Infective keratitis is a common cause for corneal blindness in India.Fungal infections are the commonest of all forms of infective keratitis 1-3.A contributing factor for development of fungal infection is ocular trauma andcontamination of corneal lesions by soil and plant material. Another factorwhich contributes to increased incidence is widespread use of broad spectrumantibiotics and steroids 4.Fungal keratitis is often difficult to manage withmedical therapy alone 5-8.The management of fungal keratitis poses severalchallenges. The reasons for poor response to medical treatment are due to adelay in diagnosis and lapse in early institution of the therapy when theinfiltrate is smaller size. One major limiting factor in the management offungal keratitis is the absence of fungicidal medications.

All medications arefungistatic and hence the treatment success with medications alone is limited.9-10 An important cause of treatment failureis fungal recurrence after surgery, with the rate of recurrence of fungalkeratitis reported to range from 5% to 14% 5-8.Thus, fungal recurrence afterkeratoplasty is still a significant challenge for ophthalmologists. The post operative period can be complicatedby recurrences of the infection. It is well known that corticosteroids aredetrimental and favour the growth of fungus; hence topical corticosteroids arewithheld immediately after keratoplasty. As a consequence the inflammation inthe initial post–operative period is prolonged, thereby affecting the graftoutcomes. The reasons for recurrence fungal infections may be due to delay indiagnosis and lapse in early institution of the therapy.9The purpose of this study was to analyse theoutcomes of therapeutic penetrating keratoplasty for fungal keratitis.

Materials and methods     The study wasapproved by the Institutional Ethics Committee and followed the tenets ofDeclaration of Helsinki.PatientsA total of 198 fungal keratitis patients who did notrespond to topical and systemic antifungal drugs underwent corneal transplantationby means of Therapeutic PK (ThPK) at L V Prasad Eye Institute, Hyderabad, Indiabetween 2008 -2010 were included in the study . Data collected includeddemographics, microbiology of ulcers, type of surgical procedure performed,details of donor tissue in terms of Donar age, graft size and endothelialdensity, duration of follow up, time period of recurrence, clinical features ofthe recurrent keratitis, and management of recurrent keratitis.Diagnostic Methodsand Medical Management before Surgery   The standard practice pattern at theinstitute for the management of keratitis is described here briefly. All eyesclinically evaluated to have infection, irrespective of their previousdiagnosis and treatments undergo a microbiological evaluation. The diagnosis offungal keratitis is made on KOH mount, smear examinations and slit lampmicroscopy.

Following a microbiological confirmation on smears and/or cultureantifungal treatment is instituted comprising of Natamycin 5% suspension everyhourly and oral Ketoconazole twice/day. If the status of corneal ulcersdeteriorated or did not improve after periodic follow up of 3 days, therapeuticpenetrating keratoplasty is planned under a local /general anaesthesia toeliminate the eye of the infection. All patients underwent B-Scan ultrasoundbefore corneal transplantation to exclude endophthalmitis.Surgical techniqueand postoperative managementThe TPK was performed under peribulbar block. Intra-operatively,care is taken to size the graft 1 mm more than the area of the infiltrate inits widest dimensions. For routine TPK, after removal of the diseased cornea, theanterior chamber angle and iris surface were irrigated carefully with saline to remove any exudates and hypopyon at the angles andcareful inspection is done at the edges of the host to ensure that the area ofinfiltrate is completely excised. In those eyes, with total corneal infiltrate,peritomy is done to inspect the sclera of any contiguous spread and part of infectedsclera (as much is feasible to preserve the angle anatomy) is included in thetrephination).

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For cases with spontaneous rupture of the lens capsule resultingfrom fungal infection or having dense cataract, extracapsular cataract extraction(ECCE) was performed. Corneal grafts were secured with 16 interrupted 10-0nylon sutures.At the time of TPK, the infected corneal tissue is dividedinto 2 parts- One part of the tissue is sent for microbiological evaluation andsecond is subjected to histological study. The post-op care post therapeutickeratoplasty comprises of receiving frequent instillation of antifungal agentsand oral ketoconazole for 2 weeks along with antibiotics drops and nonsteroidalanti-inflammatory drops. Assessment was made for any recurrence during 2 weeks timeinterval, and initiating low dose topical steroids only after a period of 10-14days when the eye is clinically evaluated to have no evidence of residual/recurrence of infection.Detection andTreatment of recurrenceIn the postoperative examination of the patients withsuspected Recurrence, Slit lamp microscopy and Corneal scrapings were incubatedand examined as wet mounts with KOH; they then were subjected to fungal cultureand strain identification. The finding of fungal filaments from any of theabove examinations served as confirmation of fungal recurrence.

