DOI: https://doi.org/10.21203/rs.2.337/v2
Fungal keratitis is an important cause of severe sight-threatening disease and has been reported to account for about 50% of all microbial keratitis cases requiring therapeutic penetrating keratoplasty [1]. Fungal keratitis is a challenging disease to diagnose and treat, it is often confused with other infectious keratitis because there is insufficient clinical and microbiological evidence during the early stages of keratitis, thus leading to delayed treatment. In the aspect of treatment, fungal keratitis has been reported to be relatively worse than bacterial keratitis [2]. Furthermore, there are few commercialized topical antifungal agents, and most of these agents cannot penetrate the cornea effectively [3, 4].
The risk factors for fungal keratitis include ocular trauma, ocular surface disease, contact lens use, topical steroid use, and systemic immunosuppression [5, 6]. Among these, the prior use of topical corticosteroids has been shown to be a clinically important factor because it can exacerbate the infection [7]. The use of topical steroids in the early stages of infectious keratitis makes it difficult to judge clinical progression because the immune-inflammatory response in the corneal stroma is temporarily improved and the immune response of the host is decreased [8].
Despite these clinical importance, clinical analysis of fungal keratitis according to prior topical steroid use is rarely reported. Therefore, we conducted a comparative study of patients with microbiologically proven fungal keratitis according to prior topical steroid use at a tertiary referral center in South Korea. The aim of this study was to compare epidemiology, predisposing factors, clinical characteristics, microbiological profiles, and treatment outcomes in patients with microbiologically proven fungal keratitis according to prior topical steroid use.
This study was conducted at the Yeungnam University Hospital, a tertiary referral center in South Korea. We retrospectively reviewed medical records of microbiologically proven fungal keratitis cases between January 2000 and December 2016. The inclusion criteria were (1) clinical evidence of fungal keratitis and clinical response to antifungal treatment plus (2) one of the following: (a) positive fungal culture from a corneal specimen, (b) positive identification of fungal elements on a 10% potassium hydroxide (KOH) smear, and (c) histopathology showing presence of fungal elements. The exclusion criteria were fungal keratitis with scleral involvement and the cases did not receive antifungal therapy. For the purpose of this study, the total cases were divided into two groups: those with prior topical steroid use before the diagnosis of fungal keratitis as PS group, and those with no prior topical steroid use before diagnosis as NPS group. This study was approved by the Institutional Review Board of the Yeungnam University Hospital (IRB No. 2018-11-015), Republic of Korea, and complied with the principles outlined in the Declaration of Helsinki.
Baseline epidemiology, predisposing factors, clinical characteristics, microbiological profiles, and treatment outcomes were evaluated and compared between the PS and NPS groups. The epidemiologic characteristics included age, sex, occupation, symptom duration and referral from primary eye clinic. The symptom duration defined as the interval from the onset of symptoms to the time of initial presentation. The predisposing factors included previous ocular surface disease (OSD), previous ocular surgery, underlying systemic disease, corneal trauma, and use of contact lens. The initial clinical characteristics included the location, size of the corneal lesion, depth of infiltration, the presence of the hypopyon, and presenting best-corrected visual acuity (BCVA) using the Snellen test. The corneal lesions were divided into central or peripheral lesions based on the half radius of the cornea. The size of corneal lesions was calculated based on the size of the corneal epithelial defect [9]. Depth of infiltration was assessed in 2 categories: superficial (more than 0% to 50%); deep (more than 50% to 100%).
Before initiation of therapy, corneal scrapings of all cases were obtained using a No. 15 Bard-Parker knife (Aspen Surgical, Caledonia, MI, USA) after application of 0.5% proparacaine hydrochloride (Alcaine®, Alcon, Fort Worth, TX, USA) for anesthesia. Simultaneously, conjunctival swab was performed for all cases using a sterile cotton-tipped swab for thioglycolate broth. Scrapings were smeared on glass slides and Gram staining was performed. For KOH smear, specimen was taken from the margins and base of the ulcer and was placed within a marked area on a glass slide. One drop of 10% KOH was put on it and clean coverslip was added. The corneal scrapings were stained by the Gram and AFB stain methods, and also inoculated onto a variety of solid and liquid media that support the growth of bacteria, fungi, and Acanthamoeba. These included thioglycolate broth, blood agar, MacConkey agar, and Sabouraud dextrose agar. All media were incubated for a period of 14 days at appropriate atmospheric conditions and examined daily for the growth of organisms.
