Corneal fungal infection, or keratomycosis, is a severe disease entity with globe- and vision-threatening potential in the horse. Fungal microorganisms are part of the normal conjunctival microflora but can become opportunistic pathogens following corneal injury.1,2 Additional factors that contribute to the development of fulminant corneal infection and disease severity include exposure to vegetative matter and dust in the horse’s environment, wind speed, warm and humid environments in certain geographic regions and seasons, administration of topical antibiotics or corticosteroids, and tear film instability.1,3–13 The clinical presentation of keratomycosis varies based on the corneal depth of the fungal infection and the presence or absence of corneal ulceration. Fungal microorganisms have an affinity for Descemet membrane, and deeper corneal infections are perceived to be more difficult to treat due to challenges in antifungal drug delivery to the deep stroma and lack of deep stromal neovascularization.14–17
Diagnostic testing is limited based on the clinical presentation. Ulcerative lesions permit collection of cytology and culture samples at the patient’s initial examination, which may allow for early detection of fungal microorganisms on in-house cytology. However, deeper stromal abscess lesions preclude sample collection for cytology and culture without use of an invasive procedure, and samples cannot be collected until the time of surgical intervention.18,19 Treatment in these cases must proceed on a presumption of fungal involvement based on lesion appearance and the likelihood of fungal disease based on geographic area and season.15 Treatment decisions also affect which diagnostic tests are performed. Stromal abscesses treated medically may never confirm etiology unless the patient fails medical therapy and histopathology is performed following enucleation. Challenges in confirming fungal infection can make it difficult for the clinician to recommend an appropriate therapeutic treatment plan and determine the length of recommended treatment.
An appropriate treatment plan is based on a variety of factors including the lesion depth, the area/size of the lesion, the location of the lesion relative to the visual axis and proximity to the limbus, the integrity of the deep stroma and the Descemet membrane, the degree of reflex uveitis, and the response to initial medical treatment.20–23 Other practical considerations include comorbidities that affect a patient’s ability to undergo general anesthesia and owner finances. Medical therapy may be appropriate in cases with superficial fungal involvement or where patient comorbidities preclude surgical options (Figure 1). Surgical treatment options are recommended in cases that do not respond to medical therapy or where medical therapy is expected to fail such as cases with limited vascular ingrowth, deep stromal lesions, and corneal perforation.21 Superficial keratectomy under standing sedation is recommended for superficial corneal lesions up to 50% depth of the cornea, deep lamellar keratectomy with overlying conjunctival graft for lesions that are approximately 50% corneal depth or greater, and penetrating keratoplasty with the placement of donor graft (harvested equine cornea or acellular xenograft) and overlying conjunctival graft for mid, deep, or full-thickness stromal lesions (Figure 2). Additional surgical options for deep stromal abscesses that spare the overlying clear anterior cornea include posterior lamellar keratoplasty and deep lamellar endothelial keratoplasty.20,24 Medical therapy is instituted before surgery in all surgical cases and continued postoperatively.
Representative clinical photographs of medical treatment at initial exam (A) and final exam (B) at 43 days.
Citation: Journal of the American Veterinary Medical Association 262, S2; 10.2460/javma.24.06.0431
Representative clinical photographs of surgical treatments including superficial keratectomy: initial exam (A), intraoperative image of the superficial keratectomy site (B), and final exam at 87 days (C); keratectomy with conjunctival graft: initial exam (D), intraoperative image of a conjunctival graft placed over the keratectomy site (E), and final exam at 49 days (F); and penetrating keratoplasty: initial exam (G), intraoperative image of full-thickness removal of diseased cornea (H), and final exam at 48 days (I).
