Abstract
Background
Invasive candidiasis (IC) is a growing concern among US healthcare facilities. A large-scale study evaluating incidence and trends of IC in the United States by species and body site is needed to understand the distribution of infection.
Methods
An electronic medical record database was used to calculate incidence and trends of IC in the United States by species and infection site from 2009 through 2017. Hospital incidence was calculated using total unique inpatient hospitalizations in hospitals reporting at least 1 Candida case as the denominator. IC incidence trends were assessed using generalized estimating equations with exchangeable correlation structure to fit Poisson regression models, controlling for changes in hospital characteristics and case mix over time.
Results
Candida albicans remains the leading cause of IC in the United States, followed by Candida glabrata. The overall incidence of IC was 90/100 000 patients, which did not change significantly over time. There were no changes in incidence among C. albicans, C. glabrata, C. parapsilosis, or C. tropicalis; the incidence of other Candida spp. as a whole increased 7.2% annually. While there was no change in candidemia 2009–2017, abdominal and nonabdominal sterile site IC increased significantly.
Conclusions
Nonbloodstream IC is increasing in the United States. Understanding the epidemiology of IC should facilitate improved management of infected patients.
Keywords: invasive candidiasis, epidemiology, electronic health record, hospital infections
Invasive candidiasis (IC) is a concern in the United States. This study evaluated incidence and trends of IC by species and body site using a large, nationally distributed electronic health record database and found increasing incidence of nonbloodstream IC.
Invasive Candida spp. infections are an increasing concern among US healthcare facilities, as candidemia ranks in the top 4 hospital-associated bloodstream infections in the country [1]. Invasive candidiasis (IC) is defined as a Candida spp. infection in the blood (known as candidemia), heart, brain, eyes, bones, liver, spleen, kidneys, or other sterile sites [2]. Common risk factors for IC include intensive care unit stay, central venous catheter use, broad-spectrum antibiotics, recent abdominal surgery, and immune suppression [1, 3]. The majority of these infections in the United States have historically been caused by C. albicans, although in recent years this species is now responsible for < 50% of all Candida bloodstream infections [4, 5]. Other species responsible for disease in the United States include C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. The proportion of illness caused by these other species varies, although C. glabrata has been reported to represent more than 30% of the non-albicans Candida in some geographic areas [4, 6–9].
Several sentinel surveillance programs for IC exist, including the Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program (EIP, 1992 to present), the National Healthcare Safety Network (2004 to present), and the SENTRY Antimicrobial Surveillance Program (1997 to present) [10]. Findings from EIP surveillance data have indicated a decrease in overall candidemia incidence in their longest-running surveillance sites of Atlanta, GA, and Baltimore, MD, with the incidence of all species decreasing except C. tropicalis [8]. A recent epidemiological study using hospital discharge data from the Agency for Healthcare Research and Quality (state inpatient databases) also reported a decrease in age-adjusted rates of hospitalization associated with IC from 2005 through 2012 [11]; however, other studies have demonstrated an increase in incidence in the United States over the last 20 years, driven by increases in incidence among non-albicans species [6, 12, 13], and several European countries have also seen increases in the incidence of IC [5, 14].
The changing epidemiology and increase in potentially drug-resistant non-albicans IC underscore the importance of understanding the longitudinal contribution of specific Candida species to IC trends in the United States. While several studies using larger cohorts to study illness and outcomes exist [11, 15–17], species-specific data from a broadly representative population have been lacking; the Cerner HealthFacts database provides a unique opportunity to describe trends and outcomes using linked microbiologic and clinical data from a large representative population of patients with IC from all regions of the United States. In the present study, we aimed to describe species-specific trends in IC from 2009 through 2017, as well as assess other relevant patient- and hospital-level factors by Candida species.
METHODS
The Cerner HealthFacts database includes linked electronic medical records for more than 63 million patients across the United States. We extracted records for all hospital encounters from 2009 through 2017 where any Candida species was isolated from a blood, sterile abdominal, or other nonabdominal sterile site microbiology test (Supplementary Table 1). Sterility was assessed using a combination of specimen collection source and body site, as well as the specific laboratory procedure. The final list of microbiology tests for inclusion was determined by clinical consensus (J. R. S., A. B., and E. E. R.). If patients had multiple encounters with the same Candida species isolated within 30 days, only the first encounter was counted. Relationships between source, species, and other patient data, including demographics and hospital characteristics, were assessed using Pearson χ 2 test of proportions. Demographic distributions by species were compared to those of C. albicans. Hospital incidence was calculated using total unique inpatient hospitalizations in the group of hospitals reporting at least 1 Candida case as the denominator. Trends in overall IC, species-, and source-specific incidence were assessed using generalized estimating equations with an exchangeable correlation structure to fit Poisson regression models. These models controlled for hospital characteristics including institution, census region, teaching status, number of beds, annual admissions, median age of hospitalized patients, sex and race distribution, and proportion of intensive care unit visits over total admissions to control for hospitals contributing different data in different years of the dataset (Supplementary Table 2). Statistical analyses were completed using R version 3.5.0 [18].
