Presentation clinical signs and symptoms may help distinguish between causative organisms in bacterial keratitis. Because it generally takes several days for microbiological diagnosis, clinical signs which are predictive of the causative organism would be useful to ensure that proper treatment is started as soon as possible. Previously, it has been shown that there may be a predictive utility of clinical signs and symptoms in determining the etiologic agent in bacterial conjunctivitis [10
]. In the current study, we found that presentation characteristics, including risk factors and markers of severity, were significantly different between organisms causing the ulcer.
caused the most severe ulcers on presentation. These ulcers were deeper and had significantly larger infiltrate sizes than non-pseudomonas ulcers. Median visual acuity in these ulcers was approximately 4 lines worse relative to the entire cohort, which was statistically significant across groups of organisms. In this study, the duration of symptoms prior to presentation for P. aeruginosa
ulcers was shorter than the overall study population, which may have been due to patients recognizing the need for care more urgently due to the aggressive nature of the pathogen and the resultant large degree of vision loss. These findings are consistent with the notoriety of P. aeruginosa
as a particularly virulent and rapidly-progressing pathogen [11
Patients with ulcers caused by Nocardia
spp. had a significantly delayed presentation compared to the entire study population. In these patients, the median baseline visual acuity was nearly 5 lines better than the overall population. Nocardia keratitis has been characterized as having a slow course [12
], which may explain the extended duration of symptoms and better relative visual acuity at presentation. Nocardia
spp. are relatively rare isolates from keratitis, especially outside of India [12
]. In this study, it was the third most commonly isolated organism; however, there were no Nocardia
spp. isolated in the United States. Previous reports have shown that patients with Nocardia keratitis who present within 15 days of symptom development have the highest rate of recovery [13
]. In our study, a quarter of patients presented after 15 days of symptom duration. It is possible these patients could have benefitted from earlier presentation, indicating that despite slow progression, treatment should be started promptly. Nocardia
keratitis has been reported to have similar presenting characteristics to fungal keratitis, which can confuse the initial diagnosis prior to microbiological confirmation of the etiologic organism [12
]. In this study, no clinical signs that are typically characteristic of fungal keratitis were reported for Nocardia
keratitis (such as ring infiltrate, feathery borders, endothelial plaque, etc.). Nocardia
keratitis was associated with a superficial infiltrate, as has been reported in the literature [13
keratitis has been associated with corneal trauma in previous series, although we were unable to confirm this here [12
was the most commonly isolated organism in this study, present in approximately half of the corneal ulcers. Dacryocystitis had a 7.3-fold increased odds of being associated with a S. pneumoniae
corneal ulcer. Chronic dacryocystitis has been well documented to be associated with pneumococcal keratitis [14
]. Presence of hypopyon has also been reported as a clinical sign of pneumococcal keratitis [15
], and was present in over half of the pneumococcal ulcers in our study, but this association was not significant after correction for multiple comparisons. The infiltrate size at baseline was smaller in pneumococcal ulcers in this study compared to non-pneumococcal ulcers. However, the ulcers were more likely to be central in location, and the median visual acuity was poor at presentation. Pneumococcal ulcers appeared to be less severe than P. aeruginosa
ulcers at presentation; median baseline visual acuity in P. aeruginosa
ulcers was nearly 4 lines worse, and the infiltrate size was larger.
Risk factors for developing an ulcer varied significantly between different subtypes of bacterial ulcers. Agricultural work was significantly associated with pneumococcal ulcers, and P. aeruginosa
ulcers appeared to be less common in agricultural workers, although this was not significant after multiple comparisons correction. Previously, agricultural work has been shown to be associated with Nocardia
keratitis, but we did not replicate that finding in this study [12
]. While very few contact lens wearers were enrolled, the vast majority of those enrolled had a P. aeruginosa
ulcer. Previous reports have shown that contact lens use is associated with P. aeruginosa
]. In our study, contact lens use was an approximately 20-fold risk factor for pseudomonas, but this association did not reach statistical significance after multiple comparisons correction.
This study presents a large series of prospectively collected corneal ulcers with standardized characteristics recorded for each patient. All study assessments were conducted by certified personnel according to a specific protocol. The large size of this series allows us to make comparisons between the major groups of organisms enrolled. However, due to the nature of the inclusion and exclusion criteria as part of the clinical trial, some biases may be introduced into this analysis. Impending perforation, patients with a history of penetrating keratoplasty in the affected eye, patients with a history of a corneal scar in the affected eye, and patients less than 16 years of age at enrollment were all excluded from this trial. We do not have information on these ulcers, and therefore cannot make comparisons. We therefore cannot assess whether there are differences in etiology in perforated or nearly perforated ulcers, or if certain organisms are more likely to cause keratitis in patients younger than 16 years of age. In addition, the standardized forms on which data was collected for the trial were designed to collect information such as the infiltrate/scar size and depth of the ulcer for the main analyses of the trial. Finally, the same clinician did not evaluate each patient in this trial. Therefore, it is possible that some intra-observer variability was introduced to our analyses. To minimize this bias, all clinicians, refractionists, and microbiologists who collected data during the trial were specifically certified for the trial, and regular site visits were made to re-certify all investigators and ensure that trial protocols were being followed. In addition, every tenth patient received repeat BSCVA measurements and clinical examinations from different refractionists and examiners. These repeated measurements showed high inter-rater reliability (κ = 0.99).
Organism-specific characteristics, such as wreath-like infiltrate for Nocardia
spp., stromal lysis and round-shaped infiltrate in P. aeruginosa
, or an active spreading edge in S. pneumoniae
, may be useful in distinguishing between different etiologic organisms in bacterial keratitis. However, since this study was not planned prospectively, data regarding these characteristics were not collected in this trial, and therefore we could not analyze them. Previous studies have suggested that such signs can distinguish between organisms in fungal keratitis [17
]. Further work should be done assessing the role of these specific signs in distinguishing between causative organisms in bacterial keratitis in a standardized, masked fashion.
The vast majority of patients enrolled in this trial were contact lens non-wearers in India. There were differences across groups of organisms isolated in each country. There were no S. pneumoniae
isolates from the United States. P. aeruginosa
was the most commonly isolated organism in the United States, and was the second most commonly isolated organism overall in the study. A small number of ulcers from the United States were enrolled in this trial, making comparisons of ulcers between the United States and India difficult. Previous reports of etiologic agents of bacterial keratitis in the United States and globally vary widely [6
]. This study enrolled a large number of ulcers that were diverse in severity and etiology. While numbers were too small to make comparisons with all organisms, we found that there exist significant differences in baseline characteristics among the top five isolates.
In conclusion, in this study of presentation characteristics of etiologic agents of bacterial keratitis, we found that P. aeruginosa ulcers were the most severe, with the largest and deepest infiltrates, and the worst presentation visual acuity. Contact lens use was associated with P. aeruginosa ulcers. Pneumococcal ulcers were less severe, although still had significant visual loss at presentation. Concomitant dacryocystitis was highly predictive of a pneumococcal ulcer. Nocardia ulcers had the best presenting visual acuity, but also were the most delayed in presentation. This series will help guide initial management decisions based on presenting characteristics, prior to microbiological diagnosis.