Citation: Journal of the American Veterinary Medical Association 262, S2; 10.2460/javma.24.06.0431
Previous studies9,25–30 with similar surgical guidelines have reported various clinical outcomes for keratomycosis patients. Most of these publications have a small sample size and were published before the widespread availability of modern antifungal agents, specifically voriconazole. The literature is lacking in analysis of clinical and diagnostic factors that may influence outcome. This knowledge may improve the ability to give accurate prognoses to horse owners at the onset of treatment and provide better estimates of treatment costs and hospitalization duration. Additionally, our clinical impression has been that cases solely treated medically had notably poorer clinical outcomes, longer hospitalization times, higher invoices, and more complications than those treated surgically. Thus, the aims of our retrospective study were 2-fold: (1) to determine the differences by treatment modality in clinical outcome, patients’ duration of hospitalization, and financial cost incurred by the client, and (2) to identify initial ophthalmic exam findings and diagnostic test results that may affect clinical outcome, the decision to pursue surgery, duration of hospitalization, and financial costs. Additional analyses of systemic and ocular complications associated with treatment are explored in our companion paper.31
Methods
Data collection
Animal owners or owners’ representatives provided written consent for the treatment provided and the use of medical records for research purposes. An electronic search of the North Carolina State University College of Veterinary Medicine (NCSU CVM) medical records was performed between the dates of January 2004 and November 2020 for the keywords “equine,” “horse,” “fungal corneal ulcer,” “keratomycosis,” “fungal ulcerative keratitis,” “fungal corneal abscess,” and “stromal abscess.” Each medical record was reviewed to determine if the case had corneal fungal infection confirmed by cytology, culture, and/or histopathology of biopsy samples or in an enucleated globe. Cases were excluded for having less than 1-month follow-up at NCSU CVM unless the affected eye was either enucleated or corneal healing was confirmed with discontinuation of medical therapy within that period. All patients underwent complete ophthalmic examinations performed at the NCSU CVM by a board-certified ophthalmologist and ophthalmology resident and were either hospitalized with daily examinations by a board-certified ophthalmologist or had ongoing outpatient care provided by the NCSU CVM.
Patient data recorded included age, sex, breed, eye affected, clinical diagnosis, etiology, ocular exam findings, diagnostic test results, treatment type, medications prescribed by the attending ophthalmologist, globe and vision retention, duration of hospitalization, NCSU CVM hospitalization invoice adjusted for inflation, and total NCSU CVM invoice adjusted for inflation. Clinical diagnoses were categorized as (1) subepithelial keratomycosis if there were small, nonulcerative, deep epithelial to superficial stromal lesions; (2) ulcerative keratitis if the main lesion was described as a corneal ulcer; and (3) stromal abscesses if the main lesion had stromal cellular infiltrate. Etiology was divided into fungal or mixed bacterial and fungal infection. Lesion depth was categorized on a 1 to 6 scale corresponding to superficial, mid stromal, deep stromal, descemetocele, perforation, or melting lesions. Aqueous flare was graded on a 0 to 4 scale as is standard in clinical practice.32
Diagnostic test results for cytology, culture, and histopathology were recorded individually as either positive, negative, or not performed for bacteria and fungus. Treatment type was categorized into medical treatment, superficial keratectomy, keratectomy with conjunctival graft, and penetrating keratoplasty. Patients with multiple surgeries performed were grouped into the category of their first surgery performed, and their total invoice was excluded from the analysis. Globe retention was defined as the presence of a normal-sized, nonpainful globe at the last examination. A positive visual outcome was considered as a positive menace response and dazzle reflex on the last examination. Cost outcomes including the hospitalization invoice and total invoice were adjusted for inflation to the year 2020 based on yearly inflation data from the US Bureau of Labor Statistics.33 Individual invoices generated from other NCSU CVM hospital services not associated with an ophthalmology exam were excluded from the total invoice. However, costs associated with treatment complications, for example, treatment for colic during hospitalization for keratomycosis, were included in the hospitalization and total invoice.
Sample collection
Sampling of corneal lesions for cytology and culture was performed after the application of proparacaine hydrochloride 0.5% ophthalmic solution. Samples were collected by 3.0-mm diameter cytobrush (PlastCare), sterile swab, or the back of a Bard-Parker No. 15 scalpel blade (Becton Dickinson and Co). Cytology was assessed following Diff-Quik stain (Fisher Scientific) by a board-certified ophthalmologist and ophthalmology resident. Samples for aerobic bacterial and fungal culture were plated on MacConkey agar and thioglycolate broth, and Sabouraud dextrose agar, respectively, and submitted to the NCSU Clinical Microbiology Laboratory. Plates were incubated at 36 °C for a minimum of 21 days. In surgical cases, corneal biopsy samples or globes for histopathology were fixed in Davidson solution and processed by the NCSU Anatomic Pathology Service. Special staining with Gomori methenamine silver and Gram stain was performed when indicated.
