Evaluation of candidemia in epidemiology and risk factors among cancer patients in a cancer center of China: an 8-year case-control study

Candidemia is one of the most important nosocomial infections and associated with extremely high morbidity and mortality [1, 2]. It was cited as the fourth most prevalent nosocomial bloodstream infection in the United States and seventh to tenth in population-based studies, and the mortality is around 40% [1, 3‐5]. A recent multi-center study, 183 US medical centers invovled, showed that candidemia ranked the first cause of primary bloodstream infections [3]. Candida albicans is the leading pathogens of candidemia worldwidely, but the shift in favor of non-albicans Candida species is occurring in recent years [1]. Candida species are the opportunistic pathogenic of human, and normally colonized in oral cavity, skin, and intestinal tracts in healthy individuals [1, 6]. They could trigger invasive infection in impaired immunological conditions, such as malignant diseases, immunodeficiency, and exposure to chemotherapy and antibiotics [1, 6, 7].

The poor prognosis of candidemia was proved be related with delayed of antifungal treatment for 12 h, which led to increased mortality up to three folds [8]. Though the rescue effect of echinocandin in case of delayed therapy, it has been reported the efficiency only among patients without severe underlying diseases [8‐10]. It is a challenge to perform antifungal treatment promptly, since the hard to distinguish candidemia from bacterial bloodstream infections. The similar clinical symptoms are confusing, with shiver, fever and high ratio of neutrophils [11, 12]. The definitive diagnosis of candidemia mainly dependent on blood culture, which has low sensitive (38–50%) and time-consuming [13‐15]. Therefore, risk factors model should be taken in consideration before establishing antifungal management strategies. Recent studies identified several risk factors for candidemia, including extreme age, prior antibiotics receiving, prior hemodialysis, parenteral nutrition, blood transfusion, abdomen as the portal of entry, and et al. [16, 17]. However, all risk factors mentioned above dramatically varied on population, living region, underlying diseases, and even the study period and methods applied [17‐20].

Cancer patients are a large population with potential-risk to candidemia, both hematologic and solid malignancies were reported as the predictor for candidemia, especially for the former which were in high risk group compared to tumors in solid organs [18, 21, 22]. Meanwhile, candidemia could exacerbate the prognosis of malignant diseases (30-day mortality is up to 56%) [20, 23, 24]. Even though, the predictive risk models of candidemia among cancer patients are still limited.

As reported here, we performed a case-control study to analyze risk factors for candidemia among cancer patients during the period of 2006–2013. This may allow to apply antifungal prophylaxis to patients at greatest risk in time, and contribute to prognosis improvement [7].

Compared with other underlying diseases, cancer patients are much more susceptible to candidemia and show higher mortality [23, 25]. In this study, the crude mortality for cancer patients with candidemia was reported up to 30.0%, about two folds higher than patients with bacterial bloodstream infections. Prophylactic and empirical antifungal therapies are highly suggested in patients with malignant disorders [19, 25, 26]. However, it is hard to determine time point to prophylactic antifungal treatment, since the potential risk factors in each individuals are hard to identify. In addition, improper prophylactic treatments select in favor of non-albicans Candida species (several species have high MICs to azoles) infections, and the severe hepatorenal toxicity of antifungal drugs would worse the underlying diseases [27, 28]. In the present study, we provided the candidemia etiology and performed a case-control study to evaluate risk factors of candidemia among cancer patients, which would contribute to the strategies of antifungal therapy and prognosis improvement.

We reported here that, susceptibility test of antifungal drugs were performed for all isolates of Candida species. Concern need be addressed on those isolates of Candida species (including C. albicans, C. tropiticals and C. glabrata complex) which had higher MICs to fluconazole than others, for the increasing MICs to fluconazole and liner linkage of MICs between fluconazole and voriconazole among Candida species as reported [29]. We validated that isolates of C. lusitaniae and C. famata were susceptible to the antifungal drugs. However, the antifungal susceptibility profile of rare species is poorly studied worldwide, and the current MICs interpretive may not be suitable for some rare species. For example, amphotericin B has been reported showing little effect on treatment of C. lusitaniae fungemia, even though it was proved originally susceptible to amphotericin B in vitro [30, 31].