When a fungal infection is clinically suspected or when a fungus is identified, systemic and topical antifungal agent was administered immediately. The first-line antifungal used was topical amphotericin B given hourly. In cases where no response was seen within 72 hours, topical 5% natamycin (Natacin®, Alcon, Fort Worth, TX, USA) was added to the above regimen. Systemic antifungal agents (fluconazole 50mg tid p.o. / intravenous amphotericin B) were administered. Topical 1% voriconazole was used in cases where there was no improvement in the lesion even after 2 weeks of continuous use of amphotericin B eyedrop and 5% natamycin, or when anterior chamber fungal ball was formed. All patients were treated topically with 3rd or 4th generation fluoroquinolones and fortified topical antibiotics (2% tobramycin, 5% ceftazidime) and systemic antibiotics before the microbiological results were obtained as empirical treatment. When topical steroids were in use at the initial presentation, they were gradually tapered. The treatment outcomes were assessed at the end of 3 months or at the completion of treatment. Treatment outcomes were evaluated by epithelial healing time (EHT), complication, surgical intervention, and final BCVA. Treatment failure was defined as the occurrence of complications or surgical treatment.
The data were statistically analyzed using the Statistical Package for the Social Sciences 20.0 (IBM, Armonk, NY, USA). Chi-squared test and Fisher's exact test were used for categorical data. Independent t-tests were used for comparison of mean values. Statistical significance was defined as p < 0.05. The risk factors for treatment failure were analyzed using logistic regression analysis. In the univariate analysis, an independent variable with a p < 0.1 was included in the multivariate analysis and a variable with a final p < 0.05 was considered a significant risk factor.
We identified 89 positive microbiologically proven fungal keratitis cases for 17 years. In those, six cases had accompanying necrotizing scleritis. These 6 cases were therefore excluded, leaving microbiologically proven 83 cases of fungal keratitis were enrolled in this study. Of these, thirty cases (36.1%) were the PS group and 53 cases (63.9%) were the NPS group.
Table 1 compares the detailed baseline epidemiology, predisposing factors, and clinical characteristics. For the total patients, mean age was 63.0 ± 14.3 years and male sex was 57.8%. Agricultural workers were the most common occupations in both groups. There were no significant differences in mean age, sex, and occupational distribution. The median time to symptom duration was 14 days in the PS group and 10 days in the NPS group, with no statistically significance. Among the PS group, 36.7% of topical steroids were used in primary eye clinic and 63.3% were used in our hospital.
Concerning the predisposing factors, corneal trauma (70.0% vs. 81.1%) was the most common in both groups with no significant difference. The ratios of previous OSD (43.3% vs. 22.6%, p = 0.048) and previous ocular surgery (33.3% vs. 18.9%, p = 0.139) were higher in the PS group. Herpetic keratitis (23.3% vs. 9.4%) was the most common previous OSD in both groups.
In the initial clinical characteristics, central corneal lesions were more common than peripheral ones in both groups. There were no differences in the location of corneal lesions and hypopyon between the two groups. The cases with epithelial defect size ≥ 10 mm2 (p = 0.228) and presenting BCVA < 0.1 (p = 0.194) were slightly higher in the PS group, but no statistically significant difference between the two groups. The cases with deep infiltration were higher in the PS group (53.3% vs. 32.1%, p = 0.057).
Table 2 shows the microbiological test results including identified fungal isolates and KOH smear result. Thirty fungal isolates out of 30 eyes were identified in the total group. In those, sixteen fungal isolates in the PS group and 14 in the NPS group were identified. The most common fungal isolates were the Candida species (6 cases, respectively), followed by Fusarium species (3 cases, 5 cases), and Aspergillus species (4 cases, 0 case). There was no difference between the PS group and the NPS in the distribution of Candida (p = 0.765) and Fusarium species (p = 0.417), while the Aspergillus species were found only in the PS group (p = 0.103). Twenty cases (66.7%) of KOH smear positive in the PS group and 46 cases (86.8%) in the NPS group were identified. Six cases (20%) of both culture and KOH smear positive in the PS group and 7 cases (13.2%) in the NPS group were identified (p = 0.532).
