This cohort study reports on the incidence and outcomes of candidemia in solid organ transplant recipients over a 10-year period.
Key Points
Question
What are the incidence and outcomes of candidemia in solid organ transplant recipients (SOTRs)?
Findings
In this cohort study of 10 249 SOTRs, candidemia occurred in 1.67% and was associated with a 30-day mortality rate of 39.3%. Mortality risk was higher in patients with fluconazole-susceptible candidemia and higher in those with fluconazole-resistant candidemia compared with SOTRs without candidemia.
Meaning
Results of this study suggest that, although uncommon, candidemia is associated with high mortality, highlighting the need for effective prevention measures.
Abstract
Importance
Current data on Candida bloodstream infection (candidemia) in solid organ transplant recipients (SOTRs) are constrained by small sample sizes. Further research may inform targeted prevention strategies for early intervention.
Objective
To determine the incidence and outcomes of candidemia in SOTRs.
Design, Setting, and Participants
A population-based cohort study using a provincewide mycology laboratory dataset of patients aged 18 or more years from Ontario, Canada, who received an organ allograft between January 1, 2011, and September 30, 2022, with follow-up through December 31, 2023, and linked to administrative health care data.
Exposure
Organ transplant.
Main Outcomes and Measures
The primary outcome was candidemia incidence, estimated using the Kaplan-Meier method, with differences across SOTRs evaluated via the log-rank test. The secondary outcome was all-cause mortality, evaluated using a Cox proportional hazards regression model with candidemia as a time-dependent variable. Analyses were adjusted for relevant covariates.
Results
This study included 10 249 SOTRs (median age, 57 [IQR, 46-64] years; 63.9% male), with kidney transplants representing the majority (59.8%). Candidemia occurred in 135 patients, with Candida albicans as the most frequent species (41.5%), followed by Nakaseomyces (Candida) glabrata (28.1%) and C parapsilosis (11.9%). The cumulative probability of candidemia was 0.87% (95% CI, 0.69%-1.05%) at 1 year, 1.33% (95% CI, 1.09%-1.57%) at 5 years, and 1.67% (95% CI, 1.34%-2.00%) at 10 years. Lung transplant recipients had the highest 10-year cumulative probability at 4.17% (95% CI, 2.96%-5.39%; log-rank P < .001). Median time to candidemia was 34 (IQR, 18.5-354) days in recipients of thoracic allografts and 174 (IQR, 20-836) days in recipients of abdominal allografts. Thirty-day mortality was 39.3% (53 of 135) and 90-day mortality was 47.4% (64 of 135) in patients with candidemia. Candidemia was associated with an increase in mortality (adjusted hazard ratio [AHR], 6.85; 95% CI, 5.59-8.39; P < .001). Fluconazole-susceptible isolates were associated with an increase in mortality (AHR, 8.45; 95% CI, 6.42-11.14; P < .001) as were fluconazole-resistant Candida isolates (AHR, 11.86; 95% CI, 6.13-22.93; P < .001).
Conclusions and Relevance
In this cohort study of SOTRs, candidemia was an uncommon complication after organ transplant, with lung transplant recipients at the highest risk. Candidemia was associated with increased mortality. Further research is needed to better identify vulnerable subpopulations and to develop targeted strategies for early intervention.
Introduction
Invasive candidiasis is the most common invasive fungal infection among solid organ transplant recipients (SOTRs), accounting for 39% to 60% of all invasive fungal infections in this population.1,2,3,4 Candida bloodstream infection (candidemia) is the most frequent manifestation of invasive candidiasis, representing 44% of cases.5 Candidemia in SOTRs may arise from perioperative and intensive care unit (ICU)–related exposures, with the relative contribution varying by transplanted organ and influencing the typically early posttransplant occurrence of infection.1,4,6 Some studies have reported a higher frequency among recipients of abdominal organ transplants, in particular, small bowel, liver, and pancreas grafts.1,4 Invasive candidiasis is associated with a high mortality rate.7 Consequently, many transplant centers implement prophylactic measures to prevent Candida infections in transplant recipients.7 Although antifungal prophylaxis may influence the risk of candidemia after solid organ transplant, there is no standardized antifungal prophylaxis strategy, and variability in institutional practices may contribute to differences in observed candidemia incidence.