Statistical analysis
Analysis was performed using SPSS Statistics, version 29 (IBM Corp), and R, version 4.2.3 (The R Foundation). A P value < .05 was considered statistically significant. Descriptive statistics were reported as the median and range. Cases with missing data were excluded from appropriate analyses and statistical tests. Fisher exact tests were used to compare outcome parameters by treatment type. Additional evaluation of clinical outcome with Fisher exact tests evaluating cases from 2004 to 2010 versus 2011 to 2020 was performed to evaluate for improvement in the management of keratomycosis over time and to account for the significant increase in the number of penetrating keratoplasty surgeries performed at NCSU CVM after 2010 (2 surgeries before 2010 vs 19 surgeries after 2010). Duration of hospitalization, hospitalization invoice, and total invoice by treatment type were evaluated by ANOVA. If the data was positively skewed, a natural log transformation was applied. The natural log scale means were transformed back into the original scale as medians. Post hoc testing included pairwise comparisons of the median ratios in log scale and transformed back into the original scale.
Logistic regression models were utilized to determine if selected variables affected the probability of a poor clinical outcome and if initial examination findings predicted the probability of choosing surgical over medical treatment. Poor clinical outcome was defined as enucleation or phthisis bulbi at the last examination. Stepwise variable selection by Akaike information criteria was performed for each model. Variables with subcategory sample sizes that were too small for logistic regression were examined individually using Fisher exact tests. Linear regression models were used to determine the relationships of selected variables with duration of hospitalization and total invoice. The outcomes of the linear regression models were log transformed.
Results
Case information
The electronic medical record search retrieved 233 horses presented to the NCSU Ophthalmology Service between January 2004 and November 2020 with keywords relating to keratomycosis. One hundred twenty-five horses (126 eyes) met the inclusion criteria. The median age at the first examination was 13 years (range, 0.3 to 32 years). The study population included 76 geldings (60.3%), 47 mares (37.3%), and 3 stallions (2.4%). The breeds presented in order of prevalence were Quarter Horse (27/125 [21.4%]); Thoroughbred (19/125 [15.1%]); Arabian (17/125 [13.5%]); warmblood (13/125 [10.3%]); Paint Horse (8/125 [6.3%]); Saddlebred (7/125 [5.6%]); Morgan and Walking Horse (4/125 [3.2% each]); Appaloosa and Hanoverian (3/125 [2.4% each]); Connemara Pony, Oldenburg, pony, Rocky Mountain Horse, Standardbred, Trakehner, and Welsh Pony (2/125 [1.6% each]); and Andalusian, Appendix Quarter Horse, Clydesdale, Dutch Warmblood, Fox Trotter, Irish Hunter Horse, and Percheron (1/125 [0.8% each]). There was a similar distribution of affected eyes in the population with 64 right eyes (50.8%) and 62 left eyes (49.2%).
Clinical exam findings and diagnosis
Ulcerative keratomycosis was the most common clinical diagnosis in 93 eyes (73.8%), followed by stromal abscesses in 28 eyes (22.2%), and subepithelial keratomycosis in 5 eyes (4.0%). Etiology was categorized as fungal only for 90 eyes (71.4%) and mixed bacterial/fungal infection for 36 eyes (28.6%). There was a larger proportion of superficial to mid stromal lesions with 42 eyes (33.3%) categorized as superficial, 30 eyes (23.8%) mid stromal, 24 eyes (19.0%) deep stromal, 11 eyes (8.7%) descemetocele, 4 eyes (3.2%) corneal perforation, and 5 eyes (4.0%) melting ulcers. Ten eyes (7.9%) were missing a description of lesion depth. Aqueous flare score was reported as absent or not recorded in 74 eyes (58.7%), 1+ in 34 eyes (27.0%), 2+ in 10 eyes (7.9%), 3+ in 6 eyes (4.8%), and 4+ in 2 eyes (1.6%). Positive fungal identification was made in 81.4% of cytology, 79.1% of culture, and 70% of histopathology samples. Positive bacterial identification was made in 15.6% of cytology, 25.7% of culture, and 4.4% of histopathology samples.