In the total group, sixty-three cases (75.9%) received topical antifungal monotherapy, while 20 cases (24.1%) received a combined antifungal treatment. Combined topical antifungal treatment (33.3% vs. 18.9%, p = 0.139) and voriconazole/natamycin combination (10% vs. 0%, p = 0.044) were more common in the PS group than in the NPS. For systemic antifungal agents, fluconazole was the most commonly used in both two groups (53.3%, 67.9%), followed by amphotericin B (26.7%, 32.1%). The use of systemic voriconazole was significantly higher in the PS group (23.3% vs. 1.9%, p = 0.003).
The median time to epithelial healing was 27 days in the PS group and 23 days in the NPS group. Sixty percent of the PS group with final BCVA < 0.1, it is higher than that of the NPS group (44.2%) (Table 3). As a complication, corneal perforation was the most common (8 cases, 7 cases) in both two groups, followed by endophthalmitis (2 cases, 1 case). The proportion of corneal perforation was slightly higher in the PS group (p = 0.126).
Twenty-four cases (28.9%) required surgical intervention and was significantly higher in the PS group (43.3% vs. 20.8%, p = 0.029). In the PS group, amniotic membrane transplantation was performed in 9 cases, and 6 cases had conjunctival flap. In the NPS group, evisceration/enucleation was performed in 7 cases. The proportion of evisceration/enucleation (13%, respectively) were similar between the two groups. The proportion of treatment failure was significantly higher in the PS group (46.7% vs. 22.6%, p = 0.023) (Table 3).
In multivariate logistic regression analysis, hypopyon (odds 6.01, 95% CI 1.70-21.23, p = 0.005) and deep infiltration (odds 4.38, 95% CI 1.37-14.08, p = 0.013) were the significant risk factors for treatment failure in the total patients, followed by prior topical steroid use (odds 2.79, 95% CI 0.85-9.18, p = 0.091) and previous OSD (odds 2.82, 95% CI 0.84-9.49, p = 0.093) (Table 4).
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 microbiological profile 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].
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 except depth of infiltration. 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. Deep infiltration at the initial presentation was higher in the PS group. In a study by Panda et al., it was reported that hyphae are located more vertically in the steroid-used group.[24] Fungi are characterized by penetration into the deep corneal matrix, and vertically located hyphae are thought to be involved in penetration. According to a study by Lixin et al., it was reported that the vertically growing hyphae had higher recurrence rate after lamellar keratoplasty than horizontally growing hyphae.[25] Therefore, it is important to evaluate the detailed characteristics of the lesion and to take detailed 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 in the microbiologically evidence positive group was higher in the PS group 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. 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. Furthermore, this study was not set as prospective design and the cases of negative microbiological test were not included, so there is a limit to evaluation and interpretation.
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 [26, 27]. 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 proportion 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). Additional statistical analysis was performed and showed that hypopyon was present at 64% of patients who underwent evisceration/enucleation. In addition, hypopyon was the only significant risk factor of evisceration/enucleation in univariate logistic regression analysis (OR 4.88, 95% CI 1.28-18.56, p = 0.020). 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 this study, significant risk factors for treatment failure were hypopyon, deep infiltration. Prior topical steroid use and previous OSD were significant in univariate logistic regression analysis but not significant in multivariate analysis. Hypopyon can be regarded as a marker of inflammation, and the study of Lalitha et al. reported that the presence of hypopyon was significant predictor of treatment failure [28]. Other studies reported risk factors for treatment failure in fungal keratitis were varied, it is associated with severe initial clinical characteristics, such as large epithelial defect size, and prior topical steroid use [29, 30]. The depth of infiltration can be a factor related to the progression of the lesion, and the relationship between deep stromal fungal keratitis and poor prognosis has been reported. Das et al. reported a retrospective study of six deep fungal keratitis, all these cases had undergone therapeutic keratoplasty and the subsequent histopathology of the corneal button revealed filamentous fungi in 83% (5/6) [31]. Since fungal keratitis can penetrate deeply into the stroma early, it is important to evaluate these features at the initial visit.
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 [24]. 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, 27, 32]. In addition to the aggravation of infection, steroids delay epithelial regeneration and have quite severe inflammatory side effects [33-36]. 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, this study was confined to South Korea, which is temperate climate, and the cases included 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. Moreover, this study is a clinical analysis of fungal keratitis in South Korea, and it is thought that this will be a good reference for various regional differences in fungal keratitis.