Large-scale studies on candidemia from North America and Europe indicate that Candida albicans, Nakaseomyces glabrata (formerly C glabrata), and C parapsilosis are the most common species. Notably, non-albicans Candida species have become increasingly prevalent, particularly in studies by Pfaller et al8 and Koehler et al.9 Despite advancements in care, 30-day mortality rates remain high, ranging from 25% to 51%, with no significant improvement over time.8,9,10
However, only a limited number of studies have specifically examined candidemia in solid organ transplant recipients, and most have been constrained by small sample sizes.6,11,12,13 The objective of our study was to describe the incidence and outcomes of candidemia in a contemporary, population-based cohort of SOTRs. Additionally, we aimed to compare the outcomes of SOTRs with fluconazole-susceptible vs fluconazole-resistant Candida isolates.
Methods
Study Design
We conducted a cohort study using population-based administrative health care databases from Ontario, Canada. Ontario, the country’s most populous province (15.8 million residents in 2024), performs nearly half of all solid organ transplants in Canada.14 Data were linked through coded identifiers and analyzed at ICES (formerly known as the Institute for Clinical Evaluative Sciences), an independent nonprofit research institute whose legal status under Ontario’s health information privacy law allows the collection and analysis of health care and demographic data, without consent, for health system evaluation and improvement. This project was approved by the Research Ethics Boards at the University Health Network and Public Health Ontario (PHO). This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Data Sources
We identified patients, their characteristics, and outcomes using multiple databases housed at ICES. Data on SOTRs were obtained from the Canadian Organ Replacement Register (CORR). Demographic information, place of residence, and vital status were derived from the Ontario Registered Persons Database. Clinical and administrative data from inpatient admissions were collected through the Canadian Institute for Health Information’s Discharge Abstract Database. Information on physician-based care, including services and diagnoses, was gathered from the Ontario Health Insurance Plan Claims Database. Microbiology results, including fungal culture and antifungal susceptibility results, were obtained from the PHO laboratory information system (Labware). As this database is not housed at ICES, it was linked to other ICES databases using health card numbers or a combination of 5 identifiers (date of birth, sex, postal code, first name, and last name). Details of all data sources used are provided in eTables 1 through 3 in Supplement 1.
Participants
We included adult SOTRs in Ontario who underwent kidney, kidney-pancreas, liver, lung, or heart transplant between January 1, 2011, and September 30, 2022. Multiorgan (with the exception of kidney-pancreas) and bowel transplants were excluded due to their rarity. Additional exclusions included individuals less than 18 years of age at the time of transplant, non-Ontario residents, patients who died on the day of transplant, those with missing sex or date of birth data, and patients lacking corresponding records in the Discharge Abstract Database. Individuals were also excluded if Candida was isolated from nonblood specimens or if non-Candida yeasts or molds were isolated from blood.
Exposure and Outcomes
For the first objective, estimating the incidence of candidemia, the exposure was solid organ transplant and the outcome was the occurrence of candidemia. Antifungal susceptibility to fluconazole was interpreted according to the Clinical and Laboratory Standards Institute guidelines.15 Isolates were categorized as susceptible minimum inhibitory concentration (MIC) of 2 μg/mL or less, susceptible dose-dependent (SDD) MIC of 32 μg/mL or less for N glabrata and 4 μg/mL or less for other Candida species, and resistant MIC of 64 μg/mL or greater for N glabrata and 8 μg/mL or greater for other Candida species. In cases of recurrent candidemia, we only included the first candidemia episode as a positive outcome. For the second objective, assessing outcomes associated with candidemia, the exposure variable was candidemia and the primary outcome was all-cause mortality at any time during follow-up. Secondary outcomes included 30-day and 90-day mortality, with comparisons between patients with and without candidemia and different Candida species.