Treatment analysis
Following referral, 40 eyes underwent medical therapy alone and 86 eyes underwent medical and surgical therapy. Within the surgical group, 25 eyes had a superficial keratectomy under standing sedation, 40 had a lamellar keratectomy with conjunctival graft under general anesthesia, and 21 had a penetrating keratoplasty with conjunctival graft under general anesthesia. Four horses in the superficial keratectomy group had conjunctival grafts placed while under standing sedation. One horse with bilateral involvement had keratectomy with conjunctival graft and superficial keratectomy performed in the right and left eyes, respectively.
Overall clinical outcomes did not vary significantly between the medical and surgical treatment or between all 4 treatment types when each surgical group was considered individually. Globe retention was not significantly different between medical versus surgical treatment (P = .369) or between individual treatment types (P = .392; Table 1). The positive visual outcome was also not significantly different between medical versus surgical treatment (P = .365) or by individual treatment type (P = .355). Although there was no statistical significance, a higher proportion of eyes achieved positive globe retention and visual outcome after keratectomy with conjunctival graft (globe retention, 92.5% of eyes; visual outcome, 89.5% of eyes) and penetrating keratoplasty (globe retention, 90.5% of eyes; visual outcome, 90.5% of eyes) surgeries compared to medical treatment alone (globe retention, 82.5% of eyes; visual outcome, 78.9% of eyes).
Two-way frequency distribution showing globe retention and positive visual outcome divided into medical treatment and surgical treatment and with surgical treatment subdivided into individual procedure type.
| Globe retention | Positive visual outcome | |||||||
|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | |||||
| Treatment | Frequency | Percent | Frequency | Percent | Frequency | Percent | Frequency | Percent |
| Medical | 33/40 | 82.5% | 7/40 | 17.5% | 30/38 | 78.9% | 8/38 | 21.1% |
| Surgical | 76/86 | 88.4% | 10/86 | 11.6% | 71/83 | 85.5% | 12/83 | 14.5% |
| Superficial keratectomy | 20/25 | 80.0% | 5/25 | 20.0% | 18/24 | 75.0% | 6/24 | 25.0% |
| Keratectomy with conjunctival graft | 37/40 | 92.5% | 3/40 | 7.5% | 34/38 | 89.5% | 4/38 | 10.5% |
| Penetrating keratectomy | 19/21 | 90.5% | 2/21 | 9.5% | 19/21 | 90.5% | 2/21 | 9.5% |
Analysis of clinical outcome was repeated by individual treatment type after dividing patients into the year ranges 2004 to 2010 and 2011 to 2020 by the first exam date. Globe retention assessed between treatment types from 2004 to 2010 (P = .125) and from 2011 to 2020 (P = .940) did not vary significantly (Table 2). The positive visual outcome in the years 2004 to 2010 (P = .157) and 2011 to 2020 (P = .591) was also not significantly different by treatment type. Although not statistically significant, there was a higher proportion of patients with a good clinical outcome following superficial keratectomy (globe retention and positive visual outcome, 82.4% of eyes), keratectomy with conjunctival graft (globe retention and positive visual outcome, 91.7% of eyes), and penetrating keratoplasty surgery (globe retention and positive visual outcome, 94.7% of eyes) performed from 2011 to 2020 compared to medical treatment alone (globe retention and positive visual outcome, 81.0% of eyes).
Two-way frequency distribution showing positive globe retention and positive visual outcome by treatment type separating cases from 2004 to 2010 and from 2011 to 2020.
