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  • Cornea/External Disease
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    Postkeratoplasty infection is an infrequent but potentially blinding occurrence, with an incidence between 0.05% and 0.4%.1,2,3,4,5,6 When penetrating keratoplasty (PK) was the most commonly performed corneal transplant, the majority of postoperative infections were bacterial in origin.2 Although bacterial endophthalmitis is a devastating event, its rarity and poor concordance between donor rim culture and patient infection did not support routine culture of PK donor rims.7,8

    However, the landscape of keratoplasty has changed over the past decade. In 2012, endothelial keratoplasty (EK) surpassed PK as the most frequently performed keratoplasty in the US. According to the EBAA statistical report,9 19,160 PK and 27,208 EK procedures were performed in the U.S. in 2015. Alongside this evolution in technique, an increase in case reports of fungal infections was noted, prompting large database studies that confirmed its rising prevalence.10,11,12 The question of whether or not to perform routine donor rim cultures is once again at the forefront and merits thoughtful review. The last Current Insight on this topic was published in 2008.8

    Background

    In 1990, the Eye Bank Association of America (EBAA) developed a system for transplanting surgeons to report adverse reactions possibly linked to donor tissus—such as primary graft failure and postoperative infection—to the source eye bank. All cases are then reported back to the EBAA, thereby producing a national donor cornea registry. Through this expansive data collection, an uptick in postkeratoplasty fungal infections was noted, and rates were found to be increasing over time.10,11 

    The surge was first noted in the early 2000s with PK cases,13,14 and it was unclear if it was related to a decrease in bacterial infections from the widespread adoption of Optisol-GS (Bausch and Lomb, Rochester, US).1 Soon after, Hassan et al1 found that storing PK donor tissue for 4 or more days was independently associated with a 3-fold increase in relative risk of fungal infection compared with the risk of bacterial infection in cases where Optisol-GS was used. More recently, Vislisel et al12 also found the median storage time of fungal culture-positive donor rims was 4 days.

    The incidence of fungal infections has continued to grow in recent years, from 0.014% in 2013 to 0.023% in 2016,11 which coincided with the popularization of EK.9 These findings support that routine donor rim culture for fungus may play a more vital role in the age of EK.

    Comparison of fungal infections after EK or PK

    Aldave et al10 found that fungal infection was twice as likely to occur in patients undergoing EK when compared with PK, although this finding did not reach statistical significance. Similarly, the retrospective cohort study by Vislisel et al12 that assessed fungal keratoplasty infections after all types of keratoplasty found that all infections occurred after lamellar surgery: 3 of 4 cases of fungal keratitis occurred after EK, and 1 of 4 occurring after deep anterior lamellar keratoplasty (DALK). 

    The additional warming period required for EK processing has been purported to allow fungus to proliferate (Tu E. The effect of repeated warming cycles of corneal storage media on fungal infection risk in endothelial keratoplasty. EBAA/ Cornea Society Educational Symposium, November 13, 2015, Las Vegas, NV). Maintaining higher temperatures during storage is also preferred because the antibiotic activity of Optisol-GS at is improved in warmer environments.15 Furthermore, the lamellar interface may be more vulnerable to fungal growth due to its relatively hypoxic environment and sequestered nature that prevents normal immune mechanisms.16,17 

    Correlation of fungal culture-positive donor rims and clinical infection

    In contrast to the discordance observed between bacterial culture-positive donor rims to clinical infection, multiple studies show fungal culture donor rims have predictive value.7,10-14,16 Keyhani et al14 studied 2,466 donor rims from 1998 to 2003, and found 28 (8.6%) were positive for fungus, specifically Candida species. All 4 patients who subsequently developed fungal endophthalmitis had positive donor rims of the same organism.

    In 2007, a large meta-analysis by Wilhelmus et al7 showed a much higher agreement between rim culture and fungal infections when compared with bacterial infections. Most recently, Vislisel et al12 performed a study of 3,414 donor cornea rims and found 71 (2.1%) with fungal culture-positive donor rims. Four of the 71 patients (3 who underwent EK and 1 who underwent DALK) developed an infection (all Candida keratitis) requiring surgery. Several studies have found Candida species to be the most common causative agent in post-EK fungal keratitis and endophthalmitis.10,11,12,16

    Aldave et al10 further examined corneas with culture-positive recipient fungal infection, and found that 73% (16 of 22) of the mate corneas were also positive. Fifteen of the 16 mate corneas were transplanted, and a subsequent infection developed in 10 of the 15 recipient eyes: endophthalmitis in 6 eyes, and keratitis in 4 eyes. This highlights the importance of sharing culture results with the source eye bank so that the mate tissue recipients may be more closely monitored. Furthermore, since fungal infections usually occur in a delayed manner, culture results may be available before clinical infection appears, and prophylactic antifungal therapy can be initiated.