Covariates
Baseline variables included age, sex, public health unit region, and income quintile (a measure of median neighborhood income based on the patient’s home address). Identified comorbidities included chronic lung disease (asthma and chronic obstructive pulmonary disease), heart failure, hypertension, diabetes, chronic kidney disease, cirrhosis, rheumatoid arthritis, inflammatory bowel disease, and HIV infection. We calculated each patient’s Charlson Comorbidity Index score16 and assessed their health resource utilization. The date of transplant served as the index date for all baseline characteristics. A 5-year look-back period was applied to identify comorbidities, and a 1-year look-back period was used to describe health resource utilization.
Statistical Analysis
We summarized the baseline characteristics of SOTRs with and without candidemia using counts and percentages for categorical variables and medians with IQRs for continuous variables. In accordance with ICES confidentiality requirements, cell sizes of 5 or less were suppressed to reduce the risk of patient reidentification. Comparisons of categorical variables were conducted using the χ2 test, while continuous variables were analyzed using the Wilcoxon rank sum test.
The 1-year, 5-year, and 10-year cumulative probabilities of candidemia, overall, by solid organ transplant type, and by fluconazole susceptibility, were calculated using the Kaplan-Meier estimator. Differences in cumulative probability among solid organ transplant types were compared using the log-rank test. Patients were censored if they died, moved out of the province, lost insurance coverage, or reached the end of follow-up (December 31, 2023).
We evaluated the risk of all-cause mortality in the entire cohort of SOTRs, with and without candidemia. An extended Cox proportional hazards regression model was used, treating candidemia as a time-dependent variable. To evaluate the association between candidemia and mortality, we constructed a multivariable Cox proportional hazards regression model that included variables plausibly associated with both candidemia and mortality. Covariates comprised transplanted organ type, Charlson Comorbidity Index score, age, and sex.17,18 The index date was the date of transplant, and patients were censored at the time of loss to follow-up or the end of the follow-up period (December 31, 2023). Models were created for overall candidemia as well as fluconazole-susceptible, fluconazole-SDD, and fluconazole-resistant candidemia.
As a secondary, exploratory analysis, we constructed a matched cohort comprising all patients with candidemia, matched in a 1:4 ratio with nonexposed patients (without candidemia). Nonexposed patients were randomly selected and matched without replacement based on transplanted organ, age (±12 years), sex, and transplant date (±1.5 years). To ensure comparable risk sets, nonexposed patients were required to be alive at the time of the exposed patients’ infection date. Balance between exposed and nonexposed patients was assessed using descriptive diagnostics. We calculated 30-day and 90-day mortality using the actual or matched candidemia date as the index date. The association between candidemia and mortality was assessed using a logistic regression model, with candidemia as the independent variable and 90-day mortality as the dependent variable. After restricting the cohort only to patients with candidemia, we assessed the association of Candida species with outcomes using a logistic regression model with Candida species as the independent variable and 30-day or 90-day mortality as the dependent variable.
Statistical tests were 2-sided with the level of significance set at P < .05. All analyses were performed at ICES using SAS, version 9.4 (SAS Institute Inc).
Results
Baseline Characteristics
We identified 10 249 SOTRs (63.9% male; 36.1% female; median age, 57 [IQR, 46-64] years) who underwent organ transplant between January 2011 and September 2022 after applying exclusion criteria to an initial cohort of 11 159 recipients (Figure 1). Exclusions comprised 67 recipients of small bowel or multiorgan transplants, given the rarity of these procedures. The final cohort included 6125 kidney (59.8%), 2043 liver (19.9%), 1232 lung (12.0%), 537 heart (5.2%), and 312 kidney-pancreas (3.0%) transplants. Demographic characteristics, including age, sex, and income quintiles, were comparable between SOTRs with and without candidemia (Table 1).
Figure 1. Study Flowchart.
