Research Article: Corneal biomechanical alterations in patients with chronic ocular Graft Versus-Host Disease

Date Published: April 25, 2019

Publisher: Public Library of Science

Author(s): Giuseppe Giannaccare, Marco Pellegrini, Leonardo Taroni, Federico Bernabei, Carlotta Senni, Arianna Grendele, Vincenzo Scorcia, Emilio C. Campos, Andrew W. Taylor.


To compare corneal biomechanics between patients with ocular graft versus-host disease (oGVHD) and healthy subjects (controls), and to further correlate these values with ocular and hematological characteristics.

The following procedures were performed in oGVHD patients and controls: Schirmer test (ST), break-up time (BUT), corneal and conjunctival staining, tear matrix metalloproteinase-9 (MMP-9) assay (InflammaDry test, Rapid Pathogen Screening, Inc, Sarasota, FL). Corneal biomechanics were calculated by using ocular response analyzer (ORA, Reichert Instruments, Depew, New York, USA). The Mann-Whitney U test was used to compare continuous variables between oGVHD patients and controls. Correlations of corneal biomechanics with ocular and hematological parameters were examined using Spearman’s correlation.

A total of 45 oGVHD patients (mean age ± SD, 51.5 ± 7.1 years) and 34 controls (47.8 ± 6.1 years) were included. Patients with oGVHD showed significantly lower values of corneal hysteresis (CH) and corneal resistance factor (CRF) compared to controls (respectively, 9.4 ± 1.8 mmHg vs 11.6 ± 1.6 and 9.7 ± 1.4 mmHg vs 12.3 ± 1.3; always p<0.001). Twenty-nine of the oGVHD eyes (64.4%) were strong-positive for MMP-9, while 16 (35.6%) were weak-positive. Conversely, only 4 of the control eyes (11.8%) were weak-positive for MMP-9. In patients with oGVHD, CH was significantly correlated with corneal staining (Rs = -0.316, p = 0.035), conjunctival staining (Rs = -0.437, p = 0.003), ST (Rs = 0.390, p = 0.008), BUT (Rs = 0.423, p = 0.004), oGVHD severity grade (Rs = -0.383, p = 0.009), and MMP-9 positivity grade (Rs = -0.429, p = 0.003), while CRF was correlated only with corneal staining (Rs = -0.317, p = 0.034). Corneal biomechanics are reduced in patients with oGVHD, and CH is negatively correlated with disease severity grade and MMP-9 tear levels.

Partial Text

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established and potentially curative treatment for a variety of malignant and non-malignant hematological disorders. Graft versus-host disease (GVHD) is a multi-organ systemic disease caused by complex interactions between donor and recipient immune systems and represents the leading cause of morbidity following HSCT.[1] Chronic ocular GVHD (oGVHD) develops in 40 to 60% of patients undergoing HSCT, and dry eye disease (DED) represents the hallmark of this condition.[2–4] The disease is thought to be the result of the progressive immune-mediate inflammatory damage of ocular surface structures, which may lead to lacrimal and meibomian glands dysfunction, conjunctival keratinization, corneal epitheliopathy, eyelid laxity and scarring, and in more severe cases even corneal melting and perforation.[5–7]

We screened a total of 51 post-HSCT patients during the study period. Of these, 45 patients fulfilled the inclusion criteria, and were finally enrolled in the study: 5 of them (11.1% of the total) belonged to the oGVHD severity grade 0, 11 (24.4%) to grade I and 29 (64.4%) to grade II. The remaining 6 patients were excluded from the analysis because the diagnosis of oGVHD was not reached (n = 3), or due to the presence of significant corneal alterations (neovessels) hampering accurate ORA measurements (n = 3). Thirty-four healthy subjects were enrolled as control group. The demographic and clinical parameters of patients included in the analysis are reported in Table 1. No significant differences in age and sex distribution between hematological patients and control subjects were found (always p > 0.05).

The cornea is a complex biomechanical composite, and the collagen present in the Bowman’s layer and stroma provides the major contribution to its biomechanical behavior.[21,22] Frequently, oGVHD determines the damage of corneal epithelium that can be observed at slit lamp examination as punctate keratopathy, filamentary keratitis, and persistent epithelial defect. In more severe cases, the persistent impairment of wound healing alters the stromal ultrastructure, with the onset of keratolysis, corneal melting and even perforation.[23] These alterations of both corneal epithelium and stroma might produce changes to a various extent of biomechanical properties of the cornea of oGVHD patients.

The present study shows that oGVHD impairs biomechanical properties of the cornea, likely as a result of the alterations of ultrastructure and architecture of stromal collagen fibrils. Since corneal biomechanical alterations are closely related to the grade of ocular surface inflammation, they might represent a possible new surrogate marker of oGVHD severity.




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