Corneal Graft Success Rates in HSV Keratitis: A Systematic Review

A B S T R AC T Herpes Simplex Virus (HSV) has worldwide prevalence. The primary objective of this systematic review was to compare penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) regarding the efficacy and complications of the treatment of corneal scarring caused by herpes simplex keratitis. Out of the 469 articles identified during the combined search of the literature based on the PubMed and Cochrane libraries, 10 retrospective and 2 prospective studies published from January 2010 to December 2019 were included. The study outcomes indicated that both surgical approaches resulted in a comparable improvement of visual acuity (VA). However, DALK demonstrated fewer complications in the majority of studies. Higher graft survival rates were associated with higher acyclovir (ACV) doses (above 800 mg/day), topical steroid and antibiotic drops. In conclusion, in terms of postoperative VA, both PK and DALK demonstrate comparable efficacy. However, DALK, which is applied in less severe HSK cases, is associated with fewer complications and better graft survival rates. High dosages of ACV, topical steroids and antibiotics contribute significantly to improved postoperative outcomes.


INTRODUCTION
Herpes Simplex Virus (HSV) which belongs to the herpesvirus family is usually asymptomatic, however, it may affect a great variety of organs (1)(2). It is estimated that in the U.S. alone 500,000 people suffer from ocular HSV and every year about 50,000 new cases of ocular HSV are diagnosed (3). Following the entry into the host, HSV replicates within the end organ. Following replication, the virus gains the ability to travel up the axon of the corresponding nerve and colonize the corresponding ganglion, where it lies in a latent state (4). For infections involving the face, the trigeminal nerve, which supplies the sensory innervation of the face, and the trigeminal ganglion are involved. In some patients, a number of stimuli, either physical, such as corneal trauma (eye injury, surgery, excimer laser) or other factors such as psychological stress, fever, systemic infection, immunodeficiency, sunlight exposure and menstruation (4)(5)(6), trigger reactivation of HSV. As a result, the virus replicates and travels down the axon of the sensory nerve to its target tissue, causing recurrent infection and stimulating an inflammatory response. The spectrum of ocular disease caused by HSV is wide and depends on the target tissue that is infected. Both the anterior and posterior segments of the eye can be involved; among them, herpetic blepharitis, conjunctivitis, keratitis, as well as herpetic uveitis (iridocyclitis or trabeculitis) are some possible manifestations. In the most severe and rare cases, necrotizing herpetic retinopathy may occur with devastating outcomes to the visual capacity.
Regarding corneal disease, Herpes Simplex Keratitis (HSK) is the leading cause of corneal infectious blindness in developed countries (7). HSV has the ability to infect all the layers of the cornea and lead to infectious epithelial keratitis, neurotrophic keratopathy, necrotizing stromal keratitis, immune stromal keratits and/or endothelitis. The most typical lesion of HSK is the dendritic ulcer and the geographic ulcer in severe cases; both can be stained positively with fluorescein. Other examinations such as polymerase chain reaction (PCR), tear collection and immunofluorescence antibody assay (IFA) have also been used in order to identify the virus (4). Corneal epithelium involvement may occur in up to two thirds of the cases with herpetic ocular disease (8). However, the relapsing and recurring disease of stroma and endothelium is responsible for most of the cases of corneal scarring and neovascularization. Disciform keratitis is related to about 2% of initial ocular HSV presentation. Nevertheless, it is responsible for 20-48% of disease recurrences (8)(9). Herpetic keratitis can result in reduction of visual acuity (VA) to <6/12 in 10-25% and corneal scarring in 18-28% (9). Patients suffering from HSK usually have a red painful eye accompanied by other symptoms such as discharge, irritation, itching, watery eyes and photophobia.
Acyclovir (ACV), either in topical, oral or intravenous form, remains until today the mainstay of treatment against all herpes ocular disease's types. ACV can be used in combination with corticosteroids or other antiviral drugs like ganciclovir (GCV) or valaciclovir (VCV). However, oral or topical drugs do not eradicate the virus but only lower the risk of recurrence of ocular disease. In case of HSV-induced corneal opacities, surgical debridement may be indicated (4).
Deep anterior lamellar keratoplasty (DALK) is a surgical procedure in which the pathological stroma is excised down to Descemet membrane (DM), leaving the original corneal endothelium intact. As a result, DALK can be used for the treatment of corneal scarring when the endothelium and DM have not been affected (10)(11)(12). On the other hand, penetrating keratoplasty (PK) is another surgical technique that could be used in HSK-induced corneal scarring, especially in those cases that is complicated with endothelial insufficiency. However, both DALK and PK suffer from a series of adverse effects (13)(14)(15); among them, endothelial rejection, cell loss or failure, damage to the iris and/or crystalline lens, microbial endophthalmitis and expulsive choroidal hemorrhage are part of the spectrum of the complications of PK. On the other hand, ruptures or microperforation of DM, double anterior chamber and recurrence of stromal cornea dystrophy in the residual bed are unique complications of DALK. Moreover, epithelial and stromal immune graft rejection, and graft failure can occur with either procedure and are commonly easily managed with topical corticosteroid drops. Corticosteroid-associated high intraocular pressure (IOP), cataract, decreased wound healing, and compromised local immunity are some additional adverse effects of both procedures, however, with DALK having fewer and less severe adverse effects in comparison with PK (16). Thus, apart from PK and DALK, several approaches have been used for the management of HSV keratitis including therapeutic contact lenses, collagenase inhibitors, tarsorrhaphy, conjuctival flap, and cyanoacrylate gluing (17)(18).
Within this context, the primary objective of this systematic review was to compare PK and DALK regarding the efficacy and complications of the treatment of corneal scarring caused by HSK.