Table 1. Characteristics of Solid Organ Transplant Recipients With and Without Candida Bloodstream Infection (Candidemia).
| Characteristics | Recipients, No. (%) | P value | |
|---|---|---|---|
| Candidemia (n = 135) | No candidemia (n = 10 114) | ||
| Age, median (IQR), y | 58 (47-64) | 57 (46-64) | .72 |
| Sex | |||
| Female | 51 (37.8) | 3651 (36.1) | .69 |
| Male | 84 (62.2) | 6463 (63.9) | |
| Public health unit regiona | |||
| East | 16 (11.9) | 2200 (21.8) | .08 |
| Central west | 29 (21.5) | 2018 (20.0) | |
| Durham | 6 (4.4) | 464 (4.6) | |
| North | 9 (6.7) | 515 (5.1) | |
| Peel | 24 (17.8) | 1038 (10.3) | |
| South west | 18 (13.3) | 1121 (11.1) | |
| Toronto | 25 (18.5) | 2008 (19.9) | |
| York | 8 (5.9) | 714 (7.1) | |
| Income quantilea | |||
| 1 (Lowest) | 32 (23.7) | 2243 (22.2) | .10 |
| 2 | 21 (15.6) | 2095 (20.7) | |
| 3 | 29 (21.5) | 1998 (19.8) | |
| 4 | 36 (26.7) | 1903 (18.8) | |
| 5 (Highest) | 17 (12.6) | 1846 (18.3) | |
| Organ transplant recipients, | |||
| Days since transplant, median (IQR) | 82 (20-624) | NA | NA |
| Thoracic organ transplant | |||
| Days since transplant, median (IQR) | 34 (18.5-354) | NA | NA |
| Lung | 47 (34.8) | 1185 (11.7) | <.001 |
| Heart | 13 (9.6) | 524 (5.2) | .02 |
| Abdominal organ transplant | |||
| Days since transplant, median (IQR) | 174 (20-836) | NA | NA |
| Kidney | 29 (21.5) | 6096 (60.3) | <.001 |
| Kidney-pancreas | 11 (8.1) | 301 (3.0) | <.001 |
| Liver | 35 (25.9) | 2008 (19.9) | .07 |
| Candida species | |||
| C albicans | 56 (41.5) | NA | NA |
| C dubliniensis | 8 (5.9) | NA | NA |
| N glabrata (formerly C glabrata) | 38 (28.1) | NA | NA |
| P kudriavzevii (formerly C krusei) | <6 | NA | NA |
| C lusitaniae | 6 (4.4) | NA | NA |
| C parapsilosis | 16 (11.9) | NA | NA |
| C tropicalis | <6 | NA | NA |
| Other Candida species | <6 | NA | NA |
| Comorbidities | |||
| Charlson Comorbidity Index, median (IQR) | 5 (3-7) | 4 (2-5) | <.001 |
| Asthma | 37 (27.4) | 1808 (17.9) | .004 |
| Inflammatory bowel disease | <6 | 121 (1.2) | .28 |
| Heart failure | 43 (31.9) | 1941 (19.2) | <.001 |
| Chronic obstructive pulmonary disease | 43 (31.9) | 2041 (20.2) | <.001 |
| HIV | <6 | 52 (0.5) | .12 |
| Hypertension | 97 (71.9) | 7855 (77.7) | .11 |
| Diabetes | 71 (52.6) | 4070 (40.2) | .004 |
| Rheumatoid arthritis | 8 (5.9) | 266 (2.6) | .01 |
| Chronic kidney disease | 84 (62.2) | 7303 (72.2) | .01 |
| Cirrhosis | 42 (31.1) | 2245 (22.2) | .01 |
| No. of admissions, past 5 y, median (IQR) | 4 (1-6) | 2 (1-4) | <.001 |
| No. of primary care visits, past 1 y, median (IQR) | 4 (2-8) | 3 (1-6) | <.001 |
Abbreviation: NA, not available.
Missing information: 36 (0.4%) individuals were missing public health unit region data; 29 (0.3%) were missing income quintile data.