All recurrentpatients received eye drops of Natamycin 5% every 30 minutes combined with eyedrops of oral ketazonol. Anterior chamber recurrence was controlled with anintracameral injection of amphotericin B along with AC wash. Patients withposterior segment recurrence also received an intravitreal injection ofamphotericin B along with IOAB if required. Surgical treatment was used whendrug therapy was shown to be ineffective after approximately 5 to 7 days.Statistical Analysis:The software Origin v 7.0 (OriginLab Corporation,Northampton, MA, USA) was used to perform the statistical analysis. Normalityof the continuous data and homoscedasticity were evaluated using Shapiro-Wilkand Levene tests respectively.

Mean (± standard deviation) and median (alongwith inter-quartile range, IQR) were used to describe the parametric andnon-parametric data respectively. Kaplan-Meier survival plots were done fortime-to-event analyses. The recurrence rate after TPK and the presence ofdifferent risk factors were compared with chi-square analysis. An initialunivariate stratified analysis was performed to identify and select importantrisk factors for recurrence in the regression model. A p-value of <0.05 wasconsidered statistically significant.  Results: Demographics - Mean age of thepatients was 44.

95 (Range 10-80) Years. 129 were males and 69 were females.Majority of the patients hailed from within the state and 25 were from outsidestates. The mean duration of symptoms to the time when seen in the clinic was16.7 (Range 1-90) days. The duration between the symptoms to the time of TPKwas 20.9 (Range 1-120) days. Pre-operative Characteristics -All patientshad infiltrate involving the central visual axis and hence the pre-operativevision was hand motions.

At the time of TPK, 41 eyes had infiltrate size <6mm, 77 eyes had infiltrate size between 6-8 mm, and 80 eyes had infiltratedimensions> 8 mm. All of them had infiltrate involving full thickness of thecornea, 54 eyes had hypopyon, 8 eyes had descemetocele with perforation, and 2eyes had sclera involvement. None of the patients had evidence of posteriorsegment involvement on B scan ultrasonography Microbiological characteristics – Inall eyes, the initial microbiological smear re-examination revealed fungal filaments.Cultures from either the initial scrapings and or half corneal button obtainedafter TPK was positive in 189 cases. The species identification onmicrobiological work up revealed Aspergillus flavus in 64 eyes, fusariumspecies in 31 eyes, acremonium species in 35, Cladosporium in 1 eye, Curuvaliain 2 eyes Scedosporium in 1 eye; 44 eyes had unidentified hyaline fungus, 10were dematicious fungi and 1 patient with unidentified hyaline fungus had aco-infection with Pseudomonas aeroginosa species. Intra-operative/Surgical characteristics – TheDonor graft size was 8-9 mm in 35 eyes, 9-11 mm in 108 eyes, > 11mm in 49 eyesand 6 had missing information.

8 eyes had a combined surgical intervention thatincluded- extracapsular cataract extraction in 4 eyes, Extra capsular cataractextraction with Anterior vitrectomy in 4 eyes, and IOL explanation in 1 eye.The preoperative characteristics of all the eyes are summarised in Table 1.Baseline Donor characteristics – Meanage of the donor corneas was   69.

7 (Range19-98) years. Mean endothelial cell density of the donor corneas was 2231.9 (1043-3436)cells/mm2.  Primary Outcomes measures      Anatomical restoration was achieved in majority of cases(192 of 198 eyes; 96.97%).Out of the 6 eyes, 3 eyes required evisceration and 3 eyeswent Phthsical. All these eyes in which anatomical stability could not beachieved had recurrence in AC along with Posterior segment involvement in 3eyes. Recurrence in these eyes occurred in a mean of 11 days (Range 1 to 28days).

Pre-operatively out of 6 eyes, 3 eyes had endo exudate, 2 had endoexudate along with Hypopyon and only 1 eye had cataract. All eyes requiredlarger graft size 9.75mm (Range -8.5 – 11.5 mm).    Out of 198 subjectswho underwent a TPK, 178 had no recurrence of fungal infection.