STUDY DESIGN AND INCLUSION CRITERIA
This systematic review followed the Preferred Reporting Items for Systematic Reviews (PRISMA) statements checklist (19). The inclusion and exclusion criteria were defined before the initiation of the research. Only original articles and case series with 5 or more subjects were included whose main or secondary goal was to demonstrate outcomes regarding DALK or PK or both interventions in populations suffering from corneal scarring as a result of HSK. Commentaries, conference abstracts, editorials, letters to the editor, case series with less than 5 patients were not considered.
The selection criteria were defined by applying the PICO (Problem/Population, Intervention, Comparison, and Outcome) framework. Participants included immunocompetent adult patients (above 18 years old) with corneal scarring as a result of HSK. Intervention consisted of PK or DALK or both and the following postoperative drug administration. Some of the included studies compared PK and DALK, but articles in which intervention were PK or DALK without any comparison were also considered. DALK was primarily indicated when the endothelial layer and the DM of the cornea remained healthy with no sign of stromal edema, while PK was indicated when all corneal layers (epithelium, stroma and endothelium) were affected or, in specific, when corneal endothelial cell count was <700 cells/mm 2 or was undetectable. Primary outcomes included rate of rejections and VA. Secondary outcomes included rate of recurrence, graft failure, microperforation, double minor anterior chamber, graft melting and any other complications that were reported.

LITERATURE SEARCH STRATEGY
A literature search was performed based on the PubMed and Cochrane libraries using the following search terms: (HSK OR herpes simplex keratitis OR herpes OR herpes simplex virus OR HSV) AND (corneal scar OR PK OR penetrating keratoplasty OR DALK OR deep anterior lamellar keratoplasty). Moreover, the reference lists of the eligible studies and relevant review articles were cross-checked to identify additional pertinent studies. We retrieved articles published in English, French and German from January 2010 to February 2020 that met the selection criteria.