In the overall cohort, the median Charlson Comorbidity Index score was 4 (IQR, 2–5). The most common comorbidities were hypertension (77.6% [7952]), chronic kidney disease (72.1% [7387]), and diabetes (40.4% [4141]) (Table 1).
Comparing patients with and without candidemia, those with candidemia had a higher Charlson Comorbidity Index score (median, 5 [IQR, 3-7] vs 4 [IQR,2-5]; P < .001) and were more likely to have asthma (27.4% vs 17.9%; P = .004), chronic obstructive pulmonary disease (31.9% vs 20.2%; P < .001), heart failure (31.9% vs 19.2%; P < .001), diabetes (52.6% vs 40.2%; P = .004), and cirrhosis (31.1% vs 22.2%; P = .01).
Candida albicans was the most frequently isolated species (56 [41.5%]) followed by N glabrata (38 [28.1%]) and C parapsilosis (16 [11.9%]). Candidemia typically occurred early posttransplant, with a median onset of 82 days (IQR, 20-624 days). Notably, thoracic organ transplant recipients developed candidemia earlier than abdominal organ recipients (median, 34 [IQR, 18.5-354] vs 174 [IQR, 20-836] days).
Incidence
We identified 135 patients with candidemia: 73 were fluconazole-susceptible, 33 were fluconazole-SDD, 13 were fluconazole-resistant, and 16 cases lacked susceptibility testing. The cumulative probability of candidemia was 0.87% (95% CI, 0.69%-1.05%) at 1 year, 1.33% (95% CI, 1.09%-1.57%) at 5 years, and 1.67% (95% CI, 1.34%-2.00%) at 10 years (Table 2). The highest incidence of candidemia was observed in lung transplant recipients (10-year cumulative probability, 4.17%; 95% CI, 2.96%-5.39%), followed by kidney-pancreas transplant recipients (4.05%; 95% CI, 1.67%-6.42%). The lowest incidence was among kidney transplant recipients (0.81%; 95% CI, 0.44%-1.18%; log-rank P < .001) (Figure 2). Fluconazole-susceptible isolates were more common, with a 10-year cumulative probability of 0.81% (95% CI, 0.62%-1.01%) compared with 0.49% (95% CI, 0.28%-0.70%) for fluconazole-SDD isolates and 0.14% (95% CI, 0.06%-0.22%) for fluconazole-resistant isolates (eFigures 1-3 in Supplement 1).
Table 2. Candida Bloodstream Infection (Candidemia) Incidence.
| Candidemia cases | No. of candidemia cases | Overall population, No. | Cumulative probability of candidemia, % (95% CI) | ||
|---|---|---|---|---|---|
| 1 y | 5 y | 10 y | |||
| Overall | 135 | 10 249 | 0.87 (0.69-1.05) | 1.33 (1.09-1.57) | 1.67 (1.34-2.00) |
| Fluconazole-S | 73 | 0 | 0.55 (0.40-0.69) | 0.75 (0.58-0.93) | 0.81 (0.62-1.01) |
| Fluconazole-SDD | 33 | 0 | 0.16 (0.08-0.24) | 0.29 (0.18-0.40) | 0.49 (0.28-0.70) |
| Fluconazole-R | 13 | 0 | 0.09 (0.03-0.15) | 0.14 (0.06-0.22) | 0.14 (0.06-0.22) |
| Heart | 12 | 537 | 1.78 (0.63-2.94) | 2.30 (0.94-3.65) | 3.63 (1.25-6.00) |
| Kidney | 23 | 6125 | 0.20 (0.09-0.31) | 0.39 (0.23-0.55) | 0.81 (0.44-1.18) |
| Kidney-pancreas | 10 | 312 | 1.62 (0.21-3.03) | 4.05 (1.67-6.42) | 4.05 (1.67-6.42) |
| Liver | 34 | 2043 | 1.30 (0.80-1.80) | 1.91 (1.27-2.55) | 1.91 (1.27-2.55) |
| Lung | 40 | 1232 | 3.00 (2.04-3.97) | 4.17 (2.96-5.39) | 4.17 (2.96-5.39) |
Abbreviations: Fluconazole-R, resistant to fluconazole; Fluconazole-S, susceptible to fluconazole; Fluconazole-SDD, susceptible dose dependent.
