|Year : 2022 | Volume
| Issue : 1 | Page : 37-41
Factors associated with poor prognosis in corneal ulcer: A clinical and epidemiological study
Mini Mathew1, AR Arya1, Ajith Cherian2
1 Department of Ophthalmology, Regional Institute of Ophthalmology, Thiruvananthapuram, Kerala, India
2 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
|Date of Submission||24-Apr-2021|
|Date of Decision||20-Jun-2021|
|Date of Acceptance||21-Jun-2021|
|Date of Web Publication||21-Apr-2022|
Dr. Mini Mathew
Department of Ophthalmology, Regional Institute of Ophthalmology, Thiruvananthapuram, Kerala
Source of Support: None, Conflict of Interest: None
Aim: To explore the factors associated with culture positivity and worsening of corneal ulcers in patients presenting to a tertiary care teaching hospital in south Kerala. Methods: We did a retrospective review of hospital-based case records from June 2018 to May 2019 and included all cases of infective corneal ulcer admitted during the period of study with corneal stromal infiltrate on slit-lamp examination. Results of gram stain, potassium hydroxide stain, and culture result were noted. The treatment history (moxifloxacin (0. 3%) or fortified cephalosporin and gentamicin or natamycin) was recorded. The data were exported to the statistical software SPSS V27.0 for further analysis. Results: The data of 125 culture-positive and 250 culture-negative ulcers were studied. Most patients were aged >55 years (n = 201, 53.6%) and 35–55 years (n = 120, 32.0%). The association of culture negativity with nontraumatic risk factors was significant (P = 0.01) but not with the size of the ulcer, progress score, or worsening clinical status of the ulcer. More persons with pretreatment (15.2%) showed worsening of the clinical status compared to those who did not (6.3%) (P = 0.005). 63% of the culture-positive cases had not taken any pretreatment. Compared to noncentral ulcers there was a marked deterioration of central ulcers (16.7%) (P = 0.005). Conclusion: Pretreatment and centrally located ulcers were significantly associated with a worsening clinical condition in this study. Culture-positive corneal ulcers showed a tendency toward improvement, but we could not find an association between the detection of the organism and its favorable response to treatment.
Keywords: Corneal ulcer, culture, prognosis
|How to cite this article:|
Mathew M, Arya A R, Cherian A. Factors associated with poor prognosis in corneal ulcer: A clinical and epidemiological study. Kerala J Ophthalmol 2022;34:37-41
|How to cite this URL:|
Mathew M, Arya A R, Cherian A. Factors associated with poor prognosis in corneal ulcer: A clinical and epidemiological study. Kerala J Ophthalmol [serial online] 2022 [cited 2022 May 16];34:37-41. Available from: http://www.kjophthal.com/text.asp?2022/34/1/37/343679
| Introduction|| |
The incidence of microbial keratitis in South India is estimated at approximately 113/100,000 population. The incidence of microbial keratitis in India is more than ten times the incidence in the US with an estimated 800,000 persons developing microbial keratitis in India each year. An estimated 1.5–2 million people each year worldwide develop uniocular blindness that is attributable to microbial keratitis. Increased severity of infection in microbial keratitis is associated with delays in presentation, inappropriate use of medications and the difficulty to obtain diagnostic cultures, especially in rural populations can lead to an increased magnitude of uniocular blindness and vision impairment and healthcare costs, especially in vulnerable populations. In the US, microbial keratitis results in an estimated 175 million dollars in direct health expenditure while a study from south India reported that the total overall cost for accessing and receiving care was 85.8 ± 4.6 USD and the mean total cost to diagnose and appropriately treat 1 case of keratitis such that the patient had vision better than 6/18 at final follow-up was 56.2 ± 3.6 USD.,
The severity of microbial keratitis is influenced by an intermix of environmental factors like geographical location, climate, and virulence of causative organisms and patient factors like population demographic, occupation, contact lens use, and associated ocular and systemic morbidity. The Asia Cornea Society Infectious Keratitis Study on etiological patterns of infectious keratitis, including viral disease, from 13 tertiary care hospitals throughout Asia reported a fungal predominance in India compared to a predominant bacterial etiology in the more developed economies. Kerala is a south Indian state with a hot, humid climate interspersed with a good monsoon. The climatic conditions of Kerala and its agrarian nature can lead to an increased risk for microbial keratitis. We designed a retrospective case record-based study to explore the factors associated with culture positivity and worsening of corneal ulcers in patients presenting to a tertiary care teaching hospital in south Kerala.
