Abstract
Objectives
Oral colonization of Candida could lead to later development of oropharyngeal candidiasis or candidemia among the immunocompromised patients. This study aims to describe the occurrence and risk factors of oral Candida colonization in patients with malignancies.
Materials and methods
From October 2012 to March 2013, 78 patients with pulmonary cancer (group I), 101 patients with gastrointestinal tract tumor (group II), 79 patients with hematopoietic system malignant tumor (group III), and 101 healthy controls were consecutively recruited in a hospital in Beijing, China. The oral rinse samples were taken and Candida species were identified; the enzymes activities were tested.
Results
In total, 110 and 27 Candida strains were isolated from 91 patients and 26 controls, respectively. The oral colonization rate with Candida albicans in group III (12.7 %) was significant lower than that in group I (30.8 %), group II (33.7 %), and control group (25.7 %). The oral colonization rates with non-albicans Candida species in group I, group II, and group III were 15.4, 10.9, and 12.7 %, respectively, while only one non-albicans Candida strain was identified in control group. The non-albicans Candida species exhibited a lower virulence than C. albicans. Age was an independent risk factor for Candida colonization in patients with pulmonary cancer and digestive tract malignant tumor, “Teeth brush <1 time/day” was an independent risk factor for Candida colonization in patients with hematopoietic system tumor.
Conclusions
The differences of risk factors for oral Candida colonization in patients with different cancers require different strategies for the prevention and control of Candida infection.
Clinical relevance
Old aged patients with pulmonary cancer and digestive tract malignant tumor are high-risk population for Candida colonization. Increasing frequency of teeth brush might be helpful for preventing Candida colonization.
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Introduction
In healthy human, Candida species present as part of normal microbial population in the oral cavity and gastrointestinal tract [1]. It has been reported that Candida could be isolated in the oral cavity of 15.2 to 75 % of healthy individuals [2, 3]. The difference in population characteristics, sampling approach, and geographic area might contribute to the diversity of detection rates [4–6]. When appropriate conditions such as local or systemic deficiencies in the host defenses exist, they multiply, even causing multiple infections [7]. The Candida infection in oral cavity is common in patients with prolonged, severe diseases, including diabetes mellitus (DM), solid organ transplant, AIDS, or undergoing antineoplastic chemotherapy [8–10]. It also happened when the diverse local factors made the buccal tissues susceptible to Candida infection, such as poor oral hygiene [11], reduced saliva flow [12], and prosthetic dentures use [13].
Oral colonization (up to 93 %) and infection (up to 30 %) occurred frequently in the radiotherapy patients [14]. The oral carriage rate of Candida in patients with advanced cancer is much higher [15, 16]. The direct factors leading to oral candidiasis seemed to be oral mucosal histological changes [17], together with salivary quantitative and qualitative changes, which were superimposed on other immunological deficiency. However, the underlying risk factors causing the oral Candida colonization and infection remain controversial.
Most Candida infections originate from endogenous host reservoirs, and the oral cavity and digestive tract are thought to be the principle source for hematogenous invasion, especially in critically ill patients. Invasive Candida infections are significantly higher in patients with prior yeast colonization compared to individuals with no evidence of colonization [18, 19]. Therefore, the increased oral fungal burden in cancer patients might play a potentially important role in the subsequent development of invasive infection and correlate with severe clinical complications.
Non-albicans Candida species played an increasingly important role in fungal infection. Many studies have shown that the prevalence of non-albicans Candida species increased significantly in uncontrolled AIDS [20], cancer [15], and critically ill patients [21]. However, to date, the study on the characterization of different oral Candida species colonized in patients with malignant tumor in China and their risk factors was rare. This study aimed to investigate the occurrence of oral Candida albicans and non-albicans Candida species colonization in several groups of cancer patients undergoing cytostatic therapy and healthy controls in China, and to determine the biological characteristics of these Candida species and analyze the risk factors for Candida colonization.
