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To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD.Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD.The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000).Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Chronic ocular graft-versus-host disease (GVHD) is a long-term complication after hematopoietic stem cell transplantation (HSCT) and leads to irreversible visual morbidity due to severe ocular surface impairments including visual disfunction. However, knowledge about the optical function in chronic ocular GVHD is limited because it is difficult to assess quantitative optical function objectively. The development of anterior segment optical coherence tomography has allowed objective quantification of optical function by evaluating corneal higher-order aberrations (HOAs). Therefore, we applied this quantification in chronic ocular GVHD patients and verified the correlation between corneal HOAs and visual acuity.We retrospectively reviewed chronic ocular GVHD patients and the recipients after HSCT. Then, analyzed the relationship between visual function and the severity of chronic ocular GVHD.The eyes of patients with chronic ocular GVHD had higher corneal HOAs than those of non-GVHD patients (HOAs; 0.481 ± 0.306 vs 0.254 ± 0.084, and 0.917 ± 0.609 vs 0.529 ± 0.130. P 0.001, and 0.002. 4-mm and 6-mm diameters respectively. Corneal HOAs were correlated with the severity of chronic ocular GVHD (r = 0.436. P 0.001). Moreover, corneal HOAs were correlated with visual acuity, especially in eyes with severe chronic ocular GVHD cases (HOAs; 4-mm r = 0.636. P = 0.036. Total 6-mm r = 0.871. P =0.001).We succeed to assess the objective value in the optical function of the chronic ocular GVHD. Quantification of corneal HOAs could be an objective evaluation to assess optical function in eyes with chronic ocular GVHD.

Purpose To investigate pathological changes in blood vessels and meibomian glands (MGs) in the eyelids of sclerodermatous chronic graft-versus-host disease (cGVHD) model mice. Methods We used an established major histocompatibility complex compatible, multiple minor histocompatibility antigen-mismatched sclerodermatous cGVHD mouse model. Blood vessels and MGs of eyelids from allogeneic bone marrow transplantation (allo-BMT) recipient mice and syngeneic bone marrow transplantation (syn-BMT) recipient mice were assessed by histopathology, immunohistochemistry and transmission electron microscopy. Peripheral blood samples from the recipients were examined by flow cytometry. Results Allo-BMT samples showed dilating, tortuous and branching vessels and shrunk MGs in the eyelids; showed significantly higher expression of VEGFR2 (p = 0.029), CD133 (p = 0.016), GFP (p = 0.006), and α-SMA (p = 0.029) in the peripheral MG area; showed endothelial damage and activation, fibrotic change, and immune cell infiltration into MGs compared with syn-BMT samples. Fewer Ki-67+ cells were observed in allo- and syn-BMT samples than in wild-type samples (p = 0.030). Ultrastructural changes including endothelial injury and activation, fibroblast activation, granulocyte degranulation, immune cell infiltration into MGs, and necrosis, apoptosis of MG basal cells were found in allo-BMT samples compared with syn-BMT samples. Conclusion A series of our studies indicated that cGVHD can cause eyelid vessel and MGs changes, including endothelial injury and activation, neovascularization, early fibrotic changes, immune cell infiltration, MG basal cell necrosis and apoptosis, and resultant MG atrophy.

Purpose To elucidate the correlation between lactoferrin concentration in the tear film and signs and symptoms of severe dry eye disease (DED) using a novel microfluidic paper-based analytical device (μPAD) and enzyme-linked immunosorbent assay (ELISA). Methods Twenty-four patients were recruited at the Keio University Hospital. Using a novel μPAD, lactoferrin concentrations were measured in 4 patients with GVHD-related DED, 3 patients with other types of DED and 2 controls (Group A). For validation by ELISA, 22 patients (7 patients from Group A) comprising 9 patients with GVHD-related DED, 6 patients with other types of DED and 7 controls were examined (Group B). The link between lactoferrin concentration and clinical data about the severity of aqueous tear deficient DED was also investigated by both μPAD and ELISA. Results The lactoferrin concentration in tear fluid of the DED patients was positively correlated between μPAD and ELISA (p = 0.006, r = 0.886). The tear fluid of the GVHD patients showed low or undetectable lactoferrin concentration. Analysis by ELISA demonstrated that lactoferrin concentrations in the tear film from the GVHD patients were significantly lower than those from the non-GVHD patients (p = 0.010576). ELISA revealed lactoferrin concentration correlated with the value of Schirmer test and tear film breakup time, whereas it was inversely correlated with OSDI, fluorescein and rose bengal scores. Conclusions The novel μPAD may pave the way for measuring lactoferrin concentration in tear fluid from DED patients. Our results suggested that lactoferrin concentration in tear fluid reflect the severity of DED.

Purpose To investigate the transformation in the composition of ocular surface microflora. Evidence shows that microbial diversity correlates with autoimmune disorders. Chronic ocular graft-versus-host disease (GVHD) is the lethal complication after hematopoietic stem cell transplantation (HSCT) which influences patients’ quality of life. It has a similar pathophysiology to autoimmune disorders but the relation of the microbial status especially in the ocular surface and chronic ocular GVHD is still unknown. Methods We prospectively harvested conjunctival microorganism with a cotton swab from following 3 groups, 32 eyes/20 ocular GVHD patients (9 males, 11 females), 28 eyes/20 nonGVHD cases (10 males, 10 females) which defined as post hematopoietic stem cell transplantation and without ocular GVHD, and 20 eyes/11 controls (7 males, 4 females). Conventional culture-based methods were performed to examine the microbial community. Results Ocular surface microbes in the GVHD patients was more complex in diversity compared with in the nonGVHD patients and the control. Staphylococcus species, Alpha-haemo Streptococcus, Corynebacterium species, Propionibacterium Acnes, Aerobic gram-positive cocci, Haemophilus Influenzae, and Aerobic gram-positive rod were observed in the GVHD patients, whereas only a few species detected in the other groups. Conclusions We found that ocular surface microbes in the GVHD patients is more diverse than that in the nonGVHD patients and the controls. These results suggest the alternation of microbes are involved in the pathogenic process of the chronic ocular GVHD. Further examination using state-of-the-art methods will be needed to gain greater insights into the diversity of microflora on the chronic GVHD-affected ocular surface.

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

Members of the DEWS Research Subcommittee reviewed research into the basic mechanisms underlying dry eye disease. Evidence was evaluated concerning the tear film, lacrimal gland and accessory lacrimal glands, ocular surface epithelia (including cornea and conjunctiva), meibomian glands, lacrimal duct system and the immune system. Consideration was given to both animal and human research data. Results are presented as a series of information matrices, identifying what is known and providing supporting references. An attempt is made to identify areas for further investigation.