| Globe retention | Positive visual outcome | |||||||
|---|---|---|---|---|---|---|---|---|
| 2004 to 2010 | 2011 to 2020 | 2004 to 2010 | 2011 to 2020 | |||||
| Treatment | Frequency | Percent | Frequency | Percent | Frequency | Percent | Frequency | Percent |
| Medical | 16/19 | 84.2% | 17/21 | 81.0% | 13/17 | 76.5% | 17/21 | 81.0% |
| Superficial keratectomy | 6/8 | 75.0% | 14/17 | 82.4% | 4/7 | 57.1% | 14/17 | 82.4% |
| Keratectomy with conjunctival graft | 26/28 | 92.9% | 11/12 | 91.7% | 23/26 | 88.5% | 11/12 | 91.7% |
| Penetrating keratectomy | 1/2 | 50.0% | 18/19 | 94.7% | 1/2 | 50.0% | 18/19 | 94.7% |
Hospitalization and follow-up time
Overall patients were hospitalized for a median of 8 days (range, 0 to 78 days) with medically treated patients hospitalized for a median of 3.5 days (range, 0 to 20 days) and surgically treated patients hospitalized for a median of 10 days (range, 0 to 78 days). Medical treatment resulted in a statistically shorter hospitalization compared to any surgical treatments (P < .001 for all). There was no evidence of differing lengths of hospital stay between the surgical treatment groups. The median duration of hospitalization for each treatment group was 3.5 days (range, 0 to 20 days) for medical treatment, 10 days (range, 0 to 78 days) for superficial keratectomy, 8 days (range, 3 to 47 days) for keratectomy with conjunctival graft, and 12 days (range, 7 to 33 days) for penetrating keratoplasty. Pairwise comparison of hospitalization duration between treatment types are provided as median ratios (Supplementary Table S1).
In the 86 patients that underwent a surgical procedure, the median time from first exam to surgery date was 2 days (range, 0 to 45 days). The median follow-up time from discharge to final exam was 43 days (range, 0 to 5,029 days) overall. Median follow-up time for individual treatment groups was as follows: 43.5 days (range, 0 to 3,136 days) for medical treatment, 40 days (range, 7 to 1,469 days) for superficial keratectomy, 43 days (range, 0 to 5,029 days) for keratectomy with conjunctival graft, and 45 days (range, 7 to 274 days) for penetrating keratoplasty. The duration of follow-up was not statistically different between treatment groups (P = .959).
Cost analysis
The total invoice for all treatment and follow-up exam costs incurred through the NCSU CVM after adjustment to the year 2020 inflation rate was $6,087.44 (range, $887.22 to $17,570.94). A total of 110 patients were hospitalized; their median hospitalization invoice after adjustment to the year 2020 inflation rate was $4,796.53 (range, $901.85 to $11,948.52).
The results of the total invoice comparison by treatment type indicated a statistically significant difference among treatments (P < .001; Figure 3). The total invoice for medical treatment was lower than all surgical treatment types (P < .001 for all), and penetrating keratoplasty patients had a higher total invoice than patients undergoing a keratectomy with conjunctival graft surgery (P = .037). Pairwise comparison of the total invoices between treatment categories are provided as median ratios (Supplementary Table S2). The hospitalization invoice was also significantly different between treatments (P < .001; Figure 4), with medical treatment being lower in cost compared to all surgery types (P < .001 for all). Penetrating keratoplasty had a higher hospitalization invoice compared to superficial keratectomy (P < .01) and keratectomy with conjunctival graft (P = .006). There was no significant cost difference in hospitalization invoice between superficial keratectomy and keratectomy with conjunctival graft (P = .067). Pairwise comparisons of hospitalization invoice costs between treatment categories are provided as median ratios (Supplementary Table S3).
Box plot of total invoice by treatment type. Five cases from 4 horses were excluded. Individual P values for each treatment comparison are provided; P < .05 is considered significant. °Outliers outside the 1.5 IQR.
Citation: Journal of the American Veterinary Medical Association 262, S2; 10.2460/javma.24.06.0431
Box plot of hospitalization invoice by treatment type. Two cases from 1 horse were excluded. Individual P values for each treatment comparison are provided; P < .05 is considered significant. °Outliers outside the 1.5 IQR.
Citation: Journal of the American Veterinary Medical Association 262, S2; 10.2460/javma.24.06.0431
Regression models
The results of the 4 regression models (poor clinical outcome, choice to pursue surgery, duration of hospitalization, and total invoice) are presented for each model separately. The variables included in the regression models are detailed (Table 3). Poor clinical outcome was significantly more likely in eyes that did not have fungal culture performed than those with a negative fungal culture result (P = .026). There was also a significantly higher probability of poor clinical outcome in eyes that had histopathology performed regardless of whether fungus was identified compared to eyes where this diagnostic test was not performed (P = .001) and a higher probability of poor clinical outcome for eyes without bacteria identified on histopathology compared to eyes that did not have histopathology performed (P = .001). There was no difference in the probability of a poor outcome based on the clinical diagnosis of ulcerative keratomycosis, stromal abscess, or subepithelial keratomycosis (P = .395). Lesion depth was not significantly associated with clinical outcome (P = .589).