Materials and methods
Study population
This prospective observational study was conducted from October 2012 to March 2013 in a large tertiary hospital (The 307th Hospital of PLA) in Beijing. Seventy-eight patients suffering from pulmonary cancer (group I), 101 patients suffering from gastrointestinal tract malignant tumor (group II), and 79 patients suffering from hematopoietic system malignant tumor (group III) were consecutively recruited from the in-patient department of the Tumor Therapy Center of the hospital. One hundred and one healthy controls were recruited randomly from the Medical Examination Center of the hospital. All the participants in each group were informed about the purpose of this study and all signed informed consent to participate in the study. The participants with certain affirmed risk factors for oral candidosis such as uncontrolled diabetes, maxillofacial radiotherapy, and intraoral prostheses were excluded from the study. The unconscious patients and those with significant physical defects were also excluded as they could not cooperate. All the participants were given oral hygiene instructions and were investigated for complete haemogram and blood sugar level. Oral sample was taken after 1 h fasting. To prevent circadian variations, the samples were collected between 9 a.m. and 12 a.m. The study was approved by the Institutional Ethics Committee of Academy of Military Medical Sciences, Beijing, China.
Data collection
The information on population demographics, medication variables, and oral local factors were collected by two trained dentists. The demographic data included age, gender, body mass index (BMI), and smoking habits. Medication variables included hospital length of stay, underlying diseases, stay in bed, neutropenia, cycles of chemotherapy, corticoid therapy, invasive treatment, present of central venous line, radiation therapy of non-oral maxillofacial region, and use of antibacterial and antifungal drug. Oral local risk factors included periodontal health status, oral mucositis, frequency of teeth brushing, use of drug mouthwash, and xerostomia.
Oral examination, specimen collection and Candida identification
Before collecting the oral rinse sample, regular oral examination was performed by two dentists. The participants were checked according to the following items: number of cavity, oral hygiene evaluation, periodontal health condition, symptom of oral mucosa, the unstimulated saliva flow. Then the oral rinse sampling was taken as previously described [22]. Each participant was supplied with 10 ml sterile phosphate-buffered saline (0.1 M PBS, pH 7.2) in a universal container and to rinse the mouth for 60 s before expectorating the saliva-buffer mixture back into the container. The sample was sent immediately to the microbiology laboratory and was centrifuged at 1700×g for 10 min. The supernatant was discarded and the pellet was resuspended in 2 ml PBS on a vortex mixer for 30 s. A spiral plater (model DU; Spiral Systems) was used to dispense the precipitated sampling.
Fifty microliters of the suspension was separately inoculated onto CHROMagar-Candida (bioMérieux, Marcy L´Etoile, France) and Sabouraud-Dextrose Agar (bioMérieux, Marcy L´Etoile, France) for 72 h in 35 °C incubator. The growth of any Candida colonies was recorded and the subject was defined as a Candida carrier. The number of colonies on each plate was counted and the Candida colonization density was calculated based on the number of colony-forming units (CFU) per milliliter rinse sample. The “high load” Candida carrier referred to those with ≥500 CFU per ml of rinse sample, while the “low load” Candida carrier with <500 CFU per ml of rinse sample [23].
Initial identification of Candida species was based on colony color because the CHROMagar-Candida medium contains chromogenic substances that allow a presumptive identification of some species of Candida. Further identification of the yeast was done by API 20C AUX (bioMérieux, Marcy L´Etoile, France) according to the method of Williamson et al. [24] and the following polymerase chain reaction (PCR) assays.
Genotyping of C. albicans
The genotype of C. albicans was determined by PCR assays and distinguished from Candida dubliniensis. Cellular DNA was extracted according to previously described methods [25]. The fungus-specific, universal primers ITS1 (5′-TCCGTAGGTGAACCTGCGG-3′) and ITS2 (5′-GCTGCGTTCTTCATCGATGC-3′) were used to amplify a small conserved portion of the 18S rDNA region and a small portion of the 28S rDNA region, yielding products with variable sizes among the major species. C. albicans resulted in a 218- or 219-bp product.
Genotyping of C. albicans was conducted according to the previous study [26]. The expected PCR product spans the site of the transposable intron in the 25S rDNA. C. albicans resulted in products for C. albicans genotypes A (450 bp), B (840 bp), C (450 and 840 bp), D (1080 bp), and E (1400 bp). The genotype of D was proved to be C. dubliniensis [27].
Determination of virulence
The biological characteristics of the Candida were evaluated by detecting the virulence activities including phospholipase activity, proteinase activity, and hemolysin activity. The C. albicans were screened for the three extracellular enzymes’ activity by measuring the ratio of the diameter of the colony to that of the precipitation or clear zone on the various culture agars. The protocol referred to the previous studies [28, 29]. Each assay was conducted in duplicate for each yeast isolate. Reference strains of C. albicans (ATCC 10231) served as positive controls and C. parapsilosis (ATCC 22019) served as a negative control.