Figure 2. Kaplan-Meier Curves Showing the Cumulative Probability of Candida Bloodstream Infection (Candidemia) According to Solid Organ Transplant Type.
Mortality
Short-term mortality after candidemia was assessed in a matched cohort comprising all patients with candidemia (n = 135) and 540 matched controls without candidemia. The 30-day mortality rate was 39.3% (53) and the 90-day mortality rate was 47.4% (64) among patients with candidemia compared with less than or equal to 0.9% (≤5) and 1.3% (7) among patients without candidemia (eTable 4 in Supplement 1). C tropicalis had the highest observed increase in 30-day mortality compared with C albicans (odds ratio [OR], 3.17; 95% CI, 0.49-20.65). In a logistic regression model, candidemia was associated with a markedly increased risk of 90-day mortality (OR, 121.54; 95% CI, 29.73-496.89) and a markedly increased overall mortality risk (AHR, 6.74; 95% CI, 5.49-8.27; P < .001). While no statistically significant association was observed between individual Candida species and mortality at 30 or 0 days, an exploratory analysis comparing non-albicans Candida species with C albicans suggested a trend toward higher mortality among non-albicans candidemia (eTable 5 in Supplement 1).
After adjustment for relevant covariates, candidemia was associated with an increased risk of mortality (adjusted hazard ratio [AHR], 6.85; 95% CI, 5.59-8.39; P < .001). Other factors associated with increased mortality included lung transplant vs kidney transplant (AHR, 3.85; 95% CI, 3.26-4.53; P < .001), heart transplant vs kidney transplant (AHR, 1.31; 95% CI, 1.11-1.55; P = .001), Charlson Comorbidity Index score (AHR, 1.20; 95% CI, 1.18-1.21; P < .001), and age (AHR, 1.04; 95% CI, 1.04-1.04; P < .001). In contrast, liver transplant compared with kidney transplant was associated with decreased mortality (AHR, 0.87; 95% CI, 0.79-0.97; P = .009) (Table 3). Compared with patients without candidemia, the risk of mortality was higher among those with fluconazole-susceptible candidemia (AHR, 8.45; 95% CI, 6.42-11.14; P < .001), higher among those with fluconazole-SDD candidemia (AHR, 4.26; 95% CI 2.91-6.22; P < .001), and higher among those with fluconazole-resistant candidemia (AHR, 11.86; 95% CI, 6.13-22.93; P < .001) (eTables 6-8 in Supplement 1).
Table 3. Association Between Candida Bloodstream Infection (Candidemia) and Mortality Using an Adjusted Cox Proportional Hazards Regression Analysis.
| Parameter | Multivariable analysis | |
|---|---|---|
| HR (95% CI) | P value | |
| Candidemia | 6.85 (5.59-8.39) | <.001 |
| Organ type | ||
| Kidney | 1 [Reference] | NA |
| Heart | 1.31 (1.11-1.55) | .001 |
| Kidney-pancreas | 1.09 (0.84-1.41) | .53 |
| Liver | 0.87 (0.79-0.97) | .009 |
| Lung | 3.38 (3.08-3.72) | <.001 |
| Charlson Comorbidity Index | 1.20 (1.18-1.21) | <.001 |
| Age, y | 1.04 (1.04-1.04) | <.001 |
| Male sex | 1.06 (0.98-1.15) | .13 |
Abbreviations: HR, hazard ratio; NA, not applicable.
