Abstract
Purpose:
Negative laboratory results make targeting microbial keratitis treatment difficult. We investigated factors associated with laboratory negativity in patients with microbial keratitis in the context of a transition to a new specimen collection method.
Methods:
Microbial keratitis patients with associated laboratory tests were identified in the electronic health record of a tertiary care facility from August 2012 to April 2022. Patient demographics and laboratory results were obtained. Random sampling of 50% of charts was performed to assess the impact of the ocular history and pretreatment measures. The relationship between probability of negative laboratory results with demographics, ocular history, pretreatment measures, and utilization of a new specimen collection method (i.e. ESwab) was evaluated by multivariable logistic regression.
Results:
Of 3395 microbial keratitis patients identified, 31% (n=1051) had laboratory tests. Laboratory testing increased over time (slope = 2.5% per year, p<0.001; 19.6% in 2013 to 42.2% in 2021). Laboratory negative rate increased over time (slope = 2.2% per year, p=0.022; 48.5% in 2013 to 62.3% in 2021). Almost one-third of patients (31.2%, n=164) were pretreated with steroids. Over two-thirds of patients were pretreated with antibiotics (69.5%, n=367). 56.5% (n=297) of patients were outside referrals. In multivariable regression, patients with corticosteroid pretreatment had lower odds of negative laboratory results (odds ratio [OR]=0.49, p=0.001). There were higher odds of negative laboratory results for every additional antibiotic prescribed to a patient prior to presentation (OR=1.30, p=0.006) and for specimens collected using ESwabs (OR=1.69, p=0.005). Age, prior eye trauma, outside referrals, and contact lens wear were not significantly associated with negative laboratory results.
Conclusion:
More microbial keratitis associated laboratory tests are being taken over time. Over 60% of tests were negative by 2022. Factors associated with negative laboratory test results included pretreatment with antibiotics and specimens collected with the new collection method.
Keywords: ESwab, Microbial Keratitis, Corneal Ulcer, Culture
Introduction
Microbial Keratitis (MK) is an ocular emergency caused by infection of the cornea. If not treated promptly, cases of MK may progress to blindness. Global estimates of MK as a cause of unilateral blindness range from 1.5 to 2 million cases per year.1,2 In order to prevent significant loss of vision and blindness, prompt antimicrobial treatment targeting the causative organism is needed. The current gold-standard diagnostic tests used to identify the causative organism are biological stains and cultures.3 However, the sensitivity of a culture is poor with culture-positivity rates ranging from 32.6 to 79.4%, with a median rate of 50.3%.1,3,4 Staining methods are less effective, achieving a diagnosis in only 27.3–61.3% of cases.1,5–8 Our recent work on MK isolates showed a laboratory-positive rate of 49.3%, where 73.5% of laboratory-positive cases were bacterial, 7.8% were fungal, 1.6% were viral, 1.4% were Acanthamoeba, and 15.6% were polymicrobial.9 Although new tools are being developed,10 it is likely that stains and cultures will be used to identify the causative organism in MK cases for the foreseeable future. It is important to assess how we can maximize the efficacy of the stain and culture to achieve better outcomes for patients with MK.
In recent years, eye centers have increasingly looked to maximize the efficacy of the stain and culture, as well as other diagnostic tests such as smears, polymerase chain reaction, antibody and antigen testing, by using faster and easier collection methods such as swabs. Current literature shows that swab associated culture positivity rates have remained similar or have increased when compared to traditional collection and transportation methods.11–13 The swabs are more user friendly, accessible, and less cumbersome when compared with the traditional methods.12
It is important to examine and understand what factors may have an effect on culture negativity rates. Our study looks to investigate factors associated with the negativity rates of laboratory tests in patients with MK in the context of a transition to new specimen collection.
Materials and Methods
The study was approved by the Institutional Review Board of the University of Michigan (UM) Medical School under IRB # AQUA EHR-Stein HUM00174520 and adhered to the tenets of the Declaration of Helsinki. MK patients with associated laboratory tests were selected from the UM electronic health record (EHR) between August 2012 and April 2022. International Classification of Diseases 9th or 10th revision codes (ICD-9 or ICD-10) were used to identify patients diagnosed with MK and an encounter in the UM ophthalmology department.9 The date of first MK diagnosis was identified. If a patient had multiple infections, only the first infection was included in the analysis. Patient age, self-reported gender, self-reported race, and self-reported ethnicity were collected.