In conclusion, 36.1% of the patients used topical steroids prior to the diagnosis of microbiologically proven fungal keratitis in this study. In baseline characteristics, the PS group was more associated with the cases of previous OSD (p = 0.048) and deep infiltration (p = 0.057) when compared with the NPS group. With respect to treatment outcomes, the use of voriconazole (topical, p=0.044; systemic, p=0.003), surgical intervention (p = 0.029) and treatment failure (p = 0.023) were more common in the PS group. The risk factors for treatment failure in the total patients were hypopyon (odds 6.01, p = 0.005), deep infiltration (odds 4.38, p = 0.013), prior topical steroid use (odds 2.79, p = 0.091), and previous OSD (odds 2.82, p = 0.093). The treatment results of fungal keratitis were thought to be related to various factors, and the use of prior topical steroids was also important. The results of this study suggest that topical steroids should be administered with caution considering the possibility of many complications such as aggravation of infection. Therefore, it is important to use topical steroids carefully in various ocular surface diseases such as keratitis, and frequent monitoring during steroid use is necessary.
BCVA, Best corrected visual acuity; CI, Confidence interval; EHT, Epithelial healing time; KOH, potassium hydroxide; NPS, no prior topical steroid use group; OR, Odds ratio; OSD, Ocular surface disease; PCR, Polymerase chain reaction; PS, prior topical steroid use group
This study was approved by the Institutional Review Board of the Yeungnam University Hospital, South Korea (file no. YUMC 2018-11-015), and complied with the principles outlined in the Declaration of Helsinki. Institutional Review Board of our institution allowed us "waiver of informed consent" because it is determined that obtaining consent from a human subject of research is impracticable in the course of research and the risk to a human subject of research is very low even if the project is exempted from consent, as per the Bioethics and Safety Act of the Republic of Korea (Chapter 3, Article 16, Paragraph 3, Act No. 14839. Enforcement Date 26. July 2017.).
Not applicable
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
The authors declare that they have no competing interests.
This work was supported by the 2018 Yeungnam University Research Grant.
CH Cho: literature research, drafting, language editing, and critical revision.
SB Lee: patient interaction, patient diagnosis, language editing, and critical revision.
All authors read and approved the final manuscript.
Not applicable
Department of Ophthalmology, Yeungnam University College of Medicine, 170, Hyunchung-ro, Nam-gu, Daegu 705-717, South Korea
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Table 1. Baseline epidemiology, predisposing factors and clinical characteristics of fungal keratitis according to prior topical steroid use
Characteristics | PS (n=30) | NPS (n=53) | p-value |
Epidemiology | |||
Male sex | 19 (63.3) | 29 (54.7) | 0.445 |
Age, years | 60.2 ± 14.9 | 64.6 ± 13.9 | 0.180 |
Occupation | |||
Agriculture | 14 (46.7) | 25 (47.2) | 0.965 |
Non-agriculture | 16 (53.3) | 28 (52.8) | |
Symptom duration, days | 19.7 ± 15.4 | 15.0 ± 13.8 | 0.154 |
Median (range) | 14 (2-150) | 10 (1-90) | 0.127† |
Referral from primary eye clinic | 11 (36.7) | 4 (7.5) | 0.001 |
Predisposing factors | |||
Corneal trauma | 21 (70.0) | 43 (81.1) | 0.246 |
Vegetable matter or wood | 8 (26.7) | 21 (39.6) | 0.234 |
Soil or water | 9 (30.0) | 16 (30.2) | 0.986 |
Other trauma | 4 (13.3) | 6 (11.3) | 1.000* |
Previous OSD | 13 (43.3) | 12 (22.6) | 0.048 |
Herpetic keratitis | 7 (23.3) | 5 (9.4) | 0.108* |
Punctate keratopathy | 3 (10.0) | 2 (3.8) | 0.346* |
Old corneal opacity | 2 (6.7) | 3 (5.7) | 1.000* |
Other keratopathy# | 1 (3.3) | 2 (3.8) | 1.000* |
Contact lens wear | 1 (3.3) | 4 (7.5) | 0.649* |
Previous ocular surgery | 10 (33.3) | 10 (18.9) | 0.139 |
Systemic disease | 12 (40.0) | 21 (39.6) | 0.973 |
Diabetes mellitus | 4 (13.3) | 10 (18.9) | 0.518 |
Hypertension | 7 (23.3) | 12 (22.6) | 0.943 |
Initial clinical characteristics | |||
Central corneal lesion | 22 (73.3) | 42 (79.2) | 0.538 |
Epithelial defect size (mm2) | 12.7 ± 12.4 | 10.5 ± 11.2 | 0.404 |
≥ 10 mm2 | 13 (43.3) | 16 (30.2) | 0.228 |
Depth of infiltration | |||
Superficial (0-50%) | 14 (46.7) | 36 (67.9) | 0.057 |
Deep (50%-100%) | 16 (53.3) | 17 (32.1) | |
Hypopyon | 9 (30.0) | 17 (32.1) | 0.845 |
Presenting BCVA (logMAR) | 1.63 ± 0.96 | 1.47 ± 1.14 | 0.486 |
< 0.1, Snellen | 20 (66.7) | 27 (51.9) | 0.194 |
Values are presented as mean ± standard deviation or number (%).