| Methods|| |
The study protocol that used a case-control design and a retrospective review of hospital-based case records was approved by the institutional ethics committee. The records of patients admitted to the study institute from June 2018 to May 2019 were retrieved and analyzed. The study included all cases of infective corneal ulcer that required admission during the period of study with the presence of corneal stromal infiltrate upon slit-lamp examination, and which required microbiological evaluation of corneal scrapings for suspected microbial keratitis. The study excluded viral ulcers, Mooren's ulcers, marginal ulcers, interstitial keratitis, sterile neurotrophic ulcers, ulcers associated with autoimmune conditions, and cases of noninfective corneal ulcer. The cases were defined as patients with culture positivity and controls were defined as patients with culture-negative results. The outcome variables of interest included the size and depth of infiltrate, presence of hypopyon, and visual acuity. The exposure variables studied included age, pretreatment, time lag, size, depth of ulcer, and culture positivity. A sample size of 350 was estimated using the Open Epi software, 80% power, least anticipated odds ratio, and a 1: 2 allocation for cases and controls.
The size and depth of the infiltrate, duration of treatment/other features like hypopyon, satellite lesions, collagenolysis, etc., are not mentioned.
The data was entered into an anonymized study form that included sociodemographic details, duration of symptoms, previous treatment, predisposing ocular conditions, and associated risk and clinical features. The size of the epithelial defect and infiltrate measured with the variable slit on the biomicroscope, and the size and depth of the stromal infiltrate were recorded in millimeters. A sketch of each ulcer was drawn on the form and the presence or absence of a hypopyon, hyphate margins, presence of immune ring, satellite lesions was recorded. Associated ocular conditions such as blepharitis, dacryocystitis, dry eyes, corneal anesthesia, or ocular leprosy were noted. The results of corneal scraping including Gram stain, potassium hydroxide stain and culture result were noted. The treatment history (moxifloxacin (0. 3%) or standard therapy of fortified cephalosporin and gentamicin drops or natamycin) was recorded. Ulcers were classified according to severity and changes in the initial size, position of ulcer, and the course of the ulcer was recorded on days 3, 6, and 14 days or till discharge.
The data were entered into a spreadsheet and exported to the statistical software IBM Statistics for Windows, version 27.0, (Armonk, NY) for further analysis. Continuous variables were expressed as mean and were compared using a t-test. Categorical variables were expressed as proportions and were compared using a Fisher's test. A logistic regression model was used to explore associations of prognosis. Each patient was given a combined score called progress score based on the vision, size, and depth of involvement at presentation, 1 day, 6 days, 2 weeks, or at discharge. The progression pattern was assessed and the improvement of the progress score was analyzed as–1 (deterioration), 0 (stabilization), and 1, to 5 for various levels of improvement. The effect of initial size, the position of ulcer, and pretreatment on the course of the ulcer was analyzed using the Chi-square test, bivariate logistic regression test, and Fischer's test. Binary logistic regression analysis was used to predict risk factors of deterioration. Age, culture result, size of ulcer, foreign body, trauma, other risk factor, site of ulcer, and pretreatment were the variables considered in the logistic regression model.