Laboratory tests were identified in the EHR and limited to those from 7 days before to 90 days after the first date of MK diagnosis to ensure they were from the targeted interaction for management of that particular infection. Tests included cultures, stains, smears, polymerase chain reaction, antibody testing, and antigen testing. Specimens included samples collected directly from the cornea and related materials. Contact lens cases or contact lens solution cultures were included as they can improve laboratory test yields (Supplemental Table 1).14 Before July 2018, specimens were collected with a spatula, needle or blade by scraping the cornea, contact lens cases, or contact lens solutions. The specimens were then directly transferred onto culture mediums by the collecting physician and sent to the laboratory team for analysis. Starting in July 2018, specimens were collected and transported to the laboratory using ESwabs (COPAN Diagnostics, Murrieta, CA, USA). ESwabs are flocked nylon swabs placed in 1 ml of liquid Amies transport medium. The laboratory team would then take the ESwab from the transport medium and directly transfer the specimen collection onto culture mediums. There were no other differences in the way samples were collected and laboratory tests were analyzed after the new specimen collection method was implemented.
Laboratory results were categorized as positive or negative. Laboratory testing was considered positive when any isolates were found and were categorized into five organism classes: bacterial, fungal, viral, Acanthamoeba, or polymicrobial. Polymicrobial infections were defined as infections caused by any combination of bacterial, fungal, viral, or Acanthamoeba organisms or by two or more organisms of different bacterial classes (e.g., gram-positive and gram-negative). Laboratory testing was considered negative when no isolates were found, as noted by negative terms and non-pathogenic findings such as polymorphonuclear leukocytes, mononuclear leukocytes, squamous epithelial cells, and skin flora. If a patient had multiple cultures taken within the time period, testing was aggregated to the patient-level based on the result of at least one positive finding.
The study team, recognizing the value of data not collected in billing records to be potentially correlated with laboratory negativity results, randomly selected and reviewed half of the patients’ chart data (n=528 out of 1051 charts, 50%), stratified by year. Variables reviewed included symptom onset date, referral date, contact lens wear, prior treatment with topical or systemic antibiotics, prior treatment with topical or systemic corticosteroids, prior eye penetrating trauma, and prior viral or neurotrophic keratitis.
Statistical Methods
Patient demographics, ocular history, referral time span and pretreatment were summarized with descriptive statistics. Prior eye penetrating trauma, viral and neurotrophic keratitis were assessed, as these conditions often predispose patients to recurrent MK, for which AAO guidelines state cultures are indicated.15,16 Prior literature has shown that recurrent MK can affect laboratory results, including the rate at which an organism is isolated and the type of organisms isolated.17 Symptom duration and referral delays were assessed given known risks of lack of access to care and care utilization, especially during the COVID-19 pandemic.18,19 Referral time span was defined as the number of days between an outside provider referral and a given patient’s initial presentation to the University of Michigan and also categorized as referral within 7 days, referral greater than 7 days, self-referral, or internal referred within UM system.
Continuous variables are presented with means, standard deviations (SD), medians, and interquartile ranges (IQR). Categorical variables are reported with frequencies and percentages. Ocular history, referral time span, pretreatment measures, and MK organism type were compared between those with laboratory positive versus laboratory negative results using Kruskal-Wallis tests for continuous measures and Chi-square for categorical measures. A two-sided p-value <0.05 was considered statistically significant. Linear regression and line plots were used to examine the trends of patients with laboratory testing and laboratory negativity rate over time from 2013 to 2021. Multivariable logistic regression was used to assess the effect of age, ocular history, and pretreatment on the probability of getting a negative laboratory result. Ocular history and pretreatment measures investigated in models included symptom onset to presentation, contact lens wear, prior corticosteroids treatment, number of antibiotics prescribed prior to the initial appointment, prior eye penetrating trauma, prior viral or neurotrophic keratitis, referral timespan, location of service (cornea vs non-cornea clinic), use of new collection method, and if the patient was an outside referral. The model estimates are reported with odds ratio (OR) and 95% confidence interval (CI). The model also tested an interaction between prior corticosteroids treatment and number of antibiotics prescribed prior to the initial appointment for a multiplicative effect on a negative laboratory result. Analyses were performed using R version 4.1.1 (Foundation for Statistical Computing, Vienna, Austria).