STUDY SELECTION AND QUALITY ASSESSMENT
The records found were checked for duplicates. Then, two independent reviewers who were blinded to each other decisions screened the articles first by title and abstract and after that full-text screening was conducted. Any conflict was dissolved by a third reviewer. Risk of bias of the eligible articles was conducted with "Quality Assessment Tool for Quantitative Studies" by Effective Public Health Practices (20). Again, the same two individual reviewers assessed the articles, blinded to each other's decisions and any conflict was resolved by a third reviewer. The results are demonstrated in Table 1.

Reference
Year of publication

DATA EXTRACTION
Data extraction was also carried out by (K.S.) and (E.C.), blinded to each other's decisions and (G.L.) resolved any conflict. The following information were noted: author, year of publication, study location, study design, total patients enrolled in the study, total patients who completed the study, patient demographic characteristics, treatment groups, dose and schedule of interventions, duration of follow-up, primary outcomes (rejection rate for the first rejection episode, VA) and complications.

LITERATURE SEARCH AND SELECTION
Overall, the combined search identified 469 articles. After the removal of duplicates, 435 studies remained. Our criteria were matched in 29 records and they were assessed in full-text form for eligibility. No additional study was identified through cross-check of reference lists. Out of twenty-nine articles, 17 were excluded due to the following reasons; 6 because of underage or immunodeficient subjects, 3 studies because they were not an acceptable article type, 3 because of missing results, 1 due to overlapping population and 4 records because they did not apply the eligible interventions (DALK or PK). A PRISMA flow chart is demonstrated in Figure 1. Finally, the 12 remaining articles were assessed for quality as it was described before and a summary of the results is demonstrated in Table 1.

STUDY CHARACTERISTICS
The 12 selected studies were published from January 2010 (21) to December 2019 (22). The present review included 10 retrospective (21, 23-31) and 2 prospective studies (22,32). The record's subjects varied from 13 eyes of 13 patients Sarnicola et al. (21) records. However, in the study of Lyall et al. (27), the rate of rejection was 50% during a follow-up period of 56-months. Rejection rate lower than 12% was noted in DALK using ACT (32) and glycerol-cryopreserved corneal tissues (GCCTs) (26). On the other hand, the rejection was 0% in DALK using precut ALC (31) and APCS (22) ( Table 3). Regarding the postoperative VA, a significant improvement was observed postoperatively after DALK using precut ALC (31) and DALK using GCCTs (26). The VA outcomes in DALK using ACT (32) and in APCS DALK (22) presented in Table 3 were mixed with other types of keratitis. In a case series of Zheng et al. (25), with mixed results of DALK and PK using APCS, VA was improved in 69.2% of the population and no rejection occurred. In the study of Shimizu et al. (23), PK and DALK procedures achieved similar improvement in VA but no data about the complications were given. PK showed graft rejection lower than 10% in the study performed by Altay et al. (30) and 93% of the patients achieved BCVA better than 1.2 logMAR. Last but not least, in the comparative study of Wu et al. (24), PK showed a significantly higher number of graft rejections when compared with full-bed DLK (41.3% and 0%, respectively, p < 0.05). Moreover, the VA was improved in 66.1% of the eyes that received full-bed DLK and 50.9% in the PK group.

SECONDARY OUTCOMES
In DALK procedure, HSK recurrence was observed from 0% (21) (Table 4). In the case series of Zheng et al. (25), PK and DALK were performed but with no comparison between interventions. The extracted data of these 12 articles are shown in Tables 2-4. The postoperative prescriptions are described in "dose and schedule of intervention" section of these tables.

PRIMARY OUTCOMES
Regarding DALK procedure (Table 2), a significant improvement in vision after the operations was described (21,(27)(28)(29). The rejection was lower than 5% in the studies of Ren et al. (28)

QUALITY ASSESSMENT
The assessment of study quality and the risk for bias is shown in the Table 1. Overall, 5 studies were classified as moderate (22,24,(30)(31)(32) in global rating, that means that the risk of bias is also moderate. On the other hand, 7 records had weak (21,23,(25)(26)(27)(28)(29) global rating and high risk of bias.