Logistic regression model variables listed with subcategories.
| Variable | Subcategory |
|---|---|
| Aqueous flare | 0: Absent 1: Trace 2: Mild 3: Moderate 4: Severe |
| Cytology (bacterial) | Positive Negative Not performed |
| Cytology (fungal) | Positive Negative Not performed |
| Culture (bacterial) | Positive Negative Not performed |
| Culture (fungal) | Positive Negative Not performed |
| Diagnosis | Stromal ulcer Subepithelial keratomycosis Ulcerative keratomycosis |
| Etiology | Fungal Mixed (bacterial and fungal) |
| Fungal type | Aspergillus fumigatus Other fungal species or type |
| Histopathology (bacterial) | Positive Negative Not performed |
| Histopathology (fungal) | Positive Negative Not performed |
| Lesion depth | 1: Superficial 2: Mid stromal 3: Deep stromal 4: Descemetocele 5: Corneal perforation 6: Melting |
| Topical antifungal | Yes No |
| Topical steroid | Yes No |
| Systemic antifungal | Yes No |
The choice to pursue the surgery model limited variables to diagnosis, etiology, flare, and lesion depth to better represent initial exam findings. Lesion depth was significantly associated with the choice to pursue surgery; for every 1-point increase in lesion depth, the odds of pursuing surgery increased 1.861 times (P = .003).
The duration of hospitalization was significantly longer for eyes diagnosed with stromal abscesses (median, 10.5 days; range, 3 to 33 days) compared to ulcerative keratomycosis (median, 7 days; range, 0 to 47; P < .010). There was no difference in hospitalization duration between subepithelial keratomycosis and ulcerative keratomycosis cases (P = .199). Positive fungal and bacterial culture findings resulted in close to and significantly longer hospitalization durations, respectively, compared to negative test results (fungal, P = .051; bacterial, P = .040). Not having histopathology performed was associated with a longer hospitalization compared to having a negative fungal result on histopathology (P < .001).
Concerning total invoices, stromal abscess cases had a significantly higher total cost (median, $7,066.57; range, $2,997.28 to $17,570.94) than ulcerative keratomycosis cases (median, $5,601.40; range, $887.22 to $12,184.59; P < .001). The total invoice was higher for cases where a negative fungal histopathology result was obtained compared to cases where histopathology was not performed (P = .002).
Discussion
Equine keratomycosis remains a time-intensive and expensive disease to treat successfully. Previous retrospective studies9–12,16,18,25–28,30,34–37 report a wide range of overall globe maintenance and positive visual outcome rates from 52.2% to 96.7% and from 43.5% to 96.7%, respectively. Publications that separated medical from surgical cases reported globe retention ranging from 38.5% to 100% for medical and 81% to 93.8% for surgical therapy and reported a positive visual outcome ranging from 38.5% to 100% for medical and 62.5% to 93.8% for surgical therapy.9,11,25 Our study found globe retention in 82.5% of medically treated cases and 88.4% of surgically treated cases and maintenance of vision in 78.9% of medically treated cases and 85.5% of surgically treated cases. While poorer clinical outcomes occurred more commonly in solely medically treated cases, overall, there was a good outcome in terms of globe and vision retention for patients treated through a university teaching hospital in the southern US with a high keratomycosis caseload. It should be noted that patients were under the care of board-certified ophthalmologists and that this outcome data may not reflect outcomes achieved in equine primary practice.
