Background
Candida sp. represent the third most common family of pathogens causing bloodstream infections in intensive care units (ICU) patients in the United States [
1]-[
3]. The global incidence of candidemia is reported to be 6.7-54 per 1000 ICU patients [
4]-[
6]. Untreated candidemia typically results in eye lesions, skin lesions and abscesses, and often lead to multiple organ failure. The mortality rate is 30-61.8% in Europe and America [
5]-[
8]. In addition, candidemia can extend hospital stay by 10-30 days, and increase inpatient hospital costs by about $40,000 in the United States [
8]. Candidemia requires treatment with an antifungal agent, and removal of the catheter alone is not an adequate therapy for candidemia [
9]. The large prospective China Survey of Candidiasis (China-SCAN) study showed that most candidemia in China were caused by non-
albicans species (58.2%), and that first-line antifungal therapy decreased mortality [
10].
Catheters are commonly used in ICU patients, and represent an easy entry route for pathogens, including
Candida sp. In general, patients with candidemia are inserted with catheters, most commonly central venous catheter (CVC), with a placement rate of 80-89% in Europe and America [
11],[
12]. CVC placement can significantly increase the risk of candidemia in hospitalized patients [
13], and is an independent risk factor for candidemia in the United States [
14]. Candidemia caused by catheter placement is named
Candida catheter-related bloodstream infection (CRCBSI). In addition to CVC, studies in Europe and America identified a number of risk factors that are associated with CRCBSI such as surgical trauma, cancer, parenteral nutrition, diabetes mellitus, urinary catheter, age, vancomycin use, and impaired acute physiology and chronic health evaluation (APACHE) score [
8],[
15]-[
19].
The epidemiology of candidemia varies with geography, but is mostly dominated by
Candida albicans; however, the proportion of non-
albicans candidemia is increasing each year [
20], sometimes reaching higher rates than that of
albicans candidemia in European countries [
21]. In many countries,
Candida parapsilosis contributes to 15-20% of candidemia, and is often associated with CRCBSI [
22],[
23]. Therefore, a better understanding of the CRCBSI epidemiology could lead to better first-line treatments, and to decreased morbidity and mortality.
The China-SCAN study assessed the epidemiology, microbiology, management and outcomes of invasive candidiasis in 67 ICUs across China, and the results were published [
10]. The aim of the present study was to assess the risk factors, microbiology, management and outcomes of CRCBSI in the China-SCAN sample. Results might lead to a better identification of patients at high risk of CRCBSI, and to adopt appropriate clinical strategies.
Discussion
To our knowledge, the China-SCAN study is the largest prospective study of invasive candidiasis in Chinese ICUs, and possibly from anywhere. In addition, it is also one of the first to describe Candida catheter-related bloodstream infections in China. The present study aimed to determine the risk factors for catheter-related candidemia in Chinese ICU. Our results showed that CRCBSI incidence in ICU was 0.03%, accounting for 9.86% of all candidemia observed in ICU (29/294), mainly caused by Candida parapsilosis in CRCBSI patients (33.3%). Univariate analyses showed that older age and lower body weight were associated with CRCBSI. Multivariate analysis showed that the SOFA score was independently associated with CRCBSI (P = 0.002). Catheter removal and immune enhancement therapy were more frequently used in CRCBSI than in NCRCBSI. Results of the present study provide clues for a better identification of CRCBSI patients.
Few studies reported large-scale epidemiological data on CRCBSI. In the present study, we reported a CRCBSI incidence in ICUs of 0.3/1000 patients, which was calculated based on the 96,060 ICU patients reported in the China-SCAN study. In the present study, some patients with NCRCBSI did not have blood sample in venous catheter; therefore, some of these patients might in reality be CRCBSI cases. In addition, some Candida-positive patients could have been excluded because of the strict inclusion criteria of the CHINA-SCAN study. Therefore, the real CRCBSI incidence may be higher.
In the present study, the mortality rate from CRCBSI was 44.8%, which was not significantly different from that of NCRCBSI (36.2%). These rates are in agreement with the published global mortality rates of 30-61.8% in hospital-based candidemia studies from western countries [
5]-[
8].
The CRCBSI and NCRCBSI groups were compared in order to identify risk factors for CRCBSI. Results showed that the two groups were similar in disease, invasive procedures, disease severity score, and the use of antibiotics within the past two weeks. However, in univariate analyses, there were significant differences in age and body weight. These results suggest that risk factors for CRCBSI, other candidemias and invasive candidiasis were similar in most ICU patients, except for those with an older age and lower body weight.