RESULTS
From 2009 through 2017, 19 381 763 unique inpatient encounters were identified at 203 hospitals that reported at least 1 case of Candida (Supplementary Table 3). From this population, 18 728 Candida spp. isolates from an invasive site (unique species within an encounter) were identified across 17 103 encounters from 16 334 patients. The population was 49% female, 70% white, and 40% aged ≥ 65 years. Overall, 192 neonates (≤4 weeks) were identified. Twenty-two percent of encounters resulted in death or discharge to hospice (Table 1). The majority (96%, n = 15 739) of patients had only 1 hospitalization with a positive Candida species during the study period.
Table 1.
Patient and Hospital Encounter Demographics by Candida Species
| Characteristic | Total IC, No. (col %) | C. albicans, No. (col %) | C. glabrata, No. (col %) | C. parapsilosis, No. (col %) | C. tropicalis, No. (col %) | Other, No. (col %) |
|---|---|---|---|---|---|---|
| Unique patients with Candida | ||||||
| Total | 16 334 | 8764 | 4304 | 1892 | 1271 | 1164 |
| Sex | ||||||
| Female | 8069 (49) | 4376 (50) | 2312 (54)* | 823 (43)* | 598 (47) | 570 (49) |
| Male | 8263 (51) | 4386 (50) | 1992 (46)* | 1069 (57)* | 673 (53) | 594 (51) |
| Age, y | ||||||
| <1 | 326 (2) | 168 (2) | 16 (0)* | 97 (5)* | 19 (1) | 35 (3)* |
| 1–17 | 538 (3) | 251 (3) | 47 (1)* | 124 (7)* | 63 (5)* | 108 (9)* |
| 18–39 | 1999 (12) | 1150 (13) | 389 (9)* | 260 (14) | 174 (14) | 217 (19)* |
| 40–64 | 6879 (42) | 3753 (43) | 1834 (43) | 771 (41) | 527 (41) | 499 (43) |
| 65 + | 6592 (40) | 3442 (39) | 2018 (47)* | 640 (34)* | 488 (38) | 305 (26)* |
| Neonates (≤4 wk) | 192 (1.2) | 115 (1.3) | 9 (0.2)* | 55 (2.9)* | <5 (NR)a | 8 (0.7) |
| Race | ||||||
| African-American | 3099 (19) | 1453 (17) | 867 (20) | 504 (27) | 285 (22) | 192 (16) |
| White | 11 464 (70) | 6398 (73) | 3016 (70) | 1138 (60) | 828 (65) | 829 (71) |
| Other | 1538 (9) | 789 (9) | 360 (8) | 221 (12) | 142 (11) | 122 (10) |
| Unknown | 233 (1) | 124 (1) | 61 (1) | 29 (2) | 16 (1) | 21 (2) |
| Hospital encounters | ||||||
| Total | 17 103 | 8989 | 4432 | 1969 | 1295 | 1189 |
| Census region | ||||||
| Midwest | 4147 (24) | 2329 (26) | 1142 (26) | 397 (20)* | 265 (21)* | 291 (24) |
| Northeast | 3628 (21) | 1964 (22) | 923 (21) | 433 (22) | 240 (18)* | 197 (17)* |
| South | 6915 (40) | 3391 (38) | 1755 (40)* | 869 (44)* | 635 (49)* | 518 (44)* |
| West | 2413 (14) | 1305(15) | 612 (14) | 270 (14) | 155 (12)* | 183 (15) |
| Died | ||||||
| Yes | 3811 (22) | 1931 (21) | 1202 (27)* | 337 (17)* | 297 (23) | 280 (24) |
| No | 12 061 (71) | 6523 (73) | 2915 (66)* | 1478 (75)* | 889 (69)* | 830 (70) |
| Unknown | 1231 (7) | 535 (6) | 315 (7)* | 154 (8)* | 109 (8)* | 79 (7) |
| Infection type | ||||||
| Candidemiab | 9839 (57) | 4198 (47) | 2983 (67)* | 1494 (76)* | 811 (63)* | 737 (62)* |
| Abdominalc | 6289 (37) | 4177 (47) | 1319 (30)* | 212 (11)* | 419 (32)* | 393 (33)* |
| Other steriled | 1113 (6) | 614 (7) | 133 (3)* | 263 (13)* | 65 (5)* | 59 (5)* |
Percent values may not sum to 100 due to rounding.
One patient with C. albicans and 1 patient with C. parapsilosis had unknown sex.
Other species included: C. auris, C. catenulata, C. ciferrii, C. collicolosa, C. dubliniensis, C. famata, C. guilliermondii, C. haemulonii (pansusceptible), C. intermedia, C. kefyr, C. krusei, C. lambica, C. lipolytica, C. lusitaniae, C. magnoliae, C. norvegensis, C. orthopsilosis, C. paratropicalis, C. pelliculosa, C. pseudotropicalis, C. pulcherrima, C. rugosa, C. sphaerica, C. stellatoidea, C. utilis, C. zeylanoides.
Abbreviations: col, column; IC, invasive candidiasis.
*P ≤ .05 compared to C. albicans distribution using Pearson χ 2 test of proportions
aNumber of cases ≤ 5, exact count and percentage not reported to preserve data anonymity.
bCandidemia with or without other invasive site.
cAbdominal sterile source without candidemia.
dNonabdominal sterile source without candidemia.
Species and Body Site Distribution
Species were distributed as follows: 48% (n = 8989) of isolates were C. albicans, 24% (n = 4432) C. glabrata, 11% (n = 1969) C. parapsilosis, 7% (n = 1295) C. tropicalis, and 6% (n = 1189) less common Candida species (“other Candida spp.”). These included C. catenulata, C. ciferrii, C. collicolosa, C. dubliniensis, C. famata, C. guilliermondii, C. haemulonii (pansusceptible), C. intermedia, C. kefyr, C. krusei, C. lambica, C. lipolytica, C. lusitaniae, C. magnoliae, C. norvegensis, C. orthopsilosis, C. paratropicalis, C. pelliculosa, C. pseudotropicalis, C. pulcherrima, C. rugosa, C. sphaerica, C. stellatoidea, C. utilis, and C. zeylanoides; there were 6 C. auris infections (all in the Middle Atlantic census division). Four percent (n = 770) of all isolates were not identified to the species level (Supplementary Table 4). Fifty-seven percent (n = 9839) of encounters had candidemia (96% candidemia only, 4% with other invasive site), 37% (n = 6289) had abdominal IC without candidemia, and 6% (n = 1113) had an infection in a nonabdominal sterile site without candidemia (Table 1). Patients with C. glabrata infections had a significantly higher unadjusted mortality than patients with C. albicans (27% vs 22%, P < .001), while patients with C. parapsilosis had lower unadjusted mortality than patients with C. albicans (17% vs 21%, P < .001). Unadjusted mortality was significantly higher in patients with candidemia (28%), compared to abdominal IC (16%, P < .001), and nonabdominal sterile site IC (10%, P < .001).
Incidence and Trends of IC
The overall incidence of inpatient IC in the 203 hospitals reporting at least 1 Candida-positive encounter from 2009–2017 was 90/100 000 hospitalizations. The incidence of overall IC did not significantly increase from 2009–2017 (annual percent change [APC], 1.3%; 95% confidence interval [CI], −1.5% to 4.1%). Species-specific incidence was 46/100 000 hospitalizations for C. albicans, 23/100 000 for C. glabrata, 10/100 000 for C. parapsilosis, 6.8/100 000 for C. tropicalis, and 6.2/100 000 for other Candida spp. There was no significant annual percent change in any species except the other Candida species, which increased 7.2% annually (CI, 2.8%–12%) (Figure 1).
Figure 1.
Annual incidence of invasive candidiasis per 100 000 hospitalizations by Candida species, 2009–2017. No significant adjusted annual percent change in incidence was observed for C. albicans, C. glabrata, C. parapsilosis, and C. tropicalis. The incidence of other Candida species increased significantly. Annual percent change (95% confidence interval) is given for Candida species.