Results
Of 3395 MK patients identified, 1051 (31%) had laboratory tests performed. These 1051 patients were on average 56.3 years old at diagnosis (SD=20.1), 56.2% were female, 87.6% identified as White, 7.7% identified as Black, and 2.8% were Hispanic (Table 1). The rate of laboratory testing significantly increased over time (slope estimate=2.5% per year, p<0.001; 19.6% of presenting cases in 2013 to 42.2% of presenting cases in 2021) with a notable shift after ESwab implementation (26.7% before vs. 38.6% after, p<0.001) (Figure 1). A negative laboratory result was found in 51% (n=538 of 1051) of patients and the rate of negative laboratory results increased over time (slope = 2.2% per year, p=0.022; 48.5% in 2013 to 62.3% in 2021).
Table 1.
Patient demographics for the sample of microbial keratitis patients who had laboratory tests performed (n=1051).
| Continuous Variable | Mean (SD), Median (IQR) |
|---|---|
| Age (years) | 56.3 (20.1), 56.7 (41.5–72.4) |
| Categorical Variable | Frequency (%) |
| Gender | |
| Female | 591 (56.2) |
| Male | 460 (43.8) |
| Ethnicity | |
| Hispanic | 28 (2.8) |
| Non-Hispanic | 970 (97.2) |
| Race | |
| White | 892 (87.6) |
| Black | 78 (7.7) |
| Asian | 26 (2.6) |
| Other | 22 (2.2) |
SD, standard deviation. IQR, interquartile range.
Figure 1.
A. Percentage of patients who had laboratory tests performed over time for the full 3395 MK sample (2013–2021); B. Percentage of patients who were laboratory-negative of those who had laboratory tests performed over time (n=500). Linear regression was used to plot the trend lines.
Of the randomly sampled 528 MK patients with laboratory results, 51% (n=271 of 528) were laboratory negative. Of the 257 MK patients with laboratory positive results, 72.4% (n=186) of infections were bacterial, 9.3% (n=24) were fungal, 1.9% (n=5) were Acanthamoeba, 1.2% (n=3) were viral, and 15.2% (n=39) were polymicrobial. No significant differences (p>0.05) in patient demographics including age, gender, ethnicity, and race were found between the randomly sampled patients and the remaining cohort (Supplemental Table 2). Almost one third of patients (31.2%, n=164) were pretreated with corticosteroids. Over two-thirds of patients had been pretreated with antibiotics (69.5%, n=367), with the average number of prior antibiotics being 1.1 medications (SD=1.1, range=0 to 6). One eighth of patients had prior eye penetrating trauma (12.9%, n=68), and one tenth had a history of viral or neurotrophic keratitis (10.6%, n=56). Almost half of patients wore contact lens (46.8%, n=247) and were swabbed using the new collection method (48.5%, n=256). More than half of patients were from outside referrals (56.5%, n=297) and seen at the Kellogg Eye Center cornea clinic (71.2%, n=376). Median time from symptom onset to presentation was 6 days (IQR=3 to 18). There were no significant differences in the proportion of positive laboratory results of bacterial infections before or after implementation of new collection method with ESwab (38.2% vs 32.0%; p=0.1614). Similarly, there were no significant differences in the proportion of positive laboratory results of fungal infections before or after implementation of the new collection method with ESwab (6.3% vs 2.7%; p=0.0838).
In univariable analyses, patients pretreated with corticosteroids were less likely to have laboratory negative results (24.4% negative vs 38.3% positive, p=0.001) (Table 2). Patients pretreated with antibiotics were more likely to have laboratory negative results (74.9% negative vs 63.8% positive, p=0.008). The number of the antibiotics prescribed prior to presentation were higher for patients who were laboratory negative (mean±SD=1.2± 1.1) versus those who were laboratory positive (0.9± 1.0, p<0.001).
Table 2.