Discussion
In this cohort study of more than 10 000 SOTRs, candidemia was uncommon (10-year incidence, 1.67%) but was associated with high mortality. Cases occurred early (median onset, 82 days), yet incidence continued to increase over time, nearly doubling by 10 years. Lung transplant recipients had the highest risk (10-year cumulative incidence, 4.17%). Candidemia was associated with poor survival, with 30-day mortality of 39.3% and a markedly increased overall mortality risk (AHR, 6.74; 95% CI, 5.49-8.27; P < .001).
To our knowledge, few studies have specifically examined the incidence of invasive candidiasis and candidemia in SOTRs. The Transplant-Associated Infection Surveillance Network (TRANSNET) study reported a 1-year cumulative incidence of invasive candidiasis of 1.95%.1 Notably, 44% of these cases involved candidemia,5 which corresponds to our findings.
Invasive candidiasis and candidemia were traditionally thought to predominantly affect recipients of abdominal organ transplants, such as small bowel, liver, and pancreas. However, our findings suggest that lung transplant recipients have the highest incidence of candidemia. Prior studies reporting higher rates of invasive candidiasis in abdominal organ recipients often relied on the proportion of cases per organ type1 or the distribution of transplant types among those who developed invasive candidiasis,4,12 rather than calculating true incidence rates. A likely contributor to the elevated incidence of candidemia among lung transplant recipients is their typically prolonged ICU stays, which are associated with increased candidemia risk, although not necessarily with other forms of invasive candidiasis. Notably, our study evaluated incidence rather than proportions, which provides a more accurate reflection of risk across organ types. Similarly, a small Australian cohort study on candidemia in SOTRs also observed the highest incidence in lung transplant recipients; however, its estimates did not adjust for differences in follow-up durations.6
Candidemia occurred at a median of 82 (IQR, 20-624) days posttransplant, with earlier onset in thoracic transplant recipients (median, 34 [IQR, 18.5-354] days) compared with abdominal transplant recipients (median, 174 [IQR, 20-836] days). While prior studies have noted early onset in thoracic organ recipients, our study confirms this pattern and provides population-level estimates of incidence and timing.3,5,6 The earlier occurrence in thoracic transplants may be attributable to ICU stays requiring mechanical ventilation, frequent broad-spectrum antibiotic exposure, greater use of central lines and drains, intensive early immunosuppression, and surgical complexity with postoperative complications requiring prolonged device use. Our findings highlight that the vulnerability to candidemia does not end after the immediate posttransplant phase; instead, recipients remain at risk long-term, with incidence continuing to increase substantially up to 10 years. This extended risk period was similarly observed in the study by Hosseini-Moghaddam et al,2 which examined invasive fungal infections more broadly.
Consistent with previous studies, the most commonly isolated Candida species were C albicans followed by N glabrata and C parapsilosis.3,5,6,11,12 While the relative distribution of species varied somewhat across studies, our findings closely align with those reported in the large TRANSNET cohort.5
We observed a 30-day mortality rate of 39.3% among patients with candidemia, falling within the range previously reported in smaller studies of SOTRs (20.8%-53.8%)6,11,12 and comparable with rates observed in ICU patients with candidemia.19 In comparison, an analysis from the TRANSNET database reported a 90-day mortality rate of 26.5%,5 which is notably lower than the 47.4% observed in our cohort. This difference is likely attributable to the higher mortality associated with candidemia compared with other forms of invasive candidiasis included in the TRANSNET analysis. While we did not find an association between Candida species and mortality, C tropicalis had the highest observed increase in 30-day mortality compared with C albicans (OR, 3.17; 95% CI, 0.49-20.65), underscoring a trend previously reported but not well described in transplant populations.5,20 Additionally, candidemia was associated with a 6.9-fold increase in overall mortality (AHR, 6.85; 95% CI, 5.59-8.39; P < .001), and fluconazole-resistant candidemia was associated with an even greater mortality risk (AHR, 11.86; 95% CI, 6.13-22.93; P < .001). While this suggests a potential increased risk of death with fluconazole-resistant isolates, a direct comparison between resistant and nonresistant cases was not feasible due to small cell sizes that prevented model convergence. Notably, previous studies have reported conflicting results regarding fluconazole resistance and mortality.21,22,23