Antifungal susceptibility test
The susceptibility of all the Candida to five antifungal drugs including 5-flucytosine, amphotericin B, fluconazole, itraconazol, and voriconazol was conducted using the commercial Candifast kit (International Micobio, France) according to the manufacturer’s instructions. Minimum inhibitory concentrations (MICs) were determined and the following resistance breakpoints were used according to CLSI guidelines [30]: for fluconazole, resistant ≥64 μg/mL, susceptible-dose dependent (S-DD) 16–32 μg/mL, and susceptible ≤8 μg/mL; for 5-flucytosine, resistant ≥32 μg/mL, S-DD 8–16 μg/mL, susceptible ≤4 μg/mL; For itraconazol, resistant ≥1 μg/mL, S-DD 0.25–0.5 μg/mL, susceptible ≤0.0125 μg/mL; for voriconazol, resistant ≥4 μg/mL, S-DD 2–4 μg/mL, susceptible ≤1 μg/mL. There were no CLSI breakpoints defined for amphotericin B. For susceptibility to amphotericin B, the breakpoint established by Yang et al. [31] was adopted as follows: resistant ≥2 μg/mL, susceptible ≤1 μg/mL.
Statistical analysis
Categorical variables were evaluated using the chi-square and teo-tailed Fisher’s exact tests as appropriate. For continuous variables, the t test or nonparametric test was used. Univariate and multivariate logistic regression analyses were performed for the risk factor analyses. Variables that were found as significant (p < 0.05) in univariate analysis were considered as candidates for multivariate analysis. Odds ratio and 95 % confidence interval were calculated. All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS Inc., Version 16.0, Chicago, IL, USA). A p value of <0.05 was considered statistically significant. All tests of significance were two-tailed.
Results
Population characteristics and the occurrence of oral Candida colonization
The demographic characteristics of the patients and randomly selected healthy controls were shown in Table 1. The age of patients in group I (pulmonary cancer) and group II (digestive tract malignant tumor) was higher than those in group III (hematopoietic system tumor) and healthy controls. There were more male participants and a higher prevalence of smoking in healthy controls, which might be due to the differences in their lifestyle and health status.
In total, 110 and 27 Candida isolates were isolated from 91 patients and 26 controls, respectively. The most common Candida species was C. albicans, which was isolated from 26.4 and 25.7 % of oral rinse samples of the patients and controls, respectively (Table 2). The oral colonization rate with C. albicans in group III (12.7 %) was significantly lower than that in group I (30.8 %), group II (33.7 %) and control group (25.7 %). The oral colonization rates with “high load” C. albicans in group I (9.0 %) and group II (7.9 %) were significantly higher than that in group III (1.3 %) and control (1 %). Only one patient from group I had combined clinical and microbiological evidence of oral candidosis. The oral colonization rates with non-albicans Candida species in groups I, II, and III were 15.4, 10.9, and 12.7 %, respectively, which were all significantly higher than that in controls (1 %). There was one case with “high load” non-albicans Candida species in group I and one case in group II.
Sixty-eight isolates (61.8 %) were identified as C. albicans among the 110 Candida isolates from patient groups. The four most common non-albicans Candida species isolated from patient groups were C. parapsilosis (n = 17), Candida tropicalis (n = 5), Candida krusei (n = 5), and Candida glabrata (n = 3), respectively, which accounted for 15.4, 4.5, 4.5, and 2.7 % of all the Candida isolates from patient groups. Twelve Candida isolates could not be classified into any sub-species based on current phenotypic assay. Only one C. parapsilosis strain was isolated from the health control group (Table 3). Among the Candida-positive participants, the proportion of co-colonization by more than two species of Candida was 21.9 % (group I), 15.0 % (group II), 21.1 % (group III), and 3.8 % (control group), respectively (Supplemental Table S1).
The genotypes and virulence of C. albicans
The predominant genotype of C. albicans from both the patient groups and control group was type A, for which the prevalence are respectively 47.8 % (group I), 61.8 % (group II), 77.8 % (group III), and 46.2 % (control group). No significant difference was found over the distribution of three genotypes in C. albicans among different population groups (p = 0.572) (Fig. 1).