Incidence of abdominal IC was 32/100 000 hospitalizations, incidence of nonabdominal sterile site IC was 5.7/100 000 hospitalizations, and incidence of candidemia was 51/100 000 hospitalizations. Abdominal and nonabdominal sterile site IC increased significantly by 5.5% (95% CI, 1.8%–9.3%) and 10% (95% CI, 5.0%–16%) per year, respectively (Figure 2). Species-specific incidence of abdominal IC increased among C. albicans (APC, 6.4%; CI, 2.2%–11%), C. tropicalis (APC, 10%; CI, 4.7%–15%), and other Candida spp. (APC, 15%; CI, 9.7%–21%). Other sterile site IC increased among C. albicans (APC, 11%; CI, 5.0%–18%), C. parapsilosis (APC, 14%; CI, 6.8%–22%), and other Candida spp. (APC, 24%; CI, 9.3%–42%) (Figure 3 and Table 2). Overall candidemia incidence did not change significantly over time although it trended downwards (Figure 2), but it did decrease significantly for C. albicans (APC, −3.2%; CI, −6.1% to −.1%) (Figure 3 and Table 2).
Figure 2.
Annual incidence of invasive candidiasis per 100 000 by infection body site, 2009–2017. Adjusted annual percent change in incidence for abdominal IC and nonabdominal sterile site IC increased significantly. Candidemia remained stable. Annual percent change (95% confidence interval) is given for infection body sites. Abbreviation: IC, invasive candidiasis.
Figure 3.
Annual site-specific incidence per 100 000 hospitalizations of invasive candidiasis by Candida species, 2009–2017: (A) C. albicans, (B) C. glabrata, (C) C. parapsilosis, (D) C. tropicalis, and (E) other Candida species. Abbreviation: IC, invasive candidiasis.
Table 2.
Adjusted Annual Percent Change of Incidence of Invasive Candidiasis by Body Site and Candida Species, 2009–2017
| Body Site | C. albicans APC (95% CI) | C. glabrata APC (95% CI) | C. parapsilosis APC (95% CI) | C. tropicalis APC (95% CI) | Other spp. APC (95% CI) |
|---|---|---|---|---|---|
| Abdominal IC | 6.4 (2.2 to 11) | 5.2 (−.4 to 11) | 8.5 (−.2 to 18) | 10 (4.7 to 15) | 15 (9.7 to 21) |
| Candidemia | −3.2 (−6.1 to −.1) | −0.6 (−3.4 to 2.3) | −4.1 (−8.0 to .02) | −1.6 (−5.7 to 2.5) | 1.0 (−2.5 to 7.3) |
| Nonabdominal sterile site IC | 11 (5.0 to 18) | 5.3 (−4.0 to 15) | 14 (6.8 to 22) | −1.0 (−13 to 13) | 24 (9.3 to 42) |
Abbreviations: APC, annual percent change; CI, confidence interval; IC, invasive candidiasis.
DISCUSSION
In this study, we present a unique longitudinal look at the incidence and trends of IC by Candida species and body site. With the growing problem of IC in the United States, particularly in species with increased antifungal resistance such as C. glabrata [13] or the newly recognized C. auris [5], it is important to understand the epidemiology of these infections. By using a large database of electronic health records (EHRs), which include microbiology data, we found the incidence of hospitalizations with IC to be 90/100 000 hospitalizations, comparable to another hospital laboratory-based study in Latin America, which found an incidence of 118/100 000 hospitalizations across all countries [19]. Past studies of IC in the United States have used population-based surveillance of a few sentinel sites [8], hospital discharge data dependent on ICD codes [11], denominators such as hospital days or central-line days that preclude comparison with persons or hospital admissions [20], or are from extensive surveillance networks that lack a denominator with which to calculate incidence [12, 13]. These methodological differences hamper efforts to obtain accurate estimates of the burden of IC in the United States and globally, and may result in an underestimation of the true number of cases [5, 21].
In these data, we observed no change in the incidence of candidemia over the study period. While this differs from older studies in the United States [8, 11], one recent study of laboratory-confirmed candidemia in the United States also found no significant change from 2012 to 2016 [22]. Analyses of older studies from other countries showed increasing incidence in candidemia globally, including Norway [23], Denmark (whose incidence stabilized between 2011 and 2014) [24], and Australia [25]. The change in trends in the United States could be due in part to the decrease in central line-associated blood stream infections observed nationally by the CDC [26]. However, with the increase in injection drug use in the United States [27], a potential explanation for the increased incidence of IC seen in 2016, it will be important to continue to monitor these trends as early studies have suggested an association between this practice and candidemia.
