In this study, 36.1% of patients were exposed to topical steroids prior to their diagnosis of fungal keratitis. A history of previous OSD and ocular surgery was more frequently observed in the PS group. These findings were likely due to the past use of steroids prescribed for treatment of the patients' underlying conditions. A previous Korean study reported that in 14.1% of fungal keratitis cases, patients had been prescribed topical steroids prior to their diagnosis [10]. Studies in other countries have reported a range from 13% to 44% [11,12,13].
The types and distribution of the microbiological profile of fungal keratitis vary according to geography, climate, and the socioeconomic characteristics of the patients involved. In this study, the most commonly identified organism in both groups was Candida species (20% in PS and 11.3% in NPS) followed by Fusarium species. Our findings in relation to Candida species are similar to the results of studies conducted across the globe, i.e., London (60.6%) [14], Paris (58%) [15], Denmark (52%) [11], and Pennsylvania (45.8%) [16]. In contrast, studies in north China (73.3%) [17], Florida (41%) [18], Mexico City (37.2%) [19], south India (37.2%) [20], central China (30.6%) [21], and Korea (29%) [10] reported that Fusarium was the most commonly identified organism. Aspergillus was the most commonly identified organism in reports from north India (41%) and Saudi Arabia (27.2%) [22, 23]. Our study determined that Aspergillus was found only in the PS group. This result can be supported by the study of Tony et al. who had reported that corticosteroids promote the growth of Aspergillus [24].
The authors anticipated that the PS group would have more severe initial clinical characteristics than the NPS group. However, our study found no significant differences in initial clinical characteristics between the two groups except in terms of depth of infiltration. We speculate that this finding may be related to the inflammation-masking effect of previous topical steroids used in early stage of keratitis. This finding may also make clinical suspicion and early diagnosis of fungal keratitis difficult. At initial presentation, deep infiltration of the infection was higher in the PS group. In a study by Panda et al., it was reported that hyphae are located more vertically in a group that used steroids [25]. Fungi are characterized by deep penetration into the corneal stroma, and vertically located hyphae are more involved in penetration and are more virulent [25]. A study by Lixin et al., found that the vertically growing hyphae had a higher recurrence rate after lamellar keratoplasty than horizontally growing hyphae [26]. Therefore, it is important to evaluate the detailed characteristics of the lesion and to collect a comprehensive patient history at the initial visit.
In this study, only microbiologically proven fungal keratitis was included, and microbiological evidences of fungus were made through potassium hydroxide smear, culture, PCR, or biopsy. The percentage of identified fungal isolates was higher in the PS group than in the NPS group. One potential interpretation of this result is that steroid use can promote fungal proliferation, thereby enhancing its identification. However, the relationship between the use of prior topical steroids and the positive rate of culture has rarely been reported. Further studies are needed to investigate the origin of relationship. Furthermore, this study does not have a prospective design, and it does not include the cases of negative microbiological tests. Therefore, there is a limit to evaluation and interpretation.
There was no significant difference in the type and proportion of antifungal agents used between the two groups, but topical and systemic voriconazole use was significantly higher in the PS group. In the medical center where the authors practice, the use of topical and systemic voriconazole when there is no response to conventional antifungal therapy. The significantly higher use of topical and systemic voriconazole in the PS group indicates that the treatment response was worse than that anticipated in this group.
The PS group had significantly higher surgical intervention and treatment failure than the NPS group. This is consistent with the results of other studies that have suggested that the prior use of topical steroids in fungal keratitis may contribute to worse outcomes [27, 28]. These results highlight the side effects of prior topical steroid use in the cases of fungal keratitis. Evisceration/enucleation was performed in 13.3% of the overall patients. These results were similar to the proportion of eviceration/enucleation (10.6%) reported in a multicenter study in Korea [10]. The authors expected that there would be higher incidence of evisceration/enucleation in the PS, just as more surgical treatments were needed in the PS group. However, in this study, no significant difference was observed in the proportion of evisceration/enucleation between the PS and the NPS groups (13.3%, 13.2%). Therefore, we performed an additional logistic regression analysis to determine the risk factors for evisceration/enucleation. As a result, hypopyon (PS: 30%, NPS: 32%) was the only significant risk factor for evisceration/enucleation (OR 4.88, 95% CI 1.28–18.56, p = 0.020). Thus, the risk factors for evisceration/enucleation was associated with initial clinical severity of the overall cohort, and further study will be needed.
In this study, significant risk factors for treatment failure were hypopyon and deep infiltration. Prior topical steroid use and previous OSD were significant in univariate logistic regression analysis but their effects were attenuated in multivariate analysis. Hypopyon can be regarded as a marker of inflammation. A study of Lalitha et al. reported that the presence of hypopyon was a significant predictor of treatment failure [29]. And deep stromal infiltration was a significant risk factor for treatment failure. The depth of infiltration may reflect the progression of the lesion, and the poor corneal penetration of antifungal agents may be related to the difficulty of treatment in the case of deep infiltration [3, 4]. Therefore, it is important to evaluate these features at the initial visit because fungal keratitis can penetrate deeply into the stroma in the early stage of infection. Other studies have reported various risk factors for treatment failure in fungal keratitis such as large epithelial defect size and prior topical steroid use [30, 31].
The reported role of steroids in fungal keratitis includes suppression of inflammation and subsequent growth promotion of the fungal genus. Moreover, vertically oriented hyphae are more commonly observed in the eyes of patients who used steroids [25]. Steroid use has been associated with a decreased response to antifungal agents, and steroid treatment itself is a known risk factor for fungal infection [8, 28, 32]. Steroid worsen infections due to severe inflammatory side effects and they also affect the delay of epithelial regeneration [33,34,35,36]. Therefore, it should be emphasized that early steroid use is contraindicated when an infection is suspected. Clinicians should be cautious when prescribing steroids for suspected cases of infectious keratitis.
This study has some limitations. First, this study was confined to South Korea, which is temperate climate. And the cases included were from one tertiary hospital. Therefore, the results of this study cannot be generalized. Second, owing to the study’s retrospective design, the authors could not accurately identify the potency and dose of the topical steroids prescribed for patients who were referred from their primary eye clinics. Third, only the patients with microbiological evidence of fungal keratitis were enrolled in this study while cases without such evidence were excluded, even if fungal keratitis was highly suspected. Despite such limitations, this study has an important clinical significance. This investigation highlighting the risk and side effects associated with prior topical steroid use in practical clinical circumstances. This study is a clinical analysis of fungal keratitis in South Korea. Clinician may use these findings as a beneficial reference for various regional differences in fungal keratitis.