DISCUSSION
The present systematic review compared PK and DALK techniques in patients suffering from HSK-related corneal scarring. For the better understanding of our findings, the different available surgical procedures should be analyzed. PK is a full-thickness transplant procedure, in which a full-thickness resection of the patient's cornea is followed by transplantation of a full-thickness donor corneal graft. On the other hand, in DALK, host tissue is removed down to the DM and transplantation of a donor cornea is applied, following the removal of the donor endothelium (34). PK is indicated when all corneal layers (epithelium, stroma and endothelium) are affected. Thus, it seems that HSK cases which are involving the endothelium and are more severe would have more adverse outcomes than the less severe, not involving the endothelium HSK cases which are treated by DALK.
Our study outcomes indicate that both surgical approaches resulted in comparable improvement in VA. A direct comparison of the VA improvement between the two surgery groups was difficult to achieve because of the heterogeneity of the outcomes presentation. However, DALK demonstrated fewer complications in almost all reports except for one by Lyall et al. (27). A possible explanation of Lyall et al. for the increased rate of post-DALK complications was the fact that they used only 800 mg/day of ACV. Graft failure or graft melting has also been associated with low dose of ACV, but also with the non-use of topical steroids and antibiotics, in the report of Li S. et al. (22). In fact, further to ACV, the increased rates of graft survival following DALK are attributed to the intact recipient's endothelium, which assumes function almost immediately following the surgical procedure. The recovery of the function of the endothelium is facilitated by local cortisone drops. In general, in 9 out of 10 studies examining DALK complications (21-22, 24-26, 28-29, 31-32), the graft rejection rate was between 0% and 23.07%, while in one study (27), graft rejection occurred in 50% of DALK cases in a 56-month follow-up period. On the other hand, in the three studies examining PK complications (24)(25)30), the rate of graft rejection ranged between 0% and 41.3%.
To the best of our knowledge, this is the first review to report on PK and DALK following HSK-related scarring. Our outcomes suggest that, despite the fact, that both surgical interventions result in comparable improvement outcomes in VA, DALK is associated with fewer complications. Higher graft survival rates are correlated with higher ACV doses (above 800 mg/day), topical steroid and antibiotic drops.
Certain limitations of our study need to be noted. First, only few literature reports compared directly PK with DALK technique in HSK patients. As a consequence, many of our results were indirectly derived from descriptive studies or studies whose main object was the comparison of patient groups based on other criteria. In addition, the literature reports showed a great heterogeneity in the way the outcomes, especially the VA, were presented. Therefore, the direct comparison of the outcomes was challenging. Moreover, we only included studies with immunocompetent subjects, so eventually a significant number of immunodeficient cases was excluded. Finally, most of the articles received a moderate or weak global rating in the quality assessment control, due to the fact that they were non-randomized reports. There is no doubt that the inherent difference between PK and DALK could be clearly specified by randomized controlled trials (RCTs) that would compare sufficiently powered sample of patients with the same HSK severity who would be divided in PK-and DALK-groups. However, this kind of studies would arise ethical issues since patients with less severe HSK would receive a more invasive treatment like PK, and patients with more severe HSK would undergo a less invasive operation like DALK. Since PK is applied in more severe HSK cases than DALK, but also the visual outcomes of these surgical approaches are equally good, someone could suggest that PK is a better procedure compared to DALK. However, these surgical approaches were difficult to be practically compared as the final VA is not the only criterion for a successful operation. In fact, other criteria should be considered such as failure rate, peri-and postperative complications, and recurrence of herpetic keratitis in the graft. In addition to that, the two procedures have different indications as the DALK cannot be used when the DM and/or the endothelium have been compromised.

CONCLUSIONS
In terms of postoperative visual acuity, both PK and DALK demonstrate comparable efficacy. DALK, which is applied in less severe HSK cases, is associated with fewer complications and better graft survival rates. High dosages of ACV, topical steroids and antibiotics contribute significantly to improved postoperative outcomes.