Total parenteral nutrition and urinary catheter have been suggested as candidemia predictors by other researchers, which is consistent with our findings. Meanwhile, we reported here that distant organ metastasis of cancer and gastrointestinal cancer were proved as independent predictors for candidemia, which have been rarely reported by others [15‐17, 32]. Distant organ metastasis of cancer is considered as the late stage of cancer, and patients are usually treated as impaired immune system and submitted to aggressive therapy, which may let to susceptible to candidemia. Gastrointestinal system, especially the upper gastrointestinal track, is recognized as the habitat of Candida species [33, 34]. It is reported that the incidence of abdominal candidiasis was 41.0% in gastroduodenal perforations, whereas 11.8% in colorectal perforations [33]. Candida species may translocate into bloodstream from impaired mucosa barrier of gastrointestinal in cancer, led to the infection [35]. Previous studies concluded that the lesions in gastrointestinal mucosa caused by invasive procedures such as nasogastric tubes imbedding and gastric acid suppressants, were the independent predictors for candidemia [5, 36]. However, more clinical data and further studies need be collected to both distant organ metastasis of cancer and gastrointestinal cancer are the risk factors to the susceptibility to candidemia for cancer patients.

Among enrolled patients in our study, age > = 65 years old, indwelling central venous catheters, surgery and previous antibiotics exposure were related with candidemia, but not considered as independent predictors, since these factors were not tightly consistent in previous reports [7, 17, 18, 20, 32]. The inconsistent findings may vary on the population, region and study design. For instance, central venous catheters has been excluded as independent indicator for candidemia when studies were designed to compare candidemia from different species of Candida [33, 37, 38]. We speculated that combined risk factors (cumulative number) might predict candidemia more accurately than single factor, which need further validations.

Neutrophils are considered as the first barrier in anti-infections reactions, and neutropenia is one of the most important indicators for impaired immune system [16]. However, the association of neutropenia with candidemia is still conflict. Karabinis A et al. proved that neutropenia significantly increase the risk of candidemia in cancer patients [20]. A study in Taiwan suggested that neutropenia predict the infection of non-albicans Candida species [39]. Another study preformed in Mainland of China found that candidiasis are more likely to occur in non-neutropenia patients in ICU [38]. We also did not prove the relationship between neutropenia and candidemia in this study. In recent years, drugs which can elevate the total number of neutrophils are widely prescribed among patients receiving chemotherapy or other immunosuppressive therapeutics, which may contribute to underestimated ratio of neutropenia patients, as well as the contribution of neutropenia to candidemia.

In addition, several risk factors recognized in other studies have been exhibited little association with candidemia in our report, including length of hospital stay > = 30 days, mechanical ventilation, chemotherapy and ICU admitted. Excepted the number of mechanical ventilation and ICU admitted were too low to without bias, the remaining could be real no discrepancies between cases and controls, since both cases and controls were cancer patients and most of them received long inpatient stay and chemotherapy [40, 41].

The crude mortality of candidemia are slightly differences when it comes to species and not consistent in different studies. In our study, C. glabrata complex and C. tropicalis are linked to higher crude mortality, consistent to previous studies (the mortality of C. glabrata complex and C. tropicalis ranged from 44.7% to 61%) [36, 42, 43]. Meanwhile, C. parapsilosis complex exhibited low mortality in both our and other reports, which was considered to be associated with the less virulent of them [43, 44]. However, the crude mortality caused by C. albicans exhibited a wide variation, slightly higher than C. parapsilosis complex in our study whereas ranked the highest mortality in other report [45]. Different study period and underlying diseases might contribute to the conflicted conclusions.

In conclusion, candidemia exhibited higher mortality than bacterial bloodstream infections among cancer patients. C. albicans contributed as the leading pathogen for candidemia. Total parenteral nutrition >5 days, urinary catheter >2 days, distant organ metastasis of cancer and gastrointestinal cancer are the independent risk factors for candidemia, which allow us to define patients at potential risk and perform prophylaxis therapies in short time. There are, however several limitations in the present study need be further studied. In this retrospective study, Candida index was not included, and causations of low number of patients with neutropenia were not been confirmed. Furthermore, all patients enrolled in a single center, the size and diversity of samples are limited. In future, prospective multi-center study with large sample size should be performed, which could provide more relevant epidemiology information.