| Results|| |
The data of 125 culture-positive and 250 culture-negative ulcers were retrieved from the case records of patients admitted with corneal ulcer during the study period. Most of the subjects were aged >55 years (n = 201, 53.6%) and 35–55 years (n = 120, 32.0%). Culture negative results were significantly more common than culture-positive results in all age groups except the 35-to-55-year age group [see [Table 1]]. Culture negativity was significantly associated with nontraumatic risk factors (P = 0.01) but was not associated with the size of the ulcer, progress score, or worsening clinical status of the ulcer [see [Table 2]]. Twelve of the 15 culture-positive ulcers that showed deterioration were fungal ulcers. The common fungi involved with corneal ulcers in this population were Fusarium and aspergillus. More patients who took pretreatment (15.2%) showed worsening of the clinical status compared to those who did not take pretreatment (6.3%) (P = 0.005). 63% of the culture-positive cases had not taken any pretreatment. There was a marked deterioration of central ulcers (16.7%) compared to ulcers (4.7%) at other locations (P = 0.005). Only 61.7% of the centrally located corneal ulcers showed improvement compared to ulcers in other locations (75.7%). A bivariate regression model was used to explore associations of age, culture positivity, size of ulcer, foreign body, trauma, other risk factors, site of ulcer, and pretreatment with deterioration of the ulcer. Pretreatment (odds ratio 2.35, 95% confidence interval [CI]: 1.11, 4.92, P = 0.02) was significantly associated with a worsening clinical condition while a noncentrally located ulcer was protective from clinical deterioration (odds ratio 0.26, 95% CI: 0.12, 0.55, P < 0.001).
|Table 1: Association of culture positivity with age in the study population|
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| Discussion|| |
The pretreatment (whether steroids are used which has a major bearing in the outcome of a corneal ulcer) details are not written.
Most subjects with corneal ulcers were aged >35 years in the study population and possibly reflect the risk factors associated with corneal ulcers like outdoor occupation and agrarian work. Nontraumatic risk factors were significantly associated with corneal ulcer in persons aged >55 years while ocular trauma was a significant risk factor in the younger ages. The association with trauma reflects in the culture positivity rates with a higher frequency of culture positivity in the younger age groups. We found that pretreatment with ophthalmic medications and centrally located ulcers were significantly associated with a worsening clinical condition in this study population. Our patients were found to have pretreament with broad-spectrum antibiotic with or without natamycin. None of our patients were recorded to have pretreatment with steroid eye drops. Culture-positive corneal ulcers showed a tendency toward improvement, but we could not find an association between the detection of the organism and its favorable response to treatment.
We found similar results in our study with more culture-positive ulcers showing a greater deterioration'.--THE CAUSE OF THIS ??
Still, it is not clear why were the fungal ulcers having a poor prognosis. Is it related to the etiological agent or is it patient related (like poor compliance/cocktail treatment/late intervention/super-added systemic illness like diabetes, etc.,)
Previous studies, have reported positive culture and ulcer size larger than 5 mm2 as a significant predictor of slow healing in ulcer. We found similar results in our study with more culture-positive ulcers showing a greater deterioration. Twelve of the 15 culture-positive ulcers that showed deterioration were fungal ulcers. Of the 45.5%of culture positivity, 15% showed fusarium growth 9% showed aspergillus and 12% constituted other fungi namely Penicillium, scopularis, aerobasidium, epicorum, and rhodoturulla. Sixty-three percent of culture-positive were seen not to have taken pretreatment.
Eighty percent of culture positive had a size >2 mm. The poor prognosis of the culture-positive fungal ulcers could be related to the etiological agent and the late presentation as most of our culture-positive ulcers were large in size. Ten percent of culture positive were associated with a nontraumatic risk factor like diabetes mellitus (DM), exposure, aphakia/pseudophakia, contact lens. In this DM was seen in 9% of culture-positive cases. As our study is retrospective in nature compliance to the drugs cannot be commented on.
Stains and culture remain a gold standard to determine the course of management for corneal ulcers. Cultures are used to supplement clinical assessments but do not identify causative organisms in most cases of microbial keratitis. The median culture positivity rate from clinically diagnosed cases of MK is 50.3% and stains achieve diagnosis in only 27.3%–61.6% of cases.,, The relative insensitivity of these methods is attributable to prior antibiotic use, technical difficulties in growing organisms from small samples, and difficulties in immediate incubation of culture plates to optimize diagnostic yield. The relatively small quantity of infected material that can be sourced from the cornea add to the difficulty. In vivo confocal microscopy is a useful clinical adjunct but has several limitations including insufficient resolution for definitive diagnostic results in all cases especially cysts, hyphae and smaller bacteria (0–5 μm), dependency on the skill of the operator, and affordability, accessibility and availability.,, These difficulties affect clinical management decisions as clinicians are often forced to depend on broad-spectrum, fortified antibiotics, or a late-generation fluoroquinolone in the presence of culture negative results. In addtion, the time to get a result, as well as the availability of lab services, are factors that must be considered. Polymicrobial keratitis is increasingly recognized and adds to the challenges as it can be difficult to differentiate from microbial keratitis.