Interestingly, several regression model data points suggested that medical therapy alone resulted in a higher probability of good clinical outcomes. Specifically, the poor clinical outcome logistic regression model demonstrated that cases in which histopathology was performed were significantly more likely to have a poor clinical outcome than cases in which histopathology was not performed, regardless of whether fungus or bacteria was identified. Corneal biopsies are standard protocol for all surgical keratectomy procedures at NCSU CVM, suggesting that surgically treated cases were more likely to have a poor outcome. However, we also found that cases treated by keratectomy with conjunctival graft and penetrating keratoplasty had higher globe retention and positive visual outcomes compared to cases treated medically, although this difference was not statistically significant. This discrepancy between the regression model and outcome data may be associated with the clinical outcome of superficial keratectomy cases. Although not significant, globe retention (80.0%) and positive visual outcome (75.0%) were lower for superficial keratectomy cases compared with the other surgically and medically treated cases, which may be associated with failure to remove all infected tissue. Evaluation of keratomycosis lesions with ultrasound biomicroscopy before the institution of treatment found that deeper lesions were associated with a poor prognosis.22 While lesion depth in this study as evaluated by slit lamp biomicroscopy did not significantly impact the clinical outcome, it was a determining factor in the choice to pursue surgery indicating that deeper corneal lesions were more likely to undergo surgical treatment. Appropriate surgical treatment based on lesion depth may have contributed to the good clinical outcome reported overall.
Duration of hospitalization reported in multiple retrospective studies found similar hospitalization times for medical and surgical treatment. Andrew et al25 reported the median hospitalization time was 15.1 ± 11.7 days and 12.1 ± 6.2 days for medical and surgical treatment respectively. A similar study by Reed et al36 reported the median hospitalization time as 12 days (range, 0 to 44 days) for medical treatment and 11.6 days (range, 6 to 60 days) for surgical treatment. In this study, medical treatment was associated with shorter hospitalization duration compared to all surgical treatment types. There was a subset of medically treated cases that were treated solely on an outpatient basis, which lowered the median duration of hospitalization and likely reflects selection bias for cases with more mild disease. It has become standard protocol at NCSU CVM to hospitalize patients for 1 week following conjunctival and/or corneal grafting procedures to monitor for graft-related complications and for 3 to 7 days following superficial keratectomy to monitor for early signs of keratectomy bed epithelialization before discharge. Severity of disease and the NCSU CVM hospitalization protocol likely contributed to the difference in hospitalization times.
The linear regression model noted multiple associations with hospitalization duration. A positive bacterial culture was a significant predictor of a longer duration of hospitalization, while a positive fungal culture was close to achieving a statistically significant (P = .051) association with longer hospitalization periods. This finding could indicate that mixed infections result in more severe corneal disease requiring longer hospitalization. Additionally, achieving fungal growth on culture may indicate a higher disease load or actively replicating fungus; therefore, cases with positive fungal culture may be infected with highly pathogenic fungal species. Since fungal culture results are reported in 1 to 3 weeks following sample collection, the decision to treat medically or surgically has already been made. Thus, it is less likely that the fungal culture results directly impact hospitalization duration by influencing treatment decisions but may be a proxy that indicates more clinically severe fungal disease. Finally, the model revealed that not having histopathology performed was related to a shorter hospitalization time. As most surgical cases had corneal biopsies collected for histopathology, this result supports our previous finding that medically treated cases were associated with a shorter duration of hospitalization and were likely selected for medical treatment based on mild disease.
Follow-up time was not significantly different between the treatment types with a median duration of 43 days overall. It is standard protocol at NCSU CVM to recommend a minimum treatment period of 6 to 8 weeks with topical antifungal medications for keratomycosis regardless of treatment type. Voriconazole, which was the most common topical antifungal prescribed by NCSU CVM during the study, achieves penetration through the cornea into the aqueous humor.31,38 Depending on the MIC of voriconazole against various fungal species and fungal resistance patterns, this medication may have a fungistatic or fungicidal effect.39–43 Other common antifungal medications may also show reduced efficacy due to resistance of specific fungal species, inability to cross epithelial barriers, and variable MIC depending on the fungal species.42,44,45 Therefore, a prolonged time course for treatment is recommended in line with the duration of follow-up reported and based on the success rate in the current study.