Fungalrecurrence developed in patient between 1 and 27 days after surgery. Among the20 recurrent patients, 8 patients developed recurrence within 7 days of TPK, 5patients recurrence developed after 8 to 20 days and 7 patients after 20 daysof TPK. There sites of recurrence were: the recipient bed (5 patients),anterior chamber (7 patient), Involving both recipient bed and AC (4 patients),AC with posterior segment (3 patient) and GHJ, 1 patient had recurrenceinvolving GHJ, AC and Posterior segment. Only 4 patient had cataractpreoperatively.  6 patients were found to be infected with samespecies of fungus as had been identified before corneal transplant; out of theremaining 13 patients, 6 patient smear report suggested the presence of fungusfilaments and 3 patients were found to have negative result by fungal culturebut responded to administration of antifungal medical therapy and 4 patientsdid not had any smear done after detection of recurrence.      Amongthe 5 patient with recipient bed infection, 2 was treated with medical therapyalone, 2 required repeat TPK and 1 had to undergo evisceration due to scleralinvolvement. Anterior chamber recurrence wascontrolled with an intracameral injection of amphotericin B along with AC washfollowed by anti fungal medical therapy in 5 patients and 1 eye went Phthsicalafter 1 month and 1 patient lost Follow Up.

Eyes involving both GHJ and AC weretreated with repeat PK for 2 eyes and 2 eyes received AC wash and intracameral injectionalong with topical medical therapy. With posterior segement involvement 2 eyesdeveloped endophtalmitis and 2 went phthsical. As soon as the recurringinfection went under the graft, drug therapy was ineffective and requiredsurgical intervention to protect the anatomical stature of the eyeTable 2 gives details mentioning the Clinical Course ofrecurrent fungal infection after Therapeutic keratoplasty. SecondaryOutcomes Measures: Graftclarity: 178 patients had complete eradication of fungal infection.

Of the 178 eyes, graft clarity was restored in 52 eyes at 3 months, 21 eyes at1 year and 11 eyes at 4 years. 45 eyes had primary graft failure at 1 month andSubsequent intervention of Regrafting (PK/DSEK) was done in 27 Eyes (13 eyesfor DSEK and 14 eyes for PK). 11 eyes (5.5%) maintained a clear graft during amedian follow up period of 48 months (range, 1- 60 months). Median graftsurvival rate was 5.

88 months. Clear TPK’s were significantly associated withsmaller graft size (P = 0.026). Themean graft size was 8.5mm with mean Donar Endothelial cell density of 2364.

83.  SecondaryInfection: Twenty four eyes (12%) developed asecondary infection after a follow up period of 1 month (range, 1 -36 months).Out of those 24 eyes, 10 eyes developed secondary bacterial infection (GPC& GNB) whereas 12 Patient did not have any smear report performed for them. VisualOutcomes: As all patients had visual axis involvement, pre-operative visualacuity was hand motions to counting fingers at 3 mtrs. The median postoperativebest-corrected visual acuity for all survived grafts was 20/100 at 3 months,20/60 at 6 months and  20/40 at 1 year.

At 5 years follow up visit, the best-corrected visual acuity was ?20/50 in 7/10eyes. No significant difference in terms of postoperative visual gain betweendifferent species of fungus was seen; however, eyes with smaller grafts(<9mm) had a postoperative BCVA >20/200 more frequently compared to eyeswith larger graft of 9-11mm and >11mm. The table 3  belowdescribes clinical characteristics of all the 11 eyes whose primary graftremained clear, maintaining a visual acuity of >20/100 upto a follow upperiod of 48 months. 10 out of 11 patients maintained BCVA ?20/50, out of whichtwo eyes had BCVA 20/20. Preoperatively, all 11 eyes had corneal infiltratesize less than 9 mm. Mean age of donor was 71.25 years (Range 40 years to 90years).

Mean ECD of donor cornea was 2364.83. Three eyes had reduction invisual acuity in subsequent follow up visit (mean follow up period 4 months).It was because the grafts had an early episode of rejection at that particulartime but was well managed with medical therapy and hence, maintained visualacuity better than 20/60 at a follow up period of 48 months.   Risk factor Analysis: Thepresumed risk factors for primary graft failure and recurrence of infection inTPK were analysed. The variables were categorized as follows: size ofinfiltrate (<6mm, 6-8mm and >8mm), size of graft (8-9mm, 9-11mm and >11mm),species of fungus (Aspergillus, Fusarium, Acremonium, Unidentified hyalinefungus and others) and additional cataract surgery with EK (presence/absence).

Graft size was the only significant risk factor for graft failure and recurrencein this series (p = 0.01) and (p = 0.02) respectively. Figure 1 shows theprobability of graft survival over time.

The probabilities of survival are 48.9%,29.4%, 13.6% and 10.5% at 6 months, 1, 3 , 4 years respectively.