In general, C. albicans exhibited higher virulence than non-albicans Candida species (data not shown). The phospholipase activity, proteinase activity, and hemolytic activity of C. albicans isolated from controls were all higher than those from three patient groups (Table 4). There were no significant differences on the virulence activities of C. albicans of different genotypes (p > 0.05).
Antifungal susceptibility
All the 66 C. albicans isolates from patients and healthy controls were sensitive to amphotericin B. Two C. albicans isolates (3.0 %) from group II were resistant to fluconazole, itraconazole, and voriconazole. Dose-dependent susceptibility to 5-flucytosine was seen in three C. albicans isolated from patient groups. None of the non-albicans Candida species from the patient groups and control group were resistant to the five antifungal drugs tested.
Risk factors for oral Candida colonization
For patients of pulmonary cancer and digestive tract malignant tumor, univariate analysis showed that age and stay in bed were significantly associated with carriage of either all Candida species or C. albicans alone. Corticoid therapy also acted as a risk factor for carriage of Candida. Multivariate analysis showed that age was an independent risk factor for the carriage of either all Candida species or C. albicans alone. Corticoid therapy was another independent risk factor of oral Candida colonization (Supplemental Table S2). Due to the differences of patient characterizations, the risk factor analysis of oral Candida colonization in hematopoietic system tumor patients was conducted independently with other two patient groups. In hematopoietic system tumor patients, “Teeth brush <1 time/day” became an important risk factor for carriage of either all Candida species or C. albicans alone. However, no association was found between age of hematopoietic system tumor patients and carriage of either all Candida species or C. albicans alone (Supplemental Table S3).
The results of univariate and multivariate analyses showed that age and invasive treatment were significantly associated with carriage of “high load” C. albicans in pulmonary cancer and digestive tract malignant patients (Table 5). In hematopoietic system tumor patients, the cases of “high load” C. albicans carriage were too few to conduct risk factor analysis. As to the carriage of non-albicans Candida species, no significant risk factor was found in all the patient groups.
Discussion
To investigate the occurrence of oral yeast carriage and oral candidiasis, the oral rinse sampling method was used in this study, as it was the most appropriate and sensitive technique for evaluating the overall yeast carriage comparing to imprint culture, swab, or saliva sampling [32]. The results showed that C. albicans was isolated from the oral cavity of 26.4 % of patients with malignant tumor and 25.7 % of healthy controls, which were similar to previous studies in healthy individuals and DM patients, but a little lower than those with uncontrolled AIDS and advanced cancer [33]. However, the prevalence of high load C. albicans in patients (6.2 %) was higher than that in controls (1 %). Unexpectedly, the oral colonization rate with C. albicans was significantly lower in hematopoietic system tumor patients. The possible reason could be that these patients were all provided with chlorhexidine and alkaline mouthwash during hospitalization. The previous study has proved the effect of chlorhexidine in decreasing colonization of Candida [33].
Although C. albicans was the most frequent yeast in all study groups, there was a significant higher proportion of non-albicans Candida species in patient groups than control group, only one healthy control was colonized with non-albicans Candida species. This result was in accordance with previous studies, which showed that non-albicans Candida species have been detected more frequently, especially in immunosuppressed individuals [34, 35]. This finding may be indicative of the possibility that several non-albicans Candida species, which are normally more vulnerable to host immunity, are allowed to thrive in the immunosuppressed host environment. The altered proportion of C. albicans and non-albicans Candida species suggested the changing epidemiology of Candida species. The main explanation for this phenomenon was supposed to be the selective pressure of long-term use of antifungal drugs [36]. It was reported that non-albicans Candida species exhibited a higher resistance rate to certain antifungal drugs [37]. However, antifungal drug resistance was rare in our study, especially in non-albicans Candida species.
Extracellular enzymes such as phospholipases, aspartyl proteinases, and hemolysin are important virulence factors contributing to the pathogenesis of Candida [38, 39]. Our study showed that the three enzymes exhibited a higher activity in C. albicans than in non-albicans Candida species for all patient groups and control group, and the C. albicans from all patients group also exhibited a higher activity of these extracellular enzymes than those from control group. Previous studies also found that the activities of proteinases and phospholipases were high in C. albicans, while non-albicans Candida species usually presented low activities of these enzymes [40]. The results suggested that the level of extracellular enzymes might be less important for successful colonization and infection of C. albicans in cancer patients although the reasons were as yet unknown. We supposed that the factors associated with colonization and infection of the Candida in oral cavity might lie in local or system performance of individual. It could also be the reason for why patients with hematopoietic system tumor were colonized with a high prevalence of non-albicans Candida species, which were seldom found in healthy controls. This finding was confirmed by Krcmery et al., who found invasive C. glabrata infection presented a higher mortality and occurred predominantly in the most critically ill patients, although C. glabrata exhibited a low enzymatic activity and virulence in animal models of infection comparing to other non-albicans Candida species [35].
