A New Treatment for Recalcitrant Neurotrophic Keratopathy of Ocular Graft-Versus-Host Disease with Virus Infection.

INTRODUCTION: Neurotrophic keratopathy (NK) is a rare degenerative ocular disease that can be difficult to treat. There were no effective resolutive treatments for severe NK caused by ocular graft-versus-host disease (oGVHD) along with virus infection. To address this question, we designed a prospective cohort study to evaluate the efficacy and safety of topical recombinant human nerve growth factor (rhNGF) in patients with recalcitrant NK of oGVHD and viral infection. METHODS: This prospective cohort study enrolled patients with recalcitrant NK diagnosed with oGVHD and treated with rhNGF. Clinical evaluations included the range of epithelial defects, best corrected visual acuity, intraocular pressure, slit-lamp examination, and corneal fluorescein staining. Examinations of the central corneal thickness, corneal sensitivity, and nerve fiber regeneration were performed at each visit at 4, 8, 12, 20 weeks and 6 months, respectively, after initiating rhNGF treatment. RESULTS: All enrolled patients were diagnosed with NK at stage 2 (7 eyes, 63.6%) or stage 3 (4 eyes, 36.4%) and responded to rhNGF treatment. Five of 11 (45.5%) and 9 of 11 eyes (81.8%) achieved complete corneal epithelial healing after 4 and 8 weeks, respectively. All 11 eyes (100%) achieved complete corneal healing after 12 weeks. There was also a significant reduction in the corneal ulcer area during each visit (P < 0.001), as well as in the corneal fluorescein staining score (P < 0.010). There was a significant improvement in corneal sensation when compared to the baseline (P < 0.050). CONCLUSION: Topical treatment with rhNGF effectively promoted the complete corneal healing of persistent epithelial defects and corneal ulcers in patients with recalcitrant NK in oGVHD and viral infection.

Development and validation of a diagnostic model for the identification of chronic ocular graft-versus-host disease (oGVHD).

Purpose: To verify the International Chronic Ocular Graft-Versus-Host Disease (ICCGVHD) Group diagnostic criteria and establish an easy-to-use and reliable diagnosis model for quick identification of chronic oGVHD. Methods: This study included 180 patients (355 eyes) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and visited the Peking University Third Hospital Cornea and Ocular Surface Disease Specialist Clinic from July 2020 to February 2021. The proportion of chronic oGVHD was 76.06% (279/355). Results: Five complaints, including eye dryness, photophobia, foreign body sensation, eye redness, and burning sensation; six ophthalmic examinations, including Ocular Surface Disease Index (OSDI) score, corneal fluorescein staining (CFS), tear break-up time (TBUT), Schirmer's test score without anesthesia, conjunctival score, tear meniscus height, and non-ocular GVHD-involved organs were significantly different between patients with chronic oGVHD and control group (p < 0.05). Binary logistic regression (backward LR algorithm) selection demonstrated that three variables retained diagnostic significance for chronic oGVHD: CFS (OR = 2.71 (1.92-3.81), p < 0.001), Schirmer's test score without anesthesia (OR = 0.83 (0.76-0.91), p < 0.001), and conjunctival score (OR = 1.96 (1.13-3.42), p = 0.031). A nomogram for the identification of chronic oGVHD was developed, and its performance was examined using an internal validation cohort (118 eyes). The areas under the curve (AUCs) for the three-variable-based nomogram were 0.976 (95% CI (0.959-0.992), p < 0.01) and 0.945 (95% CI (0.904-0.986), p < 0.01) in the development and internal validation cohorts, respectively. Conclusion: This concise three-variable-based nomogram based on ICCGVHD criteria could serve as an easy-to-use and reliable tool for rapid screening of chronic oGVHD.

Assessment of Corneal Epithelial Changes and Related Factors in Ocular Chronic Graft-Versus-Host Disease (GVHD) by in Vivo Confocal Microscopy.

PURPOSE: To evaluate corneal epithelial changes and related factors in chronic ocular graft-versus-host disease (oGVHD) patients. METHODS: 21 patients (35 eyes) with chronic oGVHD and 8 patients (12 eyes) without oGVHD after bone marrow transplantation were recruited for assessment involving in vivo confocal microscopy (IVCM) analysis, ocular surface parameter determination and tear cytokine level analysis. The IVCM corneal epithelial scoring system was used to evaluate corneal epithelial changes. RESULTS: There was a significant difference in the corneal epithelial score (p = .001) between the two groups. The corneal epithelial scores were significantly correlated with the corneal fluorescein staining scores (CFS, r = 0.463, p < .001), Schirmer's test (r = -0.389, p = .009) and tear cytokine levels of EGF (r = -0.491, p < .001) and APRIL (r = -0.318, p = .030). CONCLUSIONS: The depth of corneal epithelial defects can be estimated by the CFS. Corneal epithelial changes of chronic oGVHD are considered to be associated with lacrimal deficiency and a lack of EGF.