    Edelstein et al11 found the mean time to fungal endophthalmitis/keratitis from presentation was 33 days/45 days, whereas for bacterial endophthalmitis/keratitis, it was 2.5 days/6 days. Currently, there are no protocols to dictate the next steps when a positive fungal culture is discovered.

    Conclusion

    Although the incidence of postkeratoplasty fungal infections is low, it has been growing in recent years.11 The greater predictive value of fungal culture-positive donor rims and the high treatment burden of these cases16 support revisiting the role of routine culturing of donor rims, at least for fungus. Most recipients with fungal infections do not respond adequately to medical (topical and systemic antifungals) treatment and require surgical intervention to eradicate the infection,12 which may entail additional donor tissue as well as an increased risk of rejection. Discussion about the use of antifungal supplementation to cold storage media traces back to the PK era, but has now become of paramount interest in the age of EK. What effect antifungal supplementation has on donor rim cultures remains to be seen. In the meantime, it may be time to reconsider routine donor rim culture for fungus.

    References

    1. Hassan SS, Wilhelmus KR, Medical review subcommittee of the Eye Bank Association of America. Eye-banking risk factors for fungal endophthalmitis compared with bacterial endophthalmitis after corneal transplantation.  Am J Ophthalmol  2005;139(4):685-690.
    2. Kloess P, Stulting R, Waring G. Bacterial and fungal endophthalmitis after penetrating keratoplasty. Am J Ophthalmol 1993;115:309–316.
    3. Pardos GJ and Gallagher MA. Microbial contamination of donor eyes. Arch Ophthalmol 1982;100:1611–1613.
    4. Leveille A, McMullin F, Cavanaugh H. Endophthalmitis following penetrating keratoplasty. Ophthalmology 1983;90:38–39.
    5. Everts RJ, Fowler WC, Chang DH, et al. Corneoscleral rim cultures: lack of utility and implications for clinical decision-making and infection prevention in the care of patients undergoing corneal transplantation. Cornea 2001;20:586–589.
    6. Wiffen SJ, Weston BC, Maguire LJ, et al. The value of routine corneal rim cultures in penetrating keratoplasty. Arch Ophthalmol 1997;115:719–724.
    7. Wilhelmus KR and Hassan SS. The prognostic role of donor corneoscleral rim cultures in corneal transplantation.  Ophthalmology 2007;114(3)440-445.
    8. American Academy of Ophthalmology. Current Insight 2008.  Koreishi AF and Awdeh RM.  Are donor corneoscleral rim cultures in penetrating keratoplasty clinically relevant?  https://www.aao.org/current-insight/are-donor-corneoscleral-rim-cultures-in-penetratin.  Accessed August 29, 2017.
    9. Eye Bank Association of America. 2015 Eye Banking Statistical Report. Eye Bank Association of America; 2016.
    10. Aldave AJ, DeMatteo J, Glasser DB, et al. Report of the Eye Bank Association of America medical advisory board subcommittee on fungal infection after corneal transplantation. Cornea 2013;32(2):149-154.
    11. Edelstein SL, DeMatteo J, Stoeger CG, et al. Report of the Eye Bank Association of America medical review subcommittee on adverse reactions reported from 2007 to 2014. Cornea 2016;35(7):917-926.
    12. Vislisel JM, Goins KM, Wagoner MD, et al. Incidence and outcomes of positive donor corneoscleral rim fungal cultures after keratoplasty. Ophthalmology 2017;124:36-42.
    13. Merchant A, Zacks CM, Wilhelmus K, et al. Candidal endophthalmitis after keratoplasty. Cornea 2001;20(2):226-229.
    14. Keyhani K, Seedor JA, Shah MK, et al. The incidence of fungal keratitis and endophthalmitis following penetrating keratoplasty. Cornea 2005;24(3):288-291.
    15. Kapur R, Tu EY, Pendland SL, et al. The effect of temperature on the antimicrobial activity of Optisol-GS. Cornea 2006;25:319-324.
    16. Tsui E, Fogel E, Hansen K, et al. Candida interface infections after descemet stripping automated endothelial keratoplasty. Cornea 2016;35:456–464.
    17. Grahl N, Shepardson KM, Chung D, et al. Hypoxia and fungal pathogenesis: to air or not to air? Eukaryot Cell 2012;11:560–570.