PS=group of prior topical steroid use; NPS=group of no prior topical steroid use; OSD=ocular surface disease; BCVA=best corrected visual acuity.
*The p-value was calculated using Fisher’s exact test.
†The p-value was calculated using Kruskal-Wallis test.
#Include neurotrophic keratopathy (PS), bullous keratopathy (NPS), and exposure keratopathy (NPS).
Table 2. Microbiological test results* according to prior topical steroid use
PS (n=30) | NPS (n=53) | p-value | |
Identified fungal isolates† | 16 (53.3) | 14 (26.4) | 0.014 |
Candida species# | 6 (37.5) | 6 (42.9) | 0.765 |
Fusarium species# | 3 (18.8) | 5 (35.7) | 0.417§ |
Aspergillus species# | 4 (25.0) | 0 (0.0) | 0.103§ |
Syncephalastrum species# | 0 (0.0) | 1 (7.1) | 0.467§ |
Alternaria species# | 1 (6.2) | 0 (0.0) | 1.000§ |
Cryptococcus species# | 1 (6.2) | 0 (0.0) | 1.000§ |
Acremonium species# | 1 (6.2) | 0 (0.0) | 1.000§ |
Unknown species# | 0 (0.0) | 2 (3.8) | 0.209§ |
KOH smear positive | 20 (66.7) | 46 (86.8) | 0.029 |
Identified fungal isolates and KOH smear positive | 6 (20.0) | 7 (13.2) | 0.532§ |
Values are presented as number (%).
PS=group of prior topical steroid use; NPS=group of no prior topical steroid use; KOH=potassium hydroxide; PCR=polymerase chain reaction.
*Defined as positive result if at least one of the following is included: (a) positive fungal culture from a corneal specimen, (b) positive identification of fungal elements on a 10% KOH smear, (c) positive identification of fungal elements on multiplex PCR, or (d) histopathology showing presence of fungal elements.
†Identified by culture, multiplex PCR, and biopsy.
#Percentage and p-value of each species were calculated based on the identified fungal isolates.
§The p-value was calculated using Fisher’s exact test.
