Documenta Ophthalmologica 80: 363-369, 1992. 9 1992 Kluwer Academic Publishers. Printed in the Netherlands.
S y s t e m i c acyclovir and p e n e t r a t i n g k e r a t o p l a s t y for herpes s i m p l e x keratitis
C. STEPHEN FOSTER & NEAL P. BARNEY Immunology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston Mass., USA Accepted 3 July 1992
Key words: Acyclovir, corneal transplantation, herpes keratitis, rejection Abstract. Corneal graft survival in 13 patients (14 eyes) receiving oral acyclovir following
corneal transplantation for herpes simplex keratitis was compared to that in nine patients (9 eyes) who underwent penetrating keratoplasty for herpes simplex keratitis without receiving postoperative acyclovir. Mean age, duration of disease, and time of follow-up did not differ in the two groups. There were no recurrences of herpes simplex keratitis in any patient receiving acyclovir during a mean follow-up of 16.5 months compared to a 44% (4/9) recurrence rate in patients without acyclovir during a mean follow-up of 20.6 months (p < 0.01). Graft failure occurred in 14% (2/14) of acyclovir treatment eyes and in 56% (5/9) of the grafts in patients not receiving acyclovir. Long term prophylactic oral acyclovir significantly decreased the recurrence of herpes simplex keratitis and reduced corneal graft failure in patients with a history of recurrent herpes simplex keratitis who underwent corneal transplantation. Abbreviations: ACV - acyclovir; HSK - herpes simplex keratitis; PK - penetrating keratoplasty
Introduction Corneal scarring from herpes simplex keratitis (HSK) is a leading indication for penetrating keratoplasty (PK) in developed countries. The survival rate of corneal grafts performed for HSK ranges from 14% to 61% [1,2]. Recurrence of HSK is a leading cause of corneal graft failure in patients undergoing PK and topical antivirals given prophylactically following PK for HSK have been associated with epithelial toxicity [3] and diminished wound strength in an animal model [4]. Herpes simplex keratitis recurrence rate is not greater if prophylactic topical antivirals are withheld postoperatively [5]. Chronic (up to five years) oral acyclovir use, 400 mg twice daily, has been proven to be effective in reducing recurrences of oral and genital herpes simplex [6, 7], and a multicenter trial is currently underway to determine the effect of oral ACV on recurrent HSK. No studies to date have reported the effect of postoperative oral ACV on the survival of corneal grafts performed Presented as a paper at The American Academy of Ophthalmology, annual meeting in Anaheim, California 13-17 October 1991.
364 for HSK [8]. We studied the recurrence-free interval of herpes keratitis in patients undergoing PK for HSK who received postoperative oral acyclovir and compared this to the recurrence-free interval in patients who underwent PK for HSK without perioperative ACV. We also studied the prevalence of corneal graft rejection and irreversible graft failure secondary to rejection in these two cohorts of HSK patients.
Subjects and methods All patients from the Immunology Service of the Massachusetts Eye and Ear Infirmary undergoing penetrating keratoplasty for HSK from 1 January 1987 through 31 December 1990 were randomly assigned to one of two groups: Group A, the treatment group, received prophylactic postoperative oral ACV beginning prior to surgery or on the first postoperative day. Group B, the control group, did not receive perioperative ACV. The diagnosis of HSK was based on the findings of recurrent dendritic or geographic epithelial keratitis, metaherpetic ulceration, or disciform stromal keratitis. Patients were free from active inflammation for at least three months and usually six months prior to surgery. Pregnant or lactating females and women of child-bearing age not on oral contraceptives were excluded from the study. In all cases, the indication for surgery was HSK corneal scar and significantly impaired vision. Preoperative control of meibomian gland dysfunction was accomplished by local and systemic treatment as needed. K-sol preserved donor tissue was obtained from Tissue Banks International, Baltimore, Maryland. The 7.5mm recipient bed was prepared with a Hessburg trephine. Sixteen 10-0 monofilament nylon interrupted sutures (knots buried) were used to secure the 8.0 mm graft. Cataract surgery and other procedures were performed concurrently when indicated (Table 1). All procedures were performed by a single surgeon (CSF). Patients were examined on the first postoperative day, at one, two, and four weeks and then monthly following surgery for the first year. Loose sutures were removed as indicated. Corneal graft rejection episodes were determined