Limitations
Our study has several limitations. First, although PHO routinely performs susceptibility testing of Candida isolates from sterile sites across the province, complete ascertainment of candidemia cases cannot be guaranteed, introducing the potential for misclassification. However, PHO’s laboratory information system provided comprehensive antifungal susceptibility data and ensured consistent application of standardized clinical breakpoints across identified cases. Second, SOTRs were identified using the CORR, a national registry maintained by the Canadian Institute for Health Information. While previous studies have validated the CORR for identifying kidney transplant recipients (sensitivity, 96%; positive predictive value, 98%),24 similar validation for other organ types is needed. However, we do not anticipate major discrepancies in data accuracy across organ types. Third, the highest incidence of candidemia was observed among lung transplant recipients, which may reflect unmeasured factors such as antifungal prophylaxis practices and ICU exposure. Identifying specific risk factors was beyond the scope of this study and warrants further investigation. The absence of a provincewide immunosuppression protocol or standardized antifungal prophylaxis strategy, together with variability across institutions, could have contributed to the observed differences in candidemia incidence. Fourth, the matched-cohort analysis was exploratory and, despite good balance in matching variables, residual baseline imbalances may have remained. These results should be interpreted cautiously and considered supportive of the primary multivariable Cox proportional hazards regression models. Given the low incidence of candidemia, the large HRs observed may have been influenced by sparse-data bias.
In addition, as the study was limited to SOTRs in Ontario, generalizability may be a concern. Nonetheless, given the inclusion of multiple transplant centers and the fact that Ontario accounts for nearly half of all transplants in Canada, we believe our findings remain broadly applicable.
Conclusions
In this cohort study of SOTRs, candidemia was an uncommon but serious complication after transplant, typically occurring early in the posttransplant period. Incidence was highest in lung and lowest in kidney transplant recipients. Candidemia is associated with high 30-day mortality and long-term mortality, particularly with fluconazole-resistant isolates. Further research into risk factors for early and late candidemia may inform targeted prevention strategies.
eTable 1. ICES databases
eTable 2. Data sources used for inclusion and exclusion criteria
eTable 3. Variables.
eFigure 1. Cumulative probability of candidemia with fluconazole-susceptible isolate according to solid organ transplant type
eFigure 2. Cumulative probability of candidemia with fluconazole-resistant isolate according to solid organ transplant type
eFigure 3. Cumulative probability of candidemia with fluconazole-SDD isolate according to solid organ transplant type
eTable 4. Baseline demographics of matched cohort
eTable 5. Mortality in patients with candidemia by fluconazole susceptibility and Candida species
eTable 6. Association between fluconazole-susceptible candidemia and mortality using an adjusted Cox proportional hazards regression analysis
eTable 7. Association between fluconazole-resistant candidemia and mortality using an adjusted Cox proportional hazards regression analysis
eTable 8. Association between fluconazole-susceptible-dose-dependent candidemia and mortality using an adjusted Cox proportional hazards regression analysis
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. ICES databases
eTable 2. Data sources used for inclusion and exclusion criteria
eTable 3. Variables.
eFigure 1. Cumulative probability of candidemia with fluconazole-susceptible isolate according to solid organ transplant type
eFigure 2. Cumulative probability of candidemia with fluconazole-resistant isolate according to solid organ transplant type
eFigure 3. Cumulative probability of candidemia with fluconazole-SDD isolate according to solid organ transplant type
eTable 4. Baseline demographics of matched cohort
eTable 5. Mortality in patients with candidemia by fluconazole susceptibility and Candida species
eTable 6. Association between fluconazole-susceptible candidemia and mortality using an adjusted Cox proportional hazards regression analysis
eTable 7. Association between fluconazole-resistant candidemia and mortality using an adjusted Cox proportional hazards regression analysis
eTable 8. Association between fluconazole-susceptible-dose-dependent candidemia and mortality using an adjusted Cox proportional hazards regression analysis
Data Sharing Statement