The cost of treatment has rarely been analyzed despite being of critical importance to the horse owner and a relevant factor in clinical decisions. Utter et al30 found that medical costs related to the treatment of keratomycosis were 24% lower compared to surgical costs in the early 2000s. The current study also found that medical treatment was less costly than surgical options. On average, the total invoice for penetrating keratoplasty, superficial keratectomy, and keratectomy with conjunctival graft was 2.646, 1.927, and 1.879 times the cost of medical therapy alone. The linear regression model also indicated that cases in which histopathology was not performed (medically treated cases) were associated with a lower total invoice. This difference in cost is unsurprising given the additional costs associated with sedation or general anesthesia, the surgical procedure, and continued postoperative hospitalization. Our study also noted that hospitalization time was shorter for medically treated cases, which reduces hospitalization costs as most facilities charge a daily hospitalization rate.
Financial and hospitalization outcomes were also significantly impacted by the clinical diagnosis. An initial diagnosis of stromal abscess was associated with higher costs and longer hospitalization stays compared to ulcerative lesions. It has been our clinical impression that corneal stromal abscesses are more difficult to treat compared to ulcerative keratomycosis lesions. Our regression models supported this hypothesis: (1) not having fungal culture performed was significantly more likely to result in a poor clinical outcome than in cases where fungal culture was submitted, (2) stromal abscesses resulted in significantly longer hospitalization time compared to ulcerative keratomycosis cases, and (3) and stromal abscesses incurred a significantly higher invoice compared to ulcerative keratomycosis cases. It should be noted that culture samples are rarely collected from stromal abscesses due to an intact corneal epithelial surface. Interestingly, evaluation of clinical outcome by diagnosis in our study did not find a statistical difference between the 2 diagnoses. This discrepancy suggests that although stromal abscesses have a higher probability of a poor clinical outcome due to associated treatment challenges, aggressive and appropriate therapy may result in globe and vision retention. Penetrating keratoplasty is the recommended treatment for deep stromal abscesses at NCSU CVM, and in the recent years of this study, penetrating keratoplasty resulted in excellent globe retention (94.7% of eyes) and visual outcome (94.7% of eyes).
The present findings indicate that medical treatment is associated with lower cost, shorter hospitalization time, and a similar outcome to surgical treatment. The authors, however, would caution against the interpretation that medical treatment should be selected above surgical treatment. While a statistically significant difference in clinical outcome was not identified, likely due to the small sample size, we did note a higher rate of good clinical outcomes in surgically treated cases. Additionally, the results should be interpreted with the knowledge that the clinician’s decision to pursue medical or surgical treatment is often multifactorial and considers not only clinical factors such as lesion depth and the extent of corneal involvement but also patient factors such as patient comorbidities and owner finances. A more discerning interpretation is that clinician case selection based on lesion depth and severity of disease results in an overall good clinical outcome and that cases requiring surgical excision of infected tissue are treated with the appropriate surgical procedure.
The main limitations of this study were related to its retrospective nature. Paper medical files were not retrievable for several patients from the university’s storage system. Ophthalmic exam descriptions between clinicians were also variable. We could not evaluate additional clinical exam findings beyond lesion depth and flare score as other findings were not consistently described. The regression models were limited in power and number of variables analyzed by the low sample size. The results of the regression models were dependent on the preselected variables of interest and do not reflect all the ophthalmic exam findings and diagnostic results. Regression models can return statistically significant but not clinically relevant findings based on the variables input into the model.
Our study reports a good clinical prognosis for equine keratomycosis cases in line with publications within the past 20 years. There was no statistical difference in outcome for different treatment types, but in this sample population, there were better clinical outcomes in surgically treated cases. Increasing lesion depth predicted the decision to pursue surgical therapy. Medical treatment resulted in shorter hospitalization times and lower treatment costs compared to the 3 surgical options assessed. The diagnosis of stromal abscess predicted higher treatment costs and longer duration of hospitalization compared to ulcerative keratitis; however, clinical outcomes were comparable.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors thank Valerie Ball Basham for her assistance with medical record acquisition and organization.
Disclosures
Dr. Gilger served as Guest Editor for this JAVMA Supplemental Issue. He declares that he had no role in the editorial direction of this manuscript. The other authors have declared no conflicting interests.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
ORCID
H. L. Smith https://orcid.org/0000-0003-4463-1245
B. C. Gilger https://orcid.org/0000-0002-7771-9166
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