clinically on the basis of anterior chamber reaction with KP on the donor endothelium (without recipient endothelium involvement) or by the development of an endothelial rejection line. Recurrent HSK was determined by culture when suspected or clinically by the typical findings of epithelial dendrites or stromal keratitis. Neither the surgeon nor the subjects were masked in this study, but data tabulation by one of the authors (NB) was masked. Routine postoperative topical medications used in both groups included Polysporin ointment two times daily for ten days and prednisolone sodium phosphate 1% four times daily, tapered over three months. Topical beta blockers were continued in patients who required them preoperatively and instituted in those patients in whom increased intraocular pressure compli-
365 Table 1. Surgical procedures at the time of penetrating keratoplasty
Procedure
Group A
Group B
ECCE IOL IOL removal Anterior vitrectomy Peripheral iridectomy Synechialysis Suture replacement Tarsorrhaphy
5/14 (36%) 4/14 (29%) 1/14 (7%) 3/14 (21%) 2/14 (14%) 0 1/!4 (7%) 1/14 (7%)
4/9 (44%) 4/9 (44%) 0 1/9 (11%) 0 1/ 9 (11%) 1/9 (11%) 0
cated their course. Diflunisal 500 mg twice daily was used postoperatively by both groups for one month. Group A received 800 or 1000mg of ACV orally each day in four or five divided doses. The dose of ACV was tapered over 12 months with some patients taking ACV for up to 15 months. Recurrent epithelial HSK was treated by either topical ACV ointment or topical trifluridine drops. Corneal graft rejection episodes were treated by hourly topical administrations of prednisolone sodium phosphate 1% and prophylactic coverage with a topical antiviral. A Mann Whitney U test was used to compare the mean age at the onset of disease, the mean age at the time of surgery, the mean duration from the last episode of active HSK to surgery, the mean recurrence-free interval, and the mean rejection-free interval between the two groups. A X2 test with Yates correction, Log rank test, and Fisher's exact test were each used separately to compare groups for each of the following: the number of recurrences, number of rejections, and number of graft failures. A p ~
S y s t e m i c acyclovir and p e n e t r a t i n g k e r a t o p l a s t y for herpes s i m p l e x keratitis
C. STEPHEN FOSTER & NEAL P. BARNEY Immunology Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston Mass., USA Accepted 3 July 1992
Key words: Acyclovir, corneal transplantation, herpes keratitis, rejection Abstract. Corneal graft survival in 13 patients (14 eyes) receiving oral acyclovir following
corneal transplantation for herpes simplex keratitis was compared to that in nine patients (9 eyes) who underwent penetrating keratoplasty for herpes simplex keratitis without receiving postoperative acyclovir. Mean age, duration of disease, and time of follow-up did not differ in the two groups. There were no recurrences of herpes simplex keratitis in any patient receiving acyclovir during a mean follow-up of 16.5 months compared to a 44% (4/9) recurrence rate in patients without acyclovir during a mean follow-up of 20.6 months (p < 0.01). Graft failure occurred in 14% (2/14) of acyclovir treatment eyes and in 56% (5/9) of the grafts in patients not receiving acyclovir. Long term prophylactic oral acyclovir significantly decreased the recurrence of herpes simplex keratitis and reduced corneal graft failure in patients with a history of recurrent herpes simplex keratitis who underwent corneal transplantation. Abbreviations: ACV - acyclovir; HSK - herpes simplex keratitis; PK - penetrating keratoplasty
Introduction Corneal scarring from herpes simplex keratitis (HSK) is a leading indication for penetrating keratoplasty (PK) in developed countries. The survival rate of corneal grafts performed for HSK ranges from 14% to 61% [1,2]. Recurrence of HSK is a leading cause of corneal graft failure in patients undergoing PK and topical antivirals given prophylactically following PK for HSK have been associated with epithelial toxicity [3] and diminished wound strength in an animal model [4]. Herpes simplex keratitis recurrence rate is not greater if prophylactic topical antivirals are withheld postoperatively [5]. Chronic (up to five years) oral acyclovir use, 400 mg twice daily, has been proven to be effective in reducing recurrences of oral and genital herpes simplex [6, 7], and a multicenter trial is currently underway to determine the effect of oral ACV on recurrent HSK. No studies to date have reported the effect of postoperative oral ACV on the survival of corneal grafts performed Presented as a paper at The American Academy of Ophthalmology, annual meeting in Anaheim, California 13-17 October 1991.