Our study also provides insight into trends in noncandidemia IC, which has typically been omitted by other studies. Here, while the incidence of both abdominal and nonabdominal sterile site IC was lower than that of candidemia, there was a more pronounced and significant increase in incidence for both, especially that of nonabdominal sterile site IC. These cases are likely underrepresented, as these infections can be difficult to diagnose, with the sensitivity of blood culture around or less than 50% [28]. Nonetheless, early detection of these infections is critical, as some anatomical sites exhibit poor penetration of echinocandins, and mortality can be as high as 60% [29]. Risk factors for these types of infections include total parenteral nutrition, immunosuppression, and abdominal surgery [1].
With the rise in antifungal-resistant Candida, understanding species distribution and trends is needed so that physicians can provide appropriate therapy to patients early in their disease course. In our analysis, 48% of all infections were caused by C. albicans, which remains the most common cause of Candida-related IC worldwide, followed by C. glabrata, C. parapsilosis, and C. tropicalis, similar to other US-based findings [8, 30, 31]. We found that half of all IC was caused by C. albicans, and that while 60% of candidemia was due to this species, proportionally non-albicans species were more likely to be isolated from blood than C. albicans. The next most common species, C. glabrata, had a higher crude mortality than C. albicans and was more likely to be found in patients older than 65 years, while C. parapsilosis had a lower crude mortality than the other Candida species but caused more disease in neonates. This is consistent with what has been found in the literature [32, 33]. While studies have shown a global decline in C. albicans-related invasive disease [31, 34], we observed that C. albicans IC and candidemia-specific incidence remained stable, while abdominal and nonabdominal sterile site C. albicans IC increased. Increased incidence in noncandidemia IC was also seen for C. tropicalis and other Candida species (abdominal IC), and C. parapsilosis (nonabdominal sterile site IC). We did not observe any significant change in the incidence of C. glabrata which has been seen in other regions of the world [13]. As C. glabrata frequently exhibits azole resistance and echinocandin-resistant C. glabrata has also been noted [35], the observed stable incidence in the United States is reassuring. Continued surveillance will be critical to detect early changes in the incidence of this pathogen. The fact that only 6 C. auris patients were observed is likely due to limited laboratory testing for this pathogen and misdiagnosis over the study period; C. auris did not become a nationally notifiable species until 2018 [36].
This study has a number of limitations. One limitation is that we may be missing sterile site infections as well as candidemic patients with deep-seated infections due to limitations with current detection methods [28]. However, this limitation would be present in other studies thus enabling comparisons with our findings. Because the study data were from an EHR system of over 200 hospitals, there is likely variety in the species identification systems and their quality, without centralized confirmatory testing, which could impact the accuracy of speciation and therefore our results. Only one-third of the Candida isolates were tested for in vitro antifungal resistance, and while some inference in resistance can be made on a species basis (ie, azole resistance in C. glabrata is between 6% and 16% [31]), we were unable to assess this in our analysis. A common limitation in EHR datasets that is not present in other sources like surveillance data is that hospitals do not necessarily participate in the system every year, either having gaps in data reporting or joining the system in later years of the study observation period. Indeed, out of a total of 203 hospitals reporting Candida cases in the HealthFacts dataset, only 55 of them continuously reported Candida every year of the study period. Additionally, there were 93 hospitals that reported microbiology during the study period but no Candida cases, and these were primarily small, nonteaching facilities, largely in the West region (Supplementary Table 3). This limits the generalizability of this study to primarily larger teaching facilities, although a sensitivity analysis conducted by including these hospitals demonstrated no change in trends among the full 296 hospitals reporting microbiology (Supplementary Table 5). Another limitation in this study is that participation by hospitals is elective, meaning generalizability of these results is also limited to the types of hospitals that would elect to participate in a similar system (Supplementary Table 3). While we controlled for numerous hospital characteristics in the trend analysis to account for elective participation and discontinuity across years for some facilities, bias may still be present in the type of hospitals represented in this dataset. Additionally, it is possible that the drop in cases in 2017 is due to incomplete reporting of data that year and not an actual decrease in IC; trends did not change when data from that year were excluded.
Understanding the epidemiology of IC at the source and species level will help facilitate improved management of patients with these infections. While we did not observe an increase in commonly antifungal-resistant species, it will be critical for physicians to understand the likelihood of patients having certain types of infections so that they can provide the most appropriate therapy early in the course of disease. In addition to trends, future studies should assess factors such as risk-adjusted mortality, prescribed antifungal use, antifungal resistance, antibiotic exposure, and coinfection/secondary bacteremia to help provide a more complete picture of Candida-associated invasive disease.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Financial support. This work was supported in part by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Institutes of Health Clinical Center.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Presented in part: Infectious Disease Society of America’s IDWeek meeting, Washington, DC, 2–6 October 2019.
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