Comparison of ocular history and pretreatment by laboratory results (n=528).
| Laboratory-negative (n=271) | Laboratory-positive (n=257) | ||
|---|---|---|---|
| Continuous Variable | Mean (SD), Median (IQR) | Mean (SD), Median (IQR) | P-value |
| Symptom onset to presentation (days) | 18.7 (37.9), 6.0 (3.0–19.2) | 17.0 (31.4), 7.0 (3.0–16.0) | 0.551 |
| Number of antibiotics prescribed prior to presentation | 1.2 (1.1), 1.0 (0–2) | 0.9 (1.0), 1.0 (0–1) | <0.001 |
| # (column %) | # (column %) | P-value | |
| Cornea clinic | 200 (73.8) | 176 (68.5) | 0.210 |
| ESwab | 147 (54.2) | 109 (42.4) | 0.008 |
| Contact lens wear | 126 (46.5) | 121 (47.1) | 0.962 |
| Prior antibiotic treatment | 203 (74.9) | 164 (63.8) | 0.008 |
| Prior corticosteroids treatment | 66 (24.4) | 98 (38.3) | 0.001 |
| Prior eye penetrating trauma | 41 (15.1) | 27 (10.5) | 0.150 |
| Prior viral or neurotrophic keratitis | 28 (10.3) | 28 (10.9) | 0.933 |
| Outside referral | 158 (58.5) | 139 (54.3) | 0.374 |
| Referral time span | |||
| <7 days | 140 (53.6) | 124 (49.8) | |
| ≥7 days | 10 (3.8) | 11 (4.4) | 0.480 |
| Self | 24 (9.2) | 17 (6.8) | |
| Within UM system | 87 (33.3) | 97 (39.0) |
SD, standard deviation. IQR, interquartile range. UM, University of Michigan.
Multivariable logistic regression model results showed that the odds of obtaining a negative laboratory result increased by 30% for every additional antibiotic prescribed prior to presentation (OR=1.30, 95% CI=1.08–1.58, p=0.006) (Table 3). Laboratory tests had higher odds of being negative if specimens were collected using ESwabs (OR=1.69, 95% CI=1.18–2.44, p=0.005). Laboratory tests had lower odds of being negative if the patient had prior treatment with corticosteroids (OR=0.49, 95% CI=0.32–0.73, p=0.001). There was no significant interaction observed between prior corticosteroid treatment and number of antibiotics prescribed prior to the initial appointment on a negative laboratory result (p=0.1748). Age, having prior eye trauma, having prior viral or neurotrophic keratitis, being an outside referral, seen at a cornea clinic, and contact lens wear were not significantly associated with negative laboratory results.
Table 3.
Multivariable logistic regression model odds ratio estimates for the effect of ocular history and pretreatment measures on the probability of a negative laboratory result.
| Odds Ratio | 95% CI | P-value | |
|---|---|---|---|
| Age (years) | 0.99 | 0.98–1.00 | 0.175 |
| Number of antibiotics prescribed prior to presentation (per 1 medication) | 1.30 | 1.08–1.58 | 0.006 |
| Prior corticosteroids treatment | 0.49 | 0.32–0.73 | 0.001 |
| Prior eye penetrating trauma | 1.63 | 0.95–2.82 | 0.077 |
| Prior viral or neurotrophic keratitis | 1.18 | 0.65–2.16 | 0.580 |
| Outside referral | 0.89 | 0.60–1.32 | 0.570 |
| Cornea Clinic vs Non-cornea Clinic | 1.30 | 0.86–1.99 | 0.217 |
| ESwab | 1.69 | 1.18–2.44 | 0.005 |
| Contact lens wear | 0.84 | 0.56–1.24 | 0.374 |
CI, confidence interval.