CVC is the most common type of catheter causing CRCBSI [
28]. Studies have shown that CVC placement rate in candidemia patients is 80-96.7% [
21]. Consistent with these results, the CVC placement rates in patients with CRCBSI and those with NCRCBSI in the present study were above 80% (89.7% and 81.9%), and there was no significant different between the two groups. The CVC placement position and indwelling period were similar in both groups, indicating that the initial placement position of catheter and catheter indwelling time were not the cause of CRCBSI. The catheter removal rate was not different within 2 weeks before diagnosis between the two groups, but was significantly higher after diagnosis in the CRCBSI group (82.8%) compared with the NCRCBSI group (60.0%), in compliance with previous studies and guidelines [
18],[
29],[
30]. A recent study suggested that any delay in catheter removal and initiation of antifungal therapy was associated with increased mortality in CRCBSI patients; however, catheter removal had no impact on mortality of NCRCBSI patients [
18]. On the other hand, some studies argued that CVC removal do not affect prognosis of candidemia [
31]. The 2012 ESCMID guidelines also pointed out that catheter removal is necessary for candidemia, but that antifungal treatment can be used if catheter removal is impossible [
32].
In the present study, multivariate analysis showed that the SOFA score was the only independent variable associated with CRCBSI. We explored a number of factors that have been shown to be associated with candidemia in previous studies, but we did not observe any association between these parameters and CRCBSI. The study by MacDonald et al. [
19] showed that hyperalimentation was the only independent risk factor for candidemia in an ICU pediatric population. Another pediatric study showed that CVC, cancer, recent use of vancomycin, and use of agents against anaerobic bacteria were independent factors associated with candidemia [
8]. A study showed that independent predictors of biofilm-forming candidemia were the use of CVC, the use of urinary catheters, parenteral alimentation, and diabetes [
15]. Finally, a study showed that an inadequate antifungal therapy, infection with biofilm-forming
Candida species, and APACHE III scores were associated with higher
Candida-related mortality [
16]. However, these studies did not differentiate between CRCBSI and NCRCBSI. In addition, the only risk factor for candidemia that was common to these studies was the use of CVC.
Because there is variability in the resistance of
Candida strains to storage and transport, some samples could not be tested in the central laboratory, and the exact distribution of the different
Candida species might have suffered from this bias. However, we observed that CRCBSI was mainly associated with
Candida parapsilosis, while NCRCBSI was mainly associated with
Candida albicans, although the distribution of strains between the two groups was not different. This observation was consistent with previous studies on candidemia [
6],[
25],[
33].
Candida parapsilosis is more prone to cause CRCBSI, which may be related to its ease of growing in intravenous infusion of high-sugar-based nutrition, to its growing in CVC biofilm that can easily be spread by the hands of medical personnel, and to its long-term survival [
33]. Using catheter removal and appropriate antifungal therapy, CRCBSI microbiological clearance rate was significantly higher than that of NCRCBSI (67.9% vs. 50.0%), which was consistent with a previous study [
18].
There was no difference in antifungal treatment between CRCBSI and NCRCBSI patients in respect to antifungal treatment. The most commonly used was fluconazole, followed by caspofungin and voriconazole. In the China-SCAN flora and sensitivity analysis, patients with non-
albicans strains were more susceptible to require a therapy adjustment [
10]. Considering the high proportion of
Candida parapsilosis causing CRCBSI in the present study, we suggest to consider drugs with a higher efficacy against
Candida parapsilosis in the treatment of CRCBSI.
Although there is no clear indicator of the presence of immunosuppression in the present study, ICU physicians rely on clinical experience to use immunotherapy. More CRCBSI patients received immune enhancement therapy (72.4%
vs. 38.5%), suggesting that ICU physicians are concerned about CRCBSI-related immune suppression. From the previously identified risk factors in patients with CRCBSI [
8],[
15]-[
19], patients with old age and low body weight might be more prone to develop immunosuppression. Although no immune enhancement therapy is clearly recognized to improve CRCBSI patients' prognosis, immunoglobulins and thymosin α1 were selected as immunotherapy since these drugs have a potential to improve prognosis in sepsis patients [
34],[
35].
The China-SCAN study suffered from some limitations that also have an impact in the present study. Indeed, the lack of central validation for some samples could lead to an underestimation of the real CRCBSI incidence, as well as for the Candida strains causing CRCBSI. However, results based from the central laboratory clearly demonstrated that the proportion of Candida parapsilosis was higher in the CRCBSI group, while that of Candida albicans was higher in the NCRCBSI group. Differences in therapeutic strategies across the study centers may have contributed to biases in diagnosis, treatments and prognosis. Concerning the present study, the sample size of the CRCBSI group was small. Therefore, results need to be verified in further large-scale studies on CRCBSI.
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Competing interests
Haibo Qiu is a speaker for Pfizer and MSD China, and has received research grants from Pfizer, MSD China and Xian-Janssen. The remaining authors have no conflicts of interest to disclose. The funders participated in the design of the study, but had no role in study management, monitoring, data management, statistical analysis or development of this article. Authors accept direct responsibility for this paper.