Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients With Diabetic Macular Edema

Abstract

Citation: Lee H, Jang H, Choi YA, Kim HC, Chung H. Association between soluble CD14 in the aqueous humor and hyperreflective foci on optical coherence tomography in patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2018;59:715-721. https://doi.org/10.1167/ iovs. PURPOSE. To investigate the associations between soluble CD14 (sCD14), a cytokine released by microglia and macrophages, and hyperreflective foci (HF) and various characteristics of spectral-domain optical coherence tomography (SD-OCT) in diabetic macular edema (DME).METHODS. Sixty-nine eyes from 51 patients with DME and 28 eyes from 28 control subjects were studied. sCD14 levels in the aqueous humor (AH) were measured using ELISA before bevacizumab injection (IVB), and the associations between sCD14 and visual acuity, the number of HF, retinal volume, and the DME pattern were assessed.RESULTS. sCD14 levels were higher in DME patients than in the control subjects (29.9 6 41.6 pg/mL versus 8.1 6 3.6 pg/mL, P < 0.001). sCD14 levels in diffuse edema were higher than those in focal edema (50.0 6 65.3 pg/mL versus 19.8 6 14.7 pg/mL, P ¼ 0.039). The number of HF in the inner retina of patients with diffuse edema was significantly higher than that in patients with focal edema (4.4 6 2.3 vs. 2.6 6 2.1, P ¼ 0.001), but no difference was found in the outer retina (5.8 6 3.4 vs. 5.0 6 3.9, P ¼ 0.25). According to multivariate analyses, elevated sCD14 levels were associated with an increased inner nuclear layer volume and the total number of HF in all retinal layers on SD-OCT. Reduction of DME following IVB was correlated with reduction in the number of HF in a subset of eyes followed longitudinally in the study (n ¼ 30).CONCLUSIONS. DME patients with diffuse edema exhibit higher sCD14 levels in the AH and more HF in the inner retina than patients with focal edema, indicating severe inflammation. The strong correlation between sCD14 and HF in the inner retina suggests that the HF observed on SD-OCT may be due to activated microglia in DME.Keywords: CD14, hyperreflective foci, diabetic macular edema, diffuse edema type, focal edema type D iabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy (DR).1 The disruption of blood-retinal barriers induces the influx of fluid into the retina, resulting in DME.2 Although the pathogenesis of DR is not fully elucidated, inflammatory reactions, including monocyte/macrophage recruitment and microglia activation, are considered among the causative factors of DME. 3CD14 is a cytokine associated with the innate immune response and is expressed in microglia, monocytes, and macrophages.4 CD14 exists in two forms: membrane-bound or soluble (sCD14) 5 ; both forms are related to the activation of the inflammatory response. 6 In DME, the levels of sCD14 are elevated in the aqueous humor (AH) and vitreous humor and are associated with increased levels of VEGF.7 Microglia are resident immune cells in the retina that are involved in the inflammatory changes underlying DR. In DR, microglia p...

Hyperreflective Intraretinal Foci as an OCT Biomarker of Retinal Inflammation in Diabetic Macular Edema

“…The authors found both higher levels of sCD14, and increased number of HF in the inner retina compared to controls, and concluded that, since sCD14 is released by retinal microglia, HF might represent aggregates of activated microglial cells in DME eyes. 1 The presence of and changes in OCT HF, also called hyperreflective spots, have been previously described in detail in diabetic eyes and reported to depend on activated microglia. [2][3][4][5] DME-affected eyes treated with intravitreal anti-VEGF and steroids have also been investigated, demonstrating a reduction of HF number with both treatments-confirming HF as a retinal inflammatory biomarker.…”

“…We read with great interest the article titled ''Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients with Diabetic Macular Edema'' by Lee et al 1 The authors investigated the expression of soluble CD14 (sCD14) in aqueous humor (AH) samples of patients with diabetic macular edema (DME), and the presence of hyperreflective foci (HF) on spectral-domain optical coherence tomography (SD-OCT) in these eyes. The authors found both higher levels of sCD14, and increased number of HF in the inner retina compared to controls, and concluded that, since sCD14 is released by retinal microglia, HF might represent aggregates of activated microglial cells in DME eyes.…”

Glucose-Regulated Protein 78 in the Aqueous Humor of Patients with Diabetic Macular Edema

“…Previously, HF were suspected as subclinical features of lipoprotein extravasation or migrating pieces of retinal pigmented epithelium [36,37]. However, recent reports suggested that HF can be activated forms of microglia and markers of inflammation [38,39]. On the other hand, EZ integrity reflects the health of the photoreceptor layer; EZ disruption is associated with a poor visual prognosis in DME patients [40].…”

Author Response: Hyperreflective Intraretinal Foci as an OCT Biomarker of Retinal Inflammation in Diabetic Macular Edema

“…We would like to convey our gratitude to Midena et al 1 for their thoughtful letter to the editor and their insightful comment regarding our article. 2 As shown in a previous study by Vujosevic et al, 3 the reflectivity of hyperreflective foci (HF), as aggregates of retinal microglial cells, might be lower than that of the retinal pigment epithelium (RPE) and could be similar to that of the retinal nerve fiber layer (RNFL). We also agree with the opinion that any investigation of HF regarding optical coherence tomography (OCT) in diabetic eyes should be more precise to avoid inconsistent results because counting HF in diabetic macular edema (DME) could be fairly subjective due to its similarity with other entities, such as hard exudate.…”