Introduction
In the United States, nearly 1 million healthcare visits for keratitis (inflammation of the cornea) occur each year, and an estimated 6% of suspected microbial keratitis cases are caused by fungi [1, 2]. However, data on the causative species of fungal keratitis primarily come from decades-old single-center studies [3]. To better characterize the burden of fungal keratitis and help inform treatment practices, we used data from a major national commercial laboratory to describe testing patterns and causative species.
Methods
We analyzed nationwide Labcorp data sent to the Centers for Disease Control and Prevention’s National Syndromic Surveillance Program (https://www.cdc.gov/nssp/index.html). We identified results of fungal cultures ordered during March 1, 2019–October 1, 2023 and selected patients with International Classification of Diseases, 10th Revision code H16 (keratitis) listed as a reason for testing.
Results
Among 1,160,133 fungal culture results, 5104 had keratitis listed as a reason for testing; 182 were excluded from the analysis because of missing or non-fungal results. Among the 4922 remaining results, 774 (15.7%) were positive (Table 1). Percent positivity was highest among patients aged 45–64 years (19.2%), males (17.0%), and those in the South (19.0%).
Table 1.
Fungal culture resultsa from patients with keratitis listed as a reason for testing in a large national commercial laboratory, by result, March 2019–October 2023, United States.
| All results (n = 4922) | Mould (n = 596) | Yeast (n = 169) | |||||
|---|---|---|---|---|---|---|---|
| n positive/n tested | % positive | n | Column % | n | Column % | p-value | |
| Age group, years (n = 4812) | <0.001 | ||||||
| 0–17 | 10/88 | 11.4% | 10 | 1.7% | 0 | 0.0% | |
| 18–44 | 164/1,152 | 14.2% | 142 | 24.6% | 20 | 12.0% | |
| 45–64 | 340/1,769 | 19.2% | 270 | 46.8% | 65 | 39.2% | |
| 65+ | 238/1,803 | 13.2% | 155 | 26.9% | 81 | 48.8% | |
| Sex (n = 4822) | 0.003 | ||||||
| Male | 381/2,247 | 17.0% | 322 | 55.5% | 57 | 34.5% | |
| Female | 373/2,575 | 14.5% | 258 | 44.5% | 108 | 65.5% | |
| U.S. census region (n = 4921) | <0.001 | ||||||
| South | 648/3,410 | 19.0% | 518 | 86.9% | 126 | 74.6% | |
| Northeast | 15/157 | 9.6% | b | b | b | b | |
| West | 69/996 | 6.9% | 38 | 6.4% | 28 | 16.6% | |
| Midwest | 42/358 | 11.7% | b | b | b | b | |
| Provider type (n = 4490) | 0.024 | ||||||
| Ophthalmologist | 562/3,175 | 17.7% | 451 | 80.4% | 106 | 69.7% | |
| Optometrist | 38/338 | 11.2% | b | b | b | b | |
| Family, general practice, internal medicine | 25/133 | 18.8% | b | b | b | b | |
| Hospital | 25/124 | 20.2% | 15 | 2.7% | 10 | 6.6% | |
| Other | 72/720 | 10.0% | 52 | 9.3% | 18 | 11.8% | |
| Total | 774/4,922 | 15.7% | 596 | 77.9% | 169 | 22.1% | |
aLogical Observation Identifiers Names and Codes (LOINC®) result codes 580-1, 17947-3, 17948-1, 17949-9, 18482-0, 42804-5, 42805-2, 51723-5, 88143-3.
bNumber <10 or number that would enable calculation of another cell <10.
Positive results (>40 different species) were 76.6% moulds and 21.8% yeasts (Table 2). Among moulds, 63.1% were hyaline (mainly Fusarium [36.2%] and Aspergillus [35.4%]), and 35.9% were dematiaceous (most frequently Bipolaris (now Curvularia) [30.8%] and Curvularia [27.6%]). Candida albicans was the most common yeast (49.1%). Mould results were more common among patients in the South (86.9% vs 74.6% of yeasts, p < 0.001).
Table 2.
Fungal culture results from patients with keratitis listed as a reason for testing in a large national commercial laboratory, March 2019–October 2023, United States.