Tear Cytokines Associated With Therapeutic Effects in Chronic Ocular Graft-Versus-Host Disease.

PURPOSE: The local application of antiinflammatory and immunosuppressive agents is an effective method for the treatment of ocular graft-versus-host disease (oGVHD); however, we noticed that some patients with oGVHD did not respond to topical therapy as well as many others. This study aimed to determine whether tear cytokines were associated with therapeutic effects in oGVHD. METHODS: Forty patients with chronic oGVHD were enrolled and grouped as responders (n = 24) and nonresponders (n = 16) based on the clinical response to 1 month of topical treatment. Tear samples were collected from each participant before and after treatment, and the tear concentrations of 7 cytokines (IL-2, IL-6, IL-8, IL-10, IL-17A, TNF-α, and ICAM-1) were measured using microsphere-based immunoassay analysis. Differences between pretreatment and posttreatment tear samples were analyzed using the Wilcoxon test. RESULTS: No significant differences in ophthalmic symptoms or cytokine levels were observed between responders and nonresponders at baseline. After 1 month of topical treatment, ocular surface parameters (including Ocular Surface Disease Index, National Institutes of Health eye score, best-corrected visual acuity, corneal fluorescein staining score, and fluorescein tear film break-up time) were significantly ameliorated in responders, but not in nonresponders. Moreover, none of the cytokines exhibited significant alteration in nonresponders, whereas the tear levels of IL-6 (P = 0.031) and IL-8 (P = 0.037) exhibited significant decreases in responding patients. CONCLUSIONS: Our results revealed that tear IL-6 and IL-8 levels were significantly altered in response to topical oGVHD treatment.

A Miniaturized Piezoelectric MEMS Accelerometer with Polygon Topological Cantilever Structure.

This work proposes a miniaturized piezoelectric MEMS accelerometer based on polygonal topology with an area of only 868 × 833 µm2. The device consists of six trapezoidal cantilever beams with shorter fixed sides. Meanwhile, a device with larger fixed sides is also designed for comparison. The theoretical and finite element models are established to analyze the effect of the beam's effective stiffness on the output voltage and natural frequency. As the stiffness of the device decreases, the natural frequency of the device decreases while the output signal increases. The proposed polygonal topology with shorter fixed sides has higher voltage sensitivity than the larger fixed one based on finite element simulations. The piezoelectric accelerometers are fabricated using Cavity-SOI substrates with a core piezoelectric film of aluminum nitride (AlN) of about 928 nm. The fabricated piezoelectric MEMS accelerometers have good linearity (0.99996) at accelerations less than 2 g. The measured natural frequency of the accelerometer with shorter fixed sides is 98 kHz, and the sensitivity, resolution, and minimum detectable signal at 400 Hz are 1.553 mV/g, 1 mg, and 2 mg, respectively. Compared with the traditional trapezoidal cantilever with the same diaphragm area, its output voltage sensitivity is increased by 22.48%.

Biomarkers in Ocular Graft-Versus-Host Disease: Implications for the Involvement of B Cells.

