In this study, the proportion of cases with prior topical steroid use history was 36.1%. Previous OSD and previous ocular surgery history were higher in the PS group likely because steroids were used for treating their underlying causes. A previous Korean study reported that 14.1% of fungal keratitis cases used prior topical steroids [10], while other studies have reported similar proportions, ranging from 13 to 44% [11-13].
The types and distribution of fungi in fungal keratitis vary according to geography, climate, and socioeconomic characteristics. In this study, the most commonly identified organism was Candida species in both groups (20% in PS and 11.3% in NPS) and followed by Fusarium species in total patients. In terms of most commonly identified organisms, Candida species of our results is similar to the results reported in Pennsylvania, USA (45.8%) [14], Denmark (52%) [11], London, UK (60.6%) [15], and France (58%) [16]. In contrast, many studies such as North China (73.3%) [17], a multicenter study in Korea (29%) [10], central China (30.6%) [18], Mexico City (37.2%) [19], Florida, USA (41%) [20], and South India (37.2%) [21] reported that the Fusarium was the most commonly identified organism. In addition, some reports such as Saudi Arabia (27.2%) and North India (41%) showed that Aspergillus was the most commonly identified organism [22]. Regarding to Aspergillus, our study showed that it 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 [23].
Since the delayed diagnosis of fungal keratitis has a significant adverse impact on treatment outcomes, the importance of early suspicion and rapid diagnosis of fungal keratitis has been reported in many studies [24, 25]. We expected that the PS group had more severe initial clinical characteristics when compared with the NPS group, but our study found that there were no significant differences in initial clinical characteristics between the two groups. We thought this result is related to the inflammation-masking effect of previous topical steroids in early clinical characteristics of keratitis. This suggests to us that the use of prior topical steroid likely masked the early clinical characteristics of fungal keratitis thereby delaying its suspicion and early diagnosis. Therefore, it is critical that efforts aimed at making a diagnosis, including culture of corneal scrapings and KOH smear, be done at the time of initial presentation.
This study found that the cases of diagnosed through baseline tests was less common in the PS group when compared with the NPS. This result makes it possible to suspect that the use of prior topical steroids may be affect the positive rate of the baseline test. One possible hypothesis is due to less possibility of microorganism detection in necrotic tissue according to more aggressive inflammatory response associated with the steroid-withdrawal rebound effect in the steroid-used group. Another possible hypothesis might be related to our speculation that vertically located hyphae penetrate deeply into the corneal stroma and the surface hyphae are relatively less distributed in the steroid-used group based on Panda et al.’s study [26]. However, the relationship between the use of prior topical steroids and the positive rate of culture was rarely reported and further studies will be needed.
The cases of identified fungal isolates was more common in the PS group in our study when compared with the NPS. One of the interpretations associated with this result is that steroid use can promotes fungal proliferation, hence enhancing its identification. Second, additional laboratory testing, such as culture and histopathology examinations, was more performed in the PS group since these patients underwent more surgeries when compared with the NPS group. Therefore, the higher identification rate of fungal isolates in the PS group could be related to the increased effort in finding these organisms via repeated testing. In other study related to repeat microbiological testing, Kathryn et al. reported the significance and the utility of repeat cultures in fungal keratitis [27, 28]. These studies found that repeat culture positivity is an important predictor of poor clinical outcome in severe fungal keratitis and reported that repeat cultures provide important additional information to assess response to treatment. Thus, repeated microbiological test such as KOH smear, culture, and biopsy should be considered to detect fungal organisms when there is no sufficient response to initial treatment.
There was no significant difference in the type of antifungal agents used between the two groups, but for topical and systemic voriconazole use which was significantly higher in the PS group. In our institute, we have added 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 expected in this PS group. The PS group had significantly higher surgical intervention and treatment failure when compared with the NPS group. This is consistent with other studies, and the topical steroids use in fungal keratitis lead to worse outcomes [29, 30]. These results highlight the side effects of prior topical steroid use in the setting of fungal keratitis.
Evisceration/enucleation was performed in 13.3% of the total patients, similar to the proportion reported in a multicenter study in Korea (10.6%) [10]. The authors expected that there would be higher incidence of evisceration/enucleation in the group of prior topical steroid use, but we found no significant difference was observed between the PS and the NPS group in this study. The frequency of evisceration/enucleation within 1 month was relatively higher in the NPS group than in the PS group (5/7, 71% vs. 2/4, 50%, p = 0.576). Therefore, we thought that the evisceration/enucleation was more associated with initial clinical severity than the prior topical steroid use itself through this study. In addition, hypopyon (64%) was more common in the patients who underwent evisceration/enucleation and was the only significant risk factor of evisceration/enucleation (OR 4.88, 95% CI 1.28-18.56, p = 0.020).
In this study, significant risk factors for treatment failure included hypopyon, prior topical steroid use, and non-vegetable corneal trauma. Risk factors for treatment failure reported in other studies varied and were associated with severe initial clinical characteristics, such as large epithelial defect size, hypopyon, and prior topical steroid use [31-33]. In this study, non-vegetable corneal trauma was a significant risk factor for treatment failure. This result was thought to be associated with the difference between non-vegetable trauma and vegetable trauma in the proportion of previous OSD (42.6% vs. 6.9%, p = 0.001) and fungal isolates distribution (Candida, 11 vs. 1 case; Aspergillus, 4 vs. 0 case).
The various effects of steroids on the fungal keratitis reported in several studies include: First, suppression of inflammation and subsequent growth promotion of the fungal genus. Second, fungal keratitis is more virulent when the hyphae in corneal tissue sections are found at a right angle than when they are parallel to the corneal stroma, and also the vertically oriented hyphae are more commonly observed in the eyes of patients who used steroid [26]. Third, steroid use has been associated with decreased response to antifungal agents, and steroid treatment itself is a known risk factor for fungal infection [8, 30, 34]. In addition to the aggravation of infection, steroids delay epithelial regeneration and have quite severe inflammatory side effects [35-38]. Therefore, it should be emphasized that early steroid use is contraindicated when an infection is suspected, and clinicians should be cautious when prescribing steroids for suspected cases of infectious keratitis.
This study has some limitations. First, the included cases were confined to the patients of one tertiary hospital, therefore the results of this study cannot be generalized. Second, since it is a retrospective study, we could not accurately identify the potency and dose of topical steroids for patients referred from their primary care hospital. 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 important clinical value, illuminating the risk and side effects of prior topical steroid use in clinical practice.