| Culture result | n = 744 | % |
|---|---|---|
| Hyaline mould | 376 | 48.6% |
| Fusarium | 136 | 17.6% |
| Aspergillus | 133 | 17.2% |
| A. fumigatus | 44 | 5.7% |
| A. niger | 43 | 5.6% |
| Unspecified Aspergillus | 28 | 3.6% |
| Other specified Aspergillus | 17 | 2.3% |
| Penicillium | 18 | 2.4% |
| Non-sporulating hyaline mould | 21 | 2.7% |
| Scedosporium | 18 | 2.4% |
| Purpureocillium | 13 | 1.7% |
| Acremonium/Sarocladium | 11 | 1.4% |
| Other specified hyaline moulda | 26 | 3.5% |
| Dematiaceous mould | 213 | 27.5% |
| Bipolaris | 66 | 8.5% |
| Curvularia | 59 | 7.6% |
| Alternaria | 44 | 5.7% |
| Cladosporium | 21 | 2.7% |
| Other specified dematiaceous mouldb | 13 | 1.7% |
| Unspecified dematiaceous mould | 10 | 1.3% |
| Mucormycete mould | c | c |
| Unspecified mould | c | c |
| Yeast | 169 | 21.8% |
| Candida | 158 | 20.4% |
| C. albicans | 83 | 10.7% |
| C. parapsilosis | 44 | 5.7% |
| C. tropicalis | 11 | 1.4% |
| Other Candida speciesd | 20 | 2.7% |
| Othere or unspecified yeast | 11 | 1.4% |
| Unspecified fungus | c | c |
aPaecilomyces, Beauvaria, Trametes versicolor, Chrysosporium, Geotrichum, Scopulariopsis, Bjerkandera adusta, Verticillium, Trichoderma, Trichophyton, Irpex lacteus, Sepedonium.
bEpicoccum, Exserohilum, Chaetomium, Exophiala, Pithomyces, Phoma.
cNumber <10 or number that would enable calculation of another cell <10.
dC. glabrata, C. dubliniensis, C. guilliermondii, C. pelliculosa, C. orthopsilosis, C. sake, C. lipolytica.
eRhodotorula, Trichosporon.
Discussion
Our study provides updated epidemiologic data and highlights the fungal diversity implicated in keratitis throughout the United States. Consistent with previous literature, males, middle-aged adults, and residents of the South appeared to be disproportionately affected, possibly because of increased risk for occupational ocular trauma [3, 4]. The predominance of moulds in the South is also similar to results from single-centre studies and is likely related to the warmer climate [3]. The potential for climate-related geographic expansion of pathogenic fungi and antifungal resistance warrants increased attention to timely diagnosis and treatment of fungal keratitis.
Worldwide, most fungal keratitis cases are caused by Fusarium and Aspergillus [4], the most common moulds identified in this analysis. These fungi have demonstrated decreased susceptibility to natamycin and voriconazole in keratitis in India [5]. Species-level information was unavailable for most Fusarium results in this analysis; however, studies have shown that F. solani in particular appears to have higher in-vitro minimum inhibitory concentrations to multiple antifungals [6]. Dematiaceous moulds, isolated in over a quarter of results in this analysis, are also notable causes of fungal keratitis worldwide [2, 4]. The clinical differences between keratitis caused by dematiaceous and hyaline fungi, along with patient risk factors and geographic location, may help guide initial treatment decisions [4].
Limitations include the inability to identify contaminants or multiple results per patient. Furthermore, data about risk factors, clinical features, treatment, antifungal resistance, or outcomes were unavailable, and the dataset may not be nationally representative. Nonetheless, our study provides updated causative species data, which may inform future surveillance efforts and guide treatment practices.
Acknowledgements
This activity was reviewed by the CDC and was conducted consistent with applicable federal law and CDC policy (e.g., 45C.F.R. part 46.102(l)(2), 21C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq.). The data are fully de-identified, so this analysis was not subject to review by the Centers for Disease Control and Prevention institutional review board. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Author contributions
KB performed the data analysis, and all authors contributed to interpreting the results and writing and editing the report.
Data availability
This study used third-party data that we cannot legally distribute. All relevant summary data are within the manuscript and the supporting files.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Collier SA, Gronostaj MP, MacGurn AK, Cope JR, Awsumb KL, Yoder JS, et al. Estimated burden of keratitis—United States, 2010. MMWR Morb Mortal Wkly Rep. 2014;63:1027–30. [PMC free article] [PubMed] [Google Scholar]
- 2.Ahmadikia K, Aghaei Gharehbolagh S, Fallah B, Naeimi Eshkaleti M, Malekifar P, Rahsepar S, et al. Distribution, Prevalence, and Causative Agents of Fungal Keratitis: A Systematic Review and Meta-Analysis (1990 to 2020). Front Cell Infect Microbiol. 2021;11:698780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Estopinal CB, Ewald MD. Geographic Disparities in the Etiology of Bacterial and Fungal Keratitis in the United States of America. Semin Ophthalmol. 2016;31:345–52. [DOI] [PubMed] [Google Scholar]
- 4.Hoffman JJ, Burton MJ, Leck A. Mycotic Keratitis-A Global Threat from the Filamentous Fungi. J Fungi. 2021;7:273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Prajna NV, Lalitha P, Krishnan T, Rajaraman R, Radnakrishnan N, Srinivasan M, et al. Patterns of Antifungal Resistance in Adult Patients With Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials. JAMA Ophthalmol. 2022;140:179–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Iqbal NJ, Boey A, Park BJ, Brandt ME. Determination of in vitro susceptibility of ocular Fusarium spp. isolates from keratitis cases and comparison of Clinical and Laboratory Standards Institute M38-A2 and E test methods. Diagnostic Microbiol Infect Dis. 2008;62:348–50. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
This study used third-party data that we cannot legally distribute. All relevant summary data are within the manuscript and the supporting files.