Correlation Between Human Tear Cytokine Levels and Cellular Corneal Changes in Patients With Bacterial Keratitis by In Vivo Confocal Microscopy

PURPOSE. We investigated bilateral tear cytokine levels in patients with unilateral bacterial keratitis (BK) as associated with in vivo confocal microscopic (IVCM) alterations in corneal nerves and dendritiform immune cells (DCs). METHODS. A total of 54 (13 BK, 13 contralateral, 28 healthy controls) tear samples was collected prospectively and analyzed by multiplex microbeads assay. The IVCM of the central cornea was performed on the same day, and assessed for corneal nerve and DC alterations. RESULTS. Interleukin-1 beta, IL-6, and IL-8 were significantly elevated only in affected eyes (66.6 +/- 26.8, 7174 +/- 2430, and 810 +/- 315 Pg/mL, respectively; P = 0.04, P < 0.001, and P < 0.001, respectively), compared to healthy controls (13.0 +/- 4.0, 171.8 +/- 32.1, and 56.5 +/- 33.8 Pg/mL). Levels of chemokine ligand 2 (CCL-2), IL-10, and IL-17a were elevated only in contralateral eyes (813 +/- 478, 86.7 +/- 38.3, and 3350 +/- 881 Pg/mL, respectively; P = 0.02, P = 0.01, and P = 0.04, respectively), compared to controls (73.7 +/- 25.3, 17.5 +/- 4.9, and 1350 +/- 337 Pg/mL). Triggering receptor expressed on myeloid cells (TREM)-1 was significantly elevated in affected (551 +/- 231 Pg/mL, P = 0.02) and contralateral unaffected (545 +/- 298 Pg/mL, P = 0.03) eyes compared to controls (31.3 +/- 12.4 pg/mL). The density of DCs was significantly increased in affected (226.9 +/- 37.3 cells/mm(2), P < 0.001) and unaffected (122.3 +/- 23.7 cells/mm(2), P < 0.001) eyes compared to controls (22.7 +/- 5.9 cells/mm(2)). Sub-basal nerve density significantly decreased in affected (3337 +/- 1615 mu m/mm(2), P < 0.001) and contralateral (13,230 +/- 1635 mu m/mm(2), P < 0.001) eyes compared to controls (21,200 +/- 545 mu m/mm(2)). Levels of IL-1 beta, IL-6, and IL-8 were significantly correlated with DC density (R = 0.40, R = 0.55, and R = 0.31, all P < 0.02) and nerve density (R = -0.30, R = -0.53, and R = -0.39, all P < 0.01). CONCLUSIONS. Proinflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM.