Incidence of ocular manifestations in patients with graft versus host disease after allogeneic stem cell transplant in Riyadh, Saudi Arabia

INTRODUCTION

Allogenic hematopoietic cell transplantation (allo-HCT) is the routine treatment and a potential cure with proven efficacy for wide variety of life threatening hematological diseases

. According to World Wide Network of Blood and Bone Marrow Transplantation, more than 90 000 hematopoietic stem cell transplants (HSCTs; 53% autologous and 47% allogenic) are performed every year worldwide

.Ever since the first successful allo-HCT in 1968, it has a significant contribution towards survival of patients suffering from these diseases. The new developments in this field like better immunosuppressive regimens, improved preconditioning protocols and human leukocyte antigen (HLA) typing have led to substantial increase in the survival rates after transplants

.But, like any other successful therapy, allo-HCT is also associated with its side effects. One of the major complications of allo-HCT is graft versus host disease (GVHD). The incidence of GVHD was reported to be 70.5% in 1974

. Even today, with all the advances, the incidence remains high (25%-70%),making it a worrisome cause of morbidity and mortality

.

Ocular Findings The five years cumulative incidence of oGVHD among post-transplant patients was 56.98%(Figure 1) with 95%CI (38.6%-71.7%). The incidence of developing oGVHD was not statistically different between gender (

=0.418; Figure 2). However, the incidence oGVHD was statistically significant in patients diagnosed withacute myelocytic leukemia (AML) as compared to acute lymphocytic leukemia (ALL;

=0.038; Figure 3). The mean latent period to develop ocular symptoms was 20.51±17.80mo(669.2±626.68d). Ocular signs and severity of ocular involvement was showed in Table 3. All patients with oGVHD received lubricant drops and 42.86% patients received cyclosporine 0.5% eye drops (Table 4). Local treatment for patients with eye involvement were showed in Table 4.

Statistical Analysis Quantitative variables, patient and donor’s age, were summarized and reported in terms of median.Categorical variables gender, pre-transplant and post-transplant characteristics and patients’ outcomes were reported in terms of frequency tables and percentages. The association between ocular manifestation and chronic GVHD was analyzed using the Fisher exact test. Statistical tests were declared significant if

-value was less than 0.05. The incidence was reported in terms of incidence rate and corresponding Wilson 95%confidence intervals (95%CI).

Ocular involvement can be of variable severity. It can even restrict the daily life activities of the patient thus effecting the quality of life. Timely recognition of the problem, diagnosis and aggressive treatment can improve the quality of life and save the vision

. Effective and appropriate preventive therapies have yet to be developed for oGVHD. Once diagnosed, ocular treatment includes intense lubrication and support of the ocular surface, stabilization of existing tear film, inflammation control and surgical intervention in form of punctal plugs, punctal cautery and limbal stem cell transplants

. We aim to evaluate the incidence and severity of oGVHD in patients who underwent allogenic stem cell transplants in this institution between 2010 till 2017. After assessing the disease burden and intensity, we also aim to design a protocol for the comprehensive assessment, timely diagnosis and ophthalmologic management of oGVHD.

SUBJECTS AND METHODS

Ethical Approval This study was approved by the King Abdullah International Medical Research Center Institutional Review Board (No.RC18/165/R). The data was collected from patients’ electronic medical record. The patients’ medical record number were identified through HCT database.

很多工程在實際施工過程中忽視安全問題，更有甚者，為了節約資金，減少了安全設施的購買，更別提主動的聘請安全管理人員，就目前所發生的安全事故，很大程度上是因為安全工程管理工作存在問題，給施工進程造成極大的安全隱患。這也就使得社會對于安全工程管理崗位的需求減少，學生的學習積極性不高，學校的內在培養動力不足。

Study Procedure After receiving ethical approval, the ocular data was picked from the ophthalmology history and examination charts. It included the date of referral to ophthalmology, ocular examination findings (visual acuity,meibomian gland dysfunction, corneal and conjunctival staining with severity, corneal scarring, tear film meniscus and breakup time, anterior and posterior segment examination findings, intraocular pressure, treatment given, punctual plugs used or not, and follow up response). Visual symptoms, ocular disturbances and ocular signs was graded according to the DEWS 2007 classification. This was determined by measuring the parameters which include symptoms of dry eyes, tear film breakup time (TBUT), and other abnormalities noted in the conjunctiva, cornea, tear film, lid, and meibomian glands

.We did not take Schirmer’s test in our evaluation as the test was not being done during study period in our center.

The common sites involved in chronic GVHD in order of frequency are skin (75%), mouth (51%-63%) and liver(29%-51%)

. Literature shows that 50%-90% of transplant recipients with systemic GVHD have ocular complication

.The 40%-60% of patients receiving allo-HCT get ocular chronic GVHD

. The mean latency from the transplant to the development of ocular GVHD (oGVHD) has been reported to be 16.4mo

. It affects almost all structures of the eye (lids, lacrimal glands, conjunctiva, cornea, uvea, vitreous,and choroids), but typically affects anterior segment. Posterior segment complications are less common as compared to the ocular surface disease

.

Logistic regression was used to explore the risk factors for developing ocular manifestation among patients diagnosed with post-transplant GVHD. Dependent variable was ocular manifestation (yes/no). The independent variables were patient’s age, donor’s age, CD3 and CD34 infused, donor’s gender mismatch, use of total body irradiation (TBI) and antithymocyte globulin (ATG). The results were reported as odds ratios (OR), 95%CI, and

-values. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Study Design and Participants This retrospective cohort study was conducted in patients who underwent allo-HCT from 2010 to 2017 in King Abdul-Aziz Medical City, Riyadh,Saudi Arabia. In this study, we defined oGVHD as dry eyes occurring after HSCT in patients who developed systemic GVHD and were not known to have previous history dry eyes. The criteria set for acute oGVHD was new onset eye discomfort with classic systemic acute GVHD, and that for chronic oGVHD was newly documented keratoconjunctivitis sicca (KCS) signs detected on slit lamp examination.

RESULTS

Out of 330 patients who underwent HSCT between years 2010-2017, incidence of systemic GVHD has been 18.48%which is very low compared to other studies with reported incidence of acute and chronic GVHD to be around 40% and 30%-70% respectively among the HLA-matched patients

.In literature, oGVHD develops in about 10% of acute GVHD patients and is poor prognostic sign

. Among 28 (44.26%)patients who developed ocular manifestation in our study only one patient had acute oGVHD.

We had 28 patients with oGVHD, out of which only 1 had acute ocular GVHD with only eye manifestation. Rest 27 patients with oGVHD had chronic GVHD (including overlap).All patients with oGVHD among chronic GVHD patients had liver and skin involvement in our study. All patients received corticosteroids as a systemic treatment (Table 2).

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