Graft-versus-host disease (GVHD) is an immune-mediated inflammatory disease resulting from destruction of host tissue by donor immunoreactive cells and occurs in 30% to 70% of post-hematopoietic stem cell transplantation (HSCT) patients. Ocular involvement occurs in up to 60% to 90% of patients with chronic GVHD. T cells have long been recognized as a key driver of alloreactivity in chronic ocular GVHD (oGVHD). However, the role of B-cells has not been elucidated. To further explore the involvement of B-cells in the immune mechanism of chronic oGVHD and to uncover more sensitive biomarker indicators, we conducted this study on the tear cytokine analysis of chronic oGVHD. The study enrolled 18 patients (27 eyes) diagnosed with chronic oGVHD and 11 patients (22 eyes) diagnosed with dry eye disease (DED) as a control group. The microsphere-based immunoassay was used to determine 29 tear cytokines in both groups. Spearman's test was used to analyze the correlation between cytokine levels and different ophthalmic indexes (National Institutes of Health eye score, fluorescein tear film break-up time, corneal fluorescein staining, and Schirmer's test). Receiver operating characteristic curves were used to assess the predictive potential of the identified cytokines for chronic oGVHD. Twenty tear cytokine levels were elevated in patients with chronic oGVHD compared to those with DED (P < .05). Proliferation-inducing ligand (APRIL) and epidermal growth factor showed lower levels in patients with chronic oGVHD. Ultimately, IL-2, 6, and 8, ICAM-1 (CD54), E-selectin (CD62E), neuropilin-1, and B-cell activation factor (BAFF) levels had a strong correlation with ophthalmic indexes and an area under the curve (AUC) > 0.85. BAFF/APRIL exhibited superior diagnostic capabilities (AUC = 0.995; 95% confidence interval, 0.983-1.000). Our study identified IL-2, 6, 8, ICAM-1, CD62E, E-selectin, neuropilin-1, and BAFF as promising tear biomarkers that can indicate the severity of chronic oGVHD. Notably, APRIL/BAFF shows superior diagnostic capabilities, revealing that B cells may play an important role as immune substrates in chronic oGVHD. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Tear Cytokines as Biomarkers for Acute Ocular Graft-Versus-Host Disease.

PURPOSE: The purpose of this study was to analyze tear cytokine and complement levels in patients diagnosed with acute ocular graft-versus-host disease (oGVHD) and examine the consistency of these levels with the severity of clinical manifestations. METHODS: Ten patients with acute oGVHD (20 eyes) were enrolled for the assessment of tear cytokine levels and ocular surface parameters, and 18 healthy people (36 eyes) were selected as the control group. The tear cytokine and complement levels were measured using microsphere-based immunoassay analysis. RESULTS: The main clinical manifestations of acute oGVHD include eye redness, a large amount of purulent exudate, eye pain, and even false membranes. The levels of intercellular cell adhesion molecule-1, interleukin 6 (IL-6), interleukin 1 beta (IL-1ß), interleukin 8, epidermal growth factor (EGF), interleukin 7 (IL-7), B-cell activating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and complement in patients with acute oGVHD showed significant differences compared with those in normal people. Furthermore, the levels of IL-6, IL-1ß, EGF, GM-CSF, IL-7, and C3a showed a stronger correlation with ocular surface parameters. CONCLUSIONS: Our study was the first to enroll patients with acute oGVHD to assess tear cytokine levels as a method contributing to the diagnosis of acute oGVHD. In addition, it has been demonstrated that certain tear cytokines, including intercellular cell adhesion molecule-1, IL-6, IL-1ß, interleukin 8, B-cell activating factor, GM-CSF, IL-7, EGF, and complement, may be new diagnostic biomarkers for acute oGVHD.

Ophthalmic manifestations are associated with reduced tear lymphotoxin-α levels in chronic ocular graft-versus-host disease.

PURPOSE: To determine the role tear lymphotoxin-α (LT-α) in chronic ocular graft-versus-host disease (oGVHD). METHODS: Twenty-two chronic oGVHD and 17 control tear samples were collected, and commercial test strips were used to detect LT-α concentrations. Concentration differences between patients with and without oGVHD were determined via Mann-Whitney U test. The correlation between LT-α levels and ophthalmic parameters was analyzed using Spearman's test. RESULTS: The concentration of LT-α was significantly lower in oGVHD patients than in controls. LT-α levels were significantly correlated with OSDI, NIH eye score, T-BUT, and CFS among all participants. ROC analysis revealed that the area under the curve of LT-α was 0.847, and the cutoff value for chronic oGVHD diagnosis was 0.203 ng/mL. CONCLUSION: Our study revealed the significant decrease of tear LT-α in oGVHD, and suggested LT-α as a promising marker for chronic oGVHD diagnosis.