Table 3. Treatment outcome of fungal keratitis according to prior topical steroid use
Characteristics | PS (n=30) | NPS (n=53) | p-value |
Medical treatment: topical | |||
Antifungal agent monotherapy | 20 (66.7) | 43 (81.1) | 0.139 |
Amphotericin B | 8 (26.7) | 19 (35.8) | 0.391 |
Natamycin | 12 (40.0) | 24 (45.3) | 0.641 |
Combined antifungal agents | 10 (33.3) | 10 (18.9) | 0.139 |
Amphotericin B/ natamycin | 7 (23.3) | 10 (18.9) | 0.628 |
Voriconazole/ natamycin | 3 (10.0) | 0 (0.0) | 0.044* |
Medical treatment: systemic‡ | |||
Terbinafine | 5 (16.7) | 4 (7.5) | 0.273* |
Itraconazole | 1 (3.3) | 4 (7.5) | 0.649* |
Fluconazole | 16 (53.3) | 36 (67.9) | 0.187 |
Amphotericin B | 8 (26.7) | 17 (32.1) | 0.606 |
Voriconazole | 7 (23.3) | 1 (1.9) | 0.003* |
Treatment outcome | |||
Epithelial healing time, days# | 44.6 ± 50.5 | 29.6 ± 27.9 | 0.165 |
Median (range) | 27 (4-190) | 23 (3-150) | 0.248† |
Final BCVA§ (logMAR) | 1.36 ± 1.20 | 0.92 ± 1.08 | 0.133 |
< 0.1, Snellen | 18 (60.0) | 23 (44.2) | 0.169 |
Complications | |||
Corneal perforation | 8 (26.7) | 7 (13.2) | 0.126 |
Endophthalmitis | 2 (6.7) | 1 (1.9) | 0.295* |
Surgical intervention | 13 (43.3) | 11 (20.8) | 0.029 |
AMT | 9 (30.0) | 4 (7.5) | 0.011* |
Evisceration/enucleation | 4 (13.3) | 7 (13.2) | 1.000* |
Conjunctival flap | 6 (20.0) | 4 (7.5) | 0.157* |
Penetrating keratoplasty | 0 (0.0) | 1 (1.9) | 1.000* |
Time to evisceration/enucleation < 1 month¶ | 2/4 (50.0) | 5/7 (71.4) | 0.576 |
Duration of hospitalization, days** | 15.6 ± 6.3 | 13.0 ± 6.0 | 0.070 |
Treatment failure†† | 14 (46.7) | 12 (22.6) | 0.023 |
Values are presented as mean ± standard deviation or number (%).
PS=group of prior topical steroid use; NPS=group of no prior topical steroid use; BCVA=best corrected visual acuity; AMT=amniotic membrane transplantation.
*The p-value was calculated using Fisher’s exact test.
†The p-value was calculated using Kruskal-Wallis test.
‡Percent do not add to 100% because some cases had combined systemic medications.
#Total n=71: cases with persistent epithelial defect were excluded. (3 cases in PS, 9 cases in NPS)
§The final BCVA was assessed at the end of 3 months or at the completion of treatment.
¶Percentages and statistical values were calculated within the group of underwent evisceration/enucleation.
**Total n=77: cases of outpatients were excluded (2 cases in PS, 4 cases in NPS)
††Defined as the occurrence of complication or surgical intervention.
Table 4. Risk factors for treatment failure in fungal keratitis using univariate and multivariate logistic regression analysis
Variables | Univariate analysis | Multivariate analysis* | ||||
OR | 95% CI | p-value | OR | 95% CI | p-value | |
Female sex | 1.27 | 0.50-3.23 | 0.620 | |||
Age ≥ 60 years | 1.80 | 0.62-5.21 | 0.277 | |||
Agricultural occupation | 0.48 | 0.18-1.25 | 0.130 | |||
Corneal trauma | 0.22 | 0.08-0.66 | 0.006 | |||
Prior topical steroid use | 2.99 | 1.14-7.84 | 0.026 | 2.79 | 0.85-9.18 | 0.091 |
Previous OSD | 2.90 | 1.08-7.80 | 0.035 | 2.82 | 0.84-9.49 | 0.093 |
Previous herpetic keratitis | 2.55 | 0.74-8.85 | 0.140 | |||
Previous ocular surgery | 1.25 | 0.43-3.62 | 0.685 | |||
Diabetes mellitus | 2.63 | 0.81-8.51 | 0.106 | |||
Symptom duration ≥ 10 days | 1.34 | 0.52-3.46 | 0.543 | |||
Central corneal lesion | 1.02 | 0.34-3.06 | 0.978 | |||
Epithelial defect size ≥ 10 mm2 | 2.56 | 0.98-6.70 | 0.055 | |||
Deep infiltration | 8.34 | 2.90-23.96 | <0.001 | 4.38 | 1.37-14.08 | 0.013 |
Hypopyon | 5.70 | 2.06-15.80 | 0.001 | 6.01 | 1.70-21.23 | 0.005 |
Presenting BCVA < 0.1, Snellen | 4.85 | 1.60-14.67 | 0.005 | |||
OR=odds ratio; CI=confidence interval; OSD=ocular surface disease; BCVA=best corrected visual acuity.
Treatment failure was defined as the occurrence of complication or surgical intervention.
*Multivariate logistic regression analysis was performed using the backward-conditional method for the factors with a p-value < 0.1 in univariate logistic regression analysis.