Discussion
In our study of 1,051 MK patients, we analyzed how MK related laboratory test utilization and test negativity rates have changed over the last decade. Laboratory test utilization significantly increased over time (slope = 2.5% per year, p<0.001; 19.6% in 2013 to 42.2% in 2021). Laboratory negative rates significantly increased over time from 48.5% in 2013 to 62.1% laboratory negative in 2021 (slope = 2.2% per year, p=0.022). Multiple clinical factors were found to be significantly associated with odds of negative laboratory results. The odds of a laboratory test being negative were higher for every additional antibiotic prescribed prior to presentation (OR=1.30). The odds of tests being negative were lower if the patient was pretreated with corticosteroids (OR=0.49). The odds of a laboratory test being negative were higher if specimens were collected using the new transportation method (OR=1.69). Our methodology differ from laboratory studies comparing yields between ESwabs and other collection methods.11–13 In our study, each patient’s specimen was only collected with one technique, so other unrecognized underlying patient factors may contribute to this occurrence or changes to our patient population over time may affect yields.
Many patients were seen in the reported time period for MK (n=3395), but not all patients had laboratory testing (31%, =1051/3395). It is likely that the billing codes for microbial keratitis, which are used frequently for minor infections, over-estimate the number of cases that could warrant needing a culture. The American Academy of Ophthalmology (AAO) recommends that cultures are indicated for corneal infiltrates that are central, large (>2mm), and/or associated with significant stromal involvement or melting.15 The rate of culturing did continue to increase with the introduction of ESwabs. It is possible that the convenience and ease of use of the ESwab, compared to difficulty with traditional methods,20 led to increased laboratory test utilization.
Clinical factors associated with laboratory negativity were mainly related to prior treatments. Antibiotic use was significantly associated with higher odds of laboratory negative results. These results are consistent with the majority of studies that agree that prior treatment with antibiotics correlates with negative test results.21,22 These results differ from Wahl et al., who found that antibiotic pretreatment did not significantly affect culture positivity rates.23 Prior treatment with corticosteroids decreased the odds of laboratory negative results. Topical corticosteroids significantly predispose patients to MK, consistent with our findings.24 Laboratory negativity was not associated with symptom onset to presentation, referral time span, viral or neurotrophic keratitis, contact lens use, or prior eye trauma.
It was important to assess whether the types of organisms isolated from MK-related laboratory tests varied before versus after ESwab implementation. ESwab is FDA-approved for collection and transport of aerobic, anaerobic, and fastidious bacteria, but does not mention FDA clearance for fungal specimens.25 Gandhi et al. has shown the ESwab effectively maintained fungal organisms for at least 48 hours after collection.26 In our study, the ESwab seemed to be effective at collecting and transporting both bacterial and fungal specimens, as laboratory yields for bacteria and fungi did not differ significantly before or after ESwab implementation.
There are limitations to our study. First, although we believe that all specimens collected after July 2018 were collected with an ESwab, there is a possibility that a laboratory specimen was collected by corneal scraping if there were remaining culture plates on site. The introduction of ESwabs was implemented at a single point in time and after which the COVID-19 pandemic occurred, affecting practice patterns and not allowing conclusions to be made about type of use. The ease of use of ESwabs may have significantly affected MK related laboratory test utilization and test negativity rates, but patient-related and clinician-related confounders exist – such as the medical complexity of the patients seen over time and the choice of when to perform a culture or not, to make firm conclusions. In future, studies to investigate the effect of the morphology of the infiltrate on culture positivity will meaningfully impact the work, a task that cannot be done at scale with data from over 1,000 charts in EHR databases.
In conclusion, more cultures are being taken by clinicians. More cultures are negative with over 60% of cultures now negative in the final year of the study. There were higher odds of having a negative culture if a greater number of antibiotics were used prior to presentation (OR=1.30, p=0.006) and with the implementation of a new collection method (OR=1.69, p=0.005). There were higher odds of having a positive culture if the patient was given corticosteroids prior to presentation. Culture negativity was not associated with other factors traditionally thought to increase or decrease positivity such as contact lens wear, having prior eye trauma, and having prior viral or neurotrophic keratitis.14, 15, 16 Cornea specialists should communicate with referring providers to encourage referral of patients suspected of having MK in order to minimize the likelihood of prior treatment with antibiotics or corticosteroids.
Supplementary Material
Acknowledgements & Funding
This study was funded by grants from the National Eye Institute (R01EY031033, MAW); and Research to Prevent Blindness Career Advancement Award (MAW).
Footnotes
Declaration of Interest Statement
The authors write report there are no competing interests to disclose.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, MAK, upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, MAK, upon reasonable request.