Tear Lipid Metabolites As Potential Diagnostic Biomarkers for Ocular Chronic Graft-Versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) remains a common threat after allogeneic hematopoietic cell transplantation (allo-HSCT), and ocular manifestations occur in up to 60% to 90% of cGVHD patients. We sought to reveal major metabolic dysregulation and to determine tear metabolites as potential biomarkers for ocular cGVHD. Twenty-three ocular cGVHD and 16 control tear samples were collected for this study. Differential metabolites were identified using a liquid chromatography-mass spectrometry system. Spearman's test was used to analyze the correlation between metabolites and ophthalmic indexes (National Institutes of Health [NIH] eye score, fluorescein tear film break-up time [T-BUT], corneal fluorescein staining [CFS], and Schirmer's test). Receiver operating characteristic (ROC) curve was analyzed to evaluate the prediction potential of identified metabolites for ocular cGVHD. Differential metabolites were mainly observed in lipid metabolites, and we highlighted the lipid dysregulation in glycerophospholipid metabolism, sphingolipid metabolism, and biosynthesis of unsaturated fatty acids. In glycerophospholipid metabolism, phosphatidylcholine (34:1) (PC [34:1]) exhibited the strongest correlation with NIH eye score (r = 0.80), T-BUT (r = 0.79), CFS (r = 0.77), and Schirmer's test (r = 0.69). In sphingolipid metabolism, sphingomyelin (SM) was the most consistent with T-BUT (r = 0.74) and CFS (r = 0.71), whereas lactosylceramide (LacCer) was the most consistent with NIH eye score (r = 0.76) and Schirmer's test (r = 0.64). In biosynthesis of unsaturated fatty acids, docosahexaenoic acid (DHA) had the highest correlation with NIH eye score (r = 0.73), T-BUT (r = 0.60), CFS (r = 0.67) and Schirmer's test (r = 0.67) (P < .0001 for all). ROC analysis revealed that area under the curve (AUC) values for PC (34:1) (AUC = 0.967), LacCer (AUC = 0.946), SM (AUC = 0.932), and DHA (AUC = 0.929) were significantly correlated with cGVHD (P < .0001 for all). Our study identified PC (34:1), SM, LacCer, and DHA as promising tear biomarkers to indicate metabolic dysregulation and ophthalmic manifestations in ocular cGVHD.

A Novel Tri-Axial Piezoelectric MEMS Accelerometer with Folded Beams.

Microelectromechanical (MEMS) piezoelectric accelerometers are diversely used in consumer electronics and handheld devices due to their low power consumption as well as simple reading circuit and good dynamic performance. In this paper, a tri-axial piezoelectric accelerometer with folded beams is presented. The four beam suspensions are located at two sides of the mass aligned with edges of the mass, and the thickness of the beams is the same as the thickness of the mass block. In order to realize the multi-axis detection, a total of 16 sensing elements are distributed at the end of the folded beams. The structural deformations, stress distribution, and output characteristics due to the acceleration in x-, y-, and z-axis directions are theoretically analyzed and simulated. The proposed accelerometer is fabricated by MEMS processes to form Mo/AlN/ScAlN/Mo piezoelectric stacks as the sensing layer. Experiments show that the charge sensitivity along the x-, y-, and z-axes could reach up to ~1.07 pC/g, ~0.66 pC/g, and ~3.35 pC/g. The new structure can provide inspiration for the design of tri-axial piezoelectric accelerometers with great sensitivity and linearity.

Tear cytokine levels in the diagnosis and severity assessment of ocular chronic graft-versus-host disease(GVHD).

PURPOSE: To analyse the tear cytokine levels of patients diagnosed with ocular chronic graft-versus-host disease(GVHD)and examine the consistency of these levels with different ocular surface parameters. METHODS: 23 ocular chronic GVHD patients were selected for the assessment of tear cytokine levels and ocular surface parameters (TBUT, CFS, OSDI, and Schirmer's test), and 16 dry eye disease(DED)patients without systemic immune disease were selected as the control group. The 23 cytokines were measured using microsphere-based immunoassay analysis and their consistency with different ocular surface parameters was studied. RESULTS: ICAM-1, IL-1ß, IL-6, and IL-8 showed elevated levels in the eyes of oGVHD patients compared to DED [P < 0.001]. IL-7 and EGF showed lower levels in the eyes of patients with oGVHD than in those of patients with DED [P < 0.0001]. Furthermore, the levels of IL-6 and IL-8 showed a stronger correlation with corneal fluorescein staining (CFS) (P < 0.05), and the levels of IL-6 and ICAM-1 were most consistent with fluorescein tear film break-up time (TBUT) (P < 0.05). CONCLUSIONS: Our study demonstrated certain tear cytokines, including ICAM-1, IL-1ß, IL-6, IL-8 IL-7 and EGF, as promising new possible diagnostic markers of chronic oGVHD and criteria for chronic ocular GVHD severity. Because tear sampling is noninvasive and simple, this method is expected to be an overwhelming applicable for the screening and diagnosis of chronic GVHD.