DED (NSS-DED) subtypes. Methods A systematic review and meta-analysis following PRISMA guidelines (Prospero-CRD42023446763) were conducted including studies reporting corneal and conjunctival EIC density and/or corneal nerve parameters in DED and healthy controls using in vivo confocal microscopy. Electronic databases – PubMed, Embase, Scopus, Web of Science were searched from inception to March 2025. Results The meta-analysis included 24 studies (n=1060 DED, n=521 controls) reporting EIC density, 30 studies reporting nerve length (CNL; n= 1450 DED, n= 643 controls) and 20 studies reporting nerve density (CND; n=919 DED, n=462 controls) in the central cornea. Studies of other ocular surface locations were insufficient for meta-analysis. Higher central corneal EIC density was evident in DED compared to controls (MD: 57.9 cells/mm 2 ; 95% CI: 43.3, 72.5; p<0.001), and in, SS-DED compared to NSS-DED (51.0 cells/mm 2 ; 95% CI: 12.0, 90.0; p=0.01). DED had lower CNL (-4.0 mm/mm 2 ; 95% CI: -5.2, -2.7; p<0.001) and CND (-7.2 nerves/mm 2 ; 95% CI: -10.3, -4.1; p<0.001) compared to controls. No significant differences in nerve parameters were found between SS-DED and NSS-DED subtypes (CNL: 95% CI: -3.0, 1.4, CND: -6.8, 4.8; p≥ 0.46). Conclusion DED involves substantial EIC infiltration and reduced corneal nerve parameters. SS-DED is distinguished by higher EIC density than NSS-DED, while no differences were observed in corneal nerve parameters.