364 for HSK [8]. We studied the recurrence-free interval of herpes keratitis in patients undergoing PK for HSK who received postoperative oral acyclovir and compared this to the recurrence-free interval in patients who underwent PK for HSK without perioperative ACV. We also studied the prevalence of corneal graft rejection and irreversible graft failure secondary to rejection in these two cohorts of HSK patients.
Subjects and methods All patients from the Immunology Service of the Massachusetts Eye and Ear Infirmary undergoing penetrating keratoplasty for HSK from 1 January 1987 through 31 December 1990 were randomly assigned to one of two groups: Group A, the treatment group, received prophylactic postoperative oral ACV beginning prior to surgery or on the first postoperative day. Group B, the control group, did not receive perioperative ACV. The diagnosis of HSK was based on the findings of recurrent dendritic or geographic epithelial keratitis, metaherpetic ulceration, or disciform stromal keratitis. Patients were free from active inflammation for at least three months and usually six months prior to surgery. Pregnant or lactating females and women of child-bearing age not on oral contraceptives were excluded from the study. In all cases, the indication for surgery was HSK corneal scar and significantly impaired vision. Preoperative control of meibomian gland dysfunction was accomplished by local and systemic treatment as needed. K-sol preserved donor tissue was obtained from Tissue Banks International, Baltimore, Maryland. The 7.5mm recipient bed was prepared with a Hessburg trephine. Sixteen 10-0 monofilament nylon interrupted sutures (knots buried) were used to secure the 8.0 mm graft. Cataract surgery and other procedures were performed concurrently when indicated (Table 1). All procedures were performed by a single surgeon (CSF). Patients were examined on the first postoperative day, at one, two, and four weeks and then monthly following surgery for the first year. Loose sutures were removed as indicated. Corneal graft rejection episodes were determined clinically on the basis of anterior chamber reaction with KP on the donor endothelium (without recipient endothelium involvement) or by the development of an endothelial rejection line. Recurrent HSK was determined by culture when suspected or clinically by the typical findings of epithelial dendrites or stromal keratitis. Neither the surgeon nor the subjects were masked in this study, but data tabulation by one of the authors (NB) was masked. Routine postoperative topical medications used in both groups included Polysporin ointment two times daily for ten days and prednisolone sodium phosphate 1% four times daily, tapered over three months. Topical beta blockers were continued in patients who required them preoperatively and instituted in those patients in whom increased intraocular pressure compli-
365 Table 1. Surgical procedures at the time of penetrating keratoplasty
Procedure
Group A
Group B
ECCE IOL IOL removal Anterior vitrectomy Peripheral iridectomy Synechialysis Suture replacement Tarsorrhaphy
5/14 (36%) 4/14 (29%) 1/14 (7%) 3/14 (21%) 2/14 (14%) 0 1/!4 (7%) 1/14 (7%)
4/9 (44%) 4/9 (44%) 0 1/9 (11%) 0 1/ 9 (11%) 1/9 (11%) 0
cated their course. Diflunisal 500 mg twice daily was used postoperatively by both groups for one month. Group A received 800 or 1000mg of ACV orally each day in four or five divided doses. The dose of ACV was tapered over 12 months with some patients taking ACV for up to 15 months. Recurrent epithelial HSK was treated by either topical ACV ointment or topical trifluridine drops. Corneal graft rejection episodes were treated by hourly topical administrations of prednisolone sodium phosphate 1% and prophylactic coverage with a topical antiviral. A Mann Whitney U test was used to compare the mean age at the onset of disease, the mean age at the time of surgery, the mean duration from the last episode of active HSK to surgery, the mean recurrence-free interval, and the mean rejection-free interval between the two groups. A X2 test with Yates correction, Log rank test, and Fisher's exact test were each used separately to compare groups for each of the following: the number of recurrences, number of rejections, and number of graft failures. A p ~