The risk factors for oral Candida colonization and infection in immunosuppressed patients were complex [41], including local oral factors, such as low salivary flow rates and pH, smoking, wearing dentures, and poor oral hygiene [42, 43], and other systemic factors such as patient age, disease types, treatment methods, and the physical performance of patients [44, 45]. We found the colonization of Candida in patients with pulmonary cancer and digestive tract malignant tumor was significantly associated with age, which was the same as previous report [46]. Although neutropenia is a common pre-disposing factor [28, 47], oral Candida carriage rate and density were not associated significantly with neutropenia in this study. The reason could be that few patients suffered from prolonged severe neutropenia in this study, as it had been demonstrated that fungal colonization and infection occurred more often in patients with prolonged neutropenia, especially in patients with prolonged, severe neutropenic episodes with extreme age [48, 49].
It was still controversary whether the use of antimicrobial drugs contribute to the oral colonization and infection of Candida in the previous studies. We also found no significant relationship between them; however, systematic use of corticosteroids contributed to some cases of oral Candida colonization. The possible mechanism might be that the systematic application of corticosteroids suppresses the immune system, which results in the proliferation of yeasts. Moreover, it had been reported that the routine prophylactic use of antifungal agents in transplant patients with high levels of oral Candida colonization was probably inappropriate, unless oral infection is present [50]. In our study, the prophylactic use of antifungal agents in oral cavity was rare, which might be the reason for the low prevalence of antifungal resistance. In addition, genotype A was prominent in C. albicans from all groups, followed by genotypes B and C, which is in accordance with other studies [51, 52]. No relationship was found between the genotypes and antifungal resistance.
In hematopoietic system tumor patients, teeth brush <1 time/day was associated with oral Candida colonization. For these patients with hematologic diseases, mouth washing was usually performed instead of brushing teeth. The bacteria plaque on the surface of teeth and mucosa would make Candida more prior to adhere. We have also found that invasive treatment might contribute to high load of C. albicans in patients with pulmonary and digestive tract malignant cancer. But the reason was not clear. To date, no similar results were reported for these groups of patients because there were only a small number of patients in each group. Future studies were needed for further investigation.
In conclusion, we demonstrated firstly the higher density of carriage and the virulence of oral Candida in patients with malignant tumor in Chinese hospitals. The diversity of occurrence and risk factors of oral Candida colonization required different strategies for the prevention and control of Candida infection in patients with different cancers.
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Acknowledgments
We thank the staff in Department of the Tumor Therapy Center and Medical Examination Center, The 307th Hospital of PLA, for their help and assistance in recruiting participants and collecting samples. The study was supported by a grant from Beijing Natural Science Foundation, China (No. 7122133), a grant from National “973” Program (No. 2013CB531606), and the National Natural Scientific foundation of China (No. 81102168).
Author contribution
Li Han and Cheng Ge designed the study. Haiyan Sun, Huan Li, and Xuan Zou performed the study. Xiuyun Yin, Haifeng Qin, Rongrui Liu, Changlin Yu, Qihong Li, Kaitao Yu, and Xuelin Han participated in collecting the clinical samples and medical information. Yong Chen and Huan Li collected the data and carried out the statistical analyses. Haiyan Sun and Yong Chen wrote the paper; Jingcai Zou took in charge of reviewing and editing the research manuscript. All of the authors read and approved the final manuscript.
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The authors have no conflicts of interest to declare.
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Haiyan Sun, Yong Chen and Xuan Zou contributed equally to this work.
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Sun, H., Chen, Y., Zou, X. et al. Occurrence of oral Candida colonization and its risk factors among patients with malignancies in China. Clin Oral Invest 20, 459–467 (2016). https://doi.org/10.1007/s00784-015-1524-2
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DOI: https://doi.org/10.1007/s00784-015-1524-2