The utility of scraping and culturing every corneal ulcer has been questioned earlier. This is a pertinent and relevant question when we consider the fact that there is a lack of microbiology facilities at all eye hospitals or primary and secondary care centers. All the 375 patients in our study had specimens cultured but culture positivity was not a predictor of a good response to treatment and did not ensure an improvement in the ulcer. Pretreatment with over-the-counter drugs and from local clinics was a significant predictor of poor response to treatment in this study. Pretreatment often led to a culture-negative report and we recommend considering pretreatment as an important indicator for the immediate culture of the ulcer. There are several other important reasons to consider an immediate culture in eyes with pretreatment. These include the predilection to use broad-spectrum and latest antibiotics as over-the-counter medications, the use of steroids as a first-line treatment, the increasing use of contact lenses for refractive and therapeutic purposes, and the possibility of infectivity with newly recognized strains of organisms. Central ulcers who show a primary nonresponse to treatment with a history of pretreatment should be sent for early microbiological evaluation.
| Conclusion|| |
Time to heal may equate to the possibility of vision loss in corneal ulcers. Early identification and appropriate management are therefore essential. Corneal ulcers also have socioeconomic consequences in addition to vision loss. Time taken to heal and the visits to the hospital translate to a loss of working days and a loss in productivity for most patients with corneal ulcers, especially in the younger ages. Most patients with corneal ulcers are engaged in work in the informal sectors where a loss of a day at work will results in reduced work opportunities in the future as well. Failure in early resolution of the corneal ulcer, especially centrally located ones, can result in corneal scarring and uniocular blindness that may need keratoplasty or even evisceration and prosthetic implants. This will lead to an increase in the economic burden to the patient, a poor quality of life, and increase in the magnitude of uniocular blindness.
The retrospective nature of our study and the limited period of follow-up are limitations of our study. The case-control design does not allow us to comment on the culture positivity rates. The documentation and detailed clinical examination are strengths of the study, but the single center nature of the study does not allow us to generalize results to a larger population.
The discussion around microbial keratitis in India has predominantly limited itself to the identification of causative organisms and clinical course. Although these considerations are useful, the focus only on clinical aspects has possibly led to an underestimation of its public health impact including the contribution to uniocular blindness and vision impairment and the impact on the person and society. Most patients with corneal ulcers are in the productive age groups and a loss or reduced productivity has implications on the long-term health of the community as well. The possibility of a loss of productivity must be factored in the decisions taken by the patient to self-medicate or pretreat with over-the-counter medications. The rampant use of over-the-counter medications has a role to play in the increasing prevalence of antimicrobial resistance. The steroid in corneal ulcer trial reported a 3.48-fold higher minimum inhibitory concentration for bacteria isolated from patients who had been pretreated with topical fluoroquinolones, compared to treatment-naive patients. The mycotic ulcer treatment trial I, reported a 2.14-times increase in mean minimum inhibitory concentration per year after adjusting for causative organism. Low susceptibility to moxifloxacin for coagulase-negative Staphylococcus species (61.2%) and methicillin-sensitive Staphylococcus (53.1%) has been reported from India.
Further studies to develop better clinical algorithms for the identification and management of corneal ulcers at different healthcare levels are essential. Antibiotic resistance, infectivity with newer organisms, and a possible increase in magnitude with increased use of contact lenses for refractive and therapeutic purposes must be studied. These studies must be complemented with studies on the impact of corneal ulcers on the quality of life and economic impact as well to improve benefits to patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Gonzales CA, Srinivasan M, Whitcher JP, Smolin G. Incidence of corneal ulceration in Madurai district, South India. Ophthalmic Epidemiol 1996;3:159-66.
Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: A global perspective. Bull World Health Organ 2001;79:214-21.
Burton MJ, Pithuwa J, Okello E, Afwamba I, Onyango JJ, Oates F, et al.
Microbial keratitis in East Africa: Why are the outcomes so poor? Ophthalmic Epidemiol 2011;18:158-63.
Ung L, Bispo PJ, Shanbhag SS, Gilmore MS, Chodosh J. The persistent dilemma of microbial keratitis: Global burden, diagnosis, and antimicrobial resistance. Surv Ophthalmol 2019;64:255-71.
Prajna VN, Nirmalan PK, Saravanan S, Srinivasan M. Economic analysis of corneal ulcers in South India. Cornea 2007;26:119-22.
Khor WB, Prajna VN, Garg P, Mehta JS, Xie L, Liu Z, et al.
The Asia cornea society infectious keratitis study: A prospective multicenter study of infectious keratitis in Asia. Am J Ophthalmol 2018;195:161-70.
Wilhelmus KR, Schlech BA. Clinical and epidemiological advantages of culturing bacterial keratitis. Cornea 2004;23:38-42.
Morlet N, Minassian D, Butcher J. Risk factors for treatment outcome of suspected microbial keratitis. Ofloxacin Study Group. Br J Ophthalmol 1999;83:1027-31.
Dahlgren MA, Lingappan A, Wilhelmus KR. The clinical diagnosis of microbial keratitis. Am J Ophthalmol 2007;143:940-4.
Cariello AJ, Passos RM, Yu MC, Hofling-Lima AL. Microbial keratitis at a referral center in Brazil. Int Ophthalmol 2011;31:197-204.
Khanal B, Deb M, Panda A, Sethi HS. Laboratory diagnosis in ulcerative keratitis. Ophthalmic Res 2005;37:123-7.
Leck AK, Thomas PA, Hagan M, Kaliamurthy J, Ackuaku E, John M, et al.
Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal keratitis. Br J Ophthalmol 2002;86:1211-5.
Kaye SB, Rao PG, Smith G, Scott JA, Hoyles S, Morton CE, et al.
Simplifying collection of corneal specimens in cases of suspected bacterial keratitis. J Clin Microbiol 2003;41:3192-7.
Alzubaidi R, Sharif MS, Qahwaji R, Ipson S, Brahma A. In vivo
confocal microscopic corneal images in health and disease with an emphasis on extracting features and visual signatures for corneal diseases: A review study. Br J Ophthalmol 2016;100:41-55.
Hau SC, Dart JK, Vesaluoma M, Parmar DN, Claerhout I, Bibi K, et al.
Diagnostic accuracy of microbial keratitis with in vivo
scanning laser confocal microscopy. Br J Ophthalmol 2010;94:982-7.
Kheirkhah A, Syed ZA, Satitpitakul V, Goyal S, Müller R, Tu EY, et al
. Sensitivity and specificity of laser-scanning in vivo
confocal microscopy for filamentous fungal keratitis: Role of observer experience. Am J Ophthalmol 2017;179:81-9.
McDonnell PJ. Empirical or culture-guided therapy for microbial keratitis? A plea for data. Arch Ophthalmol 1996;114:84-7.
Ray KJ, Prajna L, Srinivasan M, Geetha M, Karpagam R, Glidden D, et al.
Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis. JAMA Ophthalmol 2013;131:310-3.
Prajna NV, Lalitha P, Rajaraman R, Krishnan T, Raghavan A, Srinivasan M, et al
. Mycotic ulcer treatment trial group. Changing azole resistance: A secondary analysis of the MUTT I randomized clinical trial. JAMA Ophthalmol 2016;134:693-6.
Lalitha P, Manoharan G, Karpagam R, Prajna NV, Srinivasan M, Mascarenhas J, et al.
Trends in antibiotic resistance in bacterial keratitis isolates from South India. Br J Ophthalmol 2017;101:108-13.
[Table 1], [Table 2]