Oral Candida Lesions and Candida tropicalis: Potential Prognostic Markers in End-of-Life Cancer Patients

doi:10.21203/rs.3.rs-2958693/v1

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Research Article

Oral Candida Lesions and Candida tropicalis: Potential Prognostic Markers in End-of-Life Cancer Patients

https://doi.org/10.21203/rs.3.rs-2958693/v1

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published 02 Jan, 2024

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Purpose.

To evaluate the distribution of oral candidosis lesions and Candida species as prognostic indicators in palliative care patients with end-of-life cancer.

Methods.

We consecutively included palliative care patients and diagnosed oral candidosis in them using microbiological techniques. Samples were collected from the buccal mucosa using cotton swabs and inoculated onto CHROMagar culture plates. The extent of oral lesions was classified using Kodsi's grade, ranging from no extent (no pseudomembrane) to grade 1 and ≥ grade 2. We assessed the association between oral candidosis and overall survival using multivariate Cox proportional hazards models adjusted for clinically relevant factors.

Results.

We included 142 patients (median age 77 years; 52.8% female), and the prevalence of oral candidosis was 76.1%. The most common Candida species identified was Candida albicans (C. albicans) (80.6%). Extensive oral candidosis lesions were classified as no extent, grade 1 (28.7%) or ≥ grade 2 (14.8%). During the observation period, multivariate Cox proportional hazards models revealed that the existence of oral lesions ≥ grade 2 (adjusted hazard ratio [aHR] = 2.04; 95% confidence interval [CI]:1.18–3.54; p = 0.011) and the presence of Candida tropicalis (C. tropicalis) (aHR = 2.38; 95% CI:1.03–5.55; p = 0.044) were predictive factors.

Conclusion.

The severity of oral candidosis lesions and presence of Candida species, particularly C. tropicalis, might be prognostic indicators in patients with end-of-life cancer. These findings may help deliver prognosis-based oral care to such patients, improving their quality of life and mortality.

oral candidosis

end-of life

prognosis

C. tropicalis

palliative care

Oral candidiasis is a frequently occurring opportunistic infection of the oral cavity, characterized by the formation of white plaques and erythematous lesions, associated with risk factors such as impaired salivary gland function, drug use, prosthesis, smoking, diabetes mellitus, malignant tumors, and immunosuppressive conditions. Although the term "oral candidosis" is commonly used to describe parasitic infections, "oral candidosis" is the preferred term in this context [1]. Although most cases of oral candidosis have a favorable prognosis, its prevalence among hospitalized patients with advanced cancer ranges from 13–34% [2], its presence at end-of-life may indicate a poor prognosis [3, 4]. However, due to research design limitations, the relationship between oral candidosis and prognosis is unclear. Candida infections have been linked to sepsis in HIV and intensive care unit (ICU) settings [5–9] and may be markers for predicting death. Nevertheless, the severity and prognosis of Candida lesions in patients with cancer, especially those caused by non-albicans species and overlapping fungal infections, have not been thoroughly explored. Therefore, this study aimed to repurpose the Candida classification system to examine whether the spread and species of oral Candida could be used as biomarkers for predicting the prognosis of terminally ill cancer patients with candidosis.

Study design and participants

This prospective observational study adhered to the STROBE guidelines [10] and was conducted at a single center in Japan. The participants were recruited from the Palliative Care Unit at National Hospital Organization Kyoto Medical Center between January 2017 and November 2018. Based on the inclusion criteria, a dentist who was part of the palliative care unit team evaluated the oral cavity weekly, regardless of the presence of oral problems. Consecutive palliative care inpatients with cancer were enrolled in this study. The study protocol was approved by the Institutional Review Board of the National Hospital Organization Kyoto Medical Center (Approval ID:16-076) and registered with the UMIN Clinical Trials Registry (UMIN 000026613).

Patients

The study enrolled consecutive patients who met the following inclusion criteria: 1) a diagnosis of advanced cancer, 2) admission as a palliative care inpatient, 3) age ≥ 20 years, and 4) ability to provide informed consent. Patients who were eating or drinking during the consultation, those who were not in the terminal stage and were hospitalized for pain control purposes, and those who were unable to provide consent were excluded. Patient data were collected from medical records, including patient characteristics, primary malignancy, medication use (steroids, antibiotics, and opioids), oral intake, oxygen administration, Eastern Cooperative Group Performance Status (ECOG PS), prior chemotherapy and radiation within the last four weeks, and use of antifungal medication in the past four weeks. Two individuals, including a pharmacist verified the drug information. Hormone therapies were not included as chemotherapy because they do not affect the oral mucosa. Poor dietary intake was defined as <30% of daily oral intake [11].

Oral examination

All patients underwent a bedside oral examination according to standard clinical practice with systematic registration of oral findings from 10:30 AM to noon by one dentist (author) who is a specialist in oral and maxillofacial surgery and oral care.

The diagnosis of oral candidosis was based on a combination of clinical features and microbiological investigation [12]. We judged by the extent of oral lesions and the presence or absence of Candida species in fungal cultures. Oral dryness was measured using an oral moisture-checking device (Mucus® approval number:22200BZX00640000; Life Co., Ltd., Saitama, Japan). The device measured oral dryness in the lingual and buccal mucosae, and the results were recorded as continuous variables [13].

Microbiological investigations

Oral swabs were obtained from the oral cavity's buccal mucosa membrane, and yeasts were isolated using CHROMagar™ Candida (KANTO KAGAKU, Tokyo, Japan) selective medium. The specimens were inoculated onto the CHROMagar™ Candida medium and incubated aerobically for 24-48 h at 25˚C. Candida species were identified based on colony morphology and color after incubation with CHROMagar™ for 48 h. According to the manufacturer's instructions, Candida albicans (C. albicans) colonies exhibit a distinct green color, C. glabrata colonies exhibit a purple to pale pink color, Candida tropicalis (C. tropicalis) colonies exhibit a dark blue color with pink edges, C. krusei colonies show coarse with a pale pink center and white edges, and C. parapsilosis colonies show white or pale pink color [14].

The focus of the examination was the clinical manifestation of fungal infection in the oral buccal mucosa, which was evaluated using Kodsi's grading system for oral candidosis [15]. The extent of oral lesions was classified based on Kodsi's grade, ranging from no extent (no pseudomembrane), grade 1 (few raised white plaques up to 2 mm in size), and ≥ Grade 2 (multiple raised white plaques greater than 2 mm in size but no ulceration, or confluent, linear, and nodular elevated plaques) (Fig 1.).

Sample size

To ensure an appropriate sample size for our external validation study, we estimated a minimum of 100 events based on the sample size guidelines provided for investigators in the study design [16].

Statistical analyses

Continuous variables were presented as mean ± standard deviation (SD) or median [25%, 75%], while categorical variables were expressed as absolute values and percentages. The data were analyzed using various statistical tests, including Student's t-test, Fisher's exact test, Cochran-Armitage test, and Jonckheere-Terpstra t-test. Overall survival was determined using Kaplan-Meier curves and a log-rank test with a cut-off point. Furthermore, we used a Cox proportional hazards model for multivariate analysis to examine the associations with oral candidosis after adjusting for confounding factors. Statistical significance was set at p < 0.05, and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), was used for all statistical analyses.

Table 1 presents the characteristics of the study participants. We enrolled 142 patients. One patient was excluded for pain relief purposes. The median age was 77 years, and 52.8% of participants were female. Gastrointestinal cancer accounted for 26.8% of the cancer sites, 26.8% of the participants had a performance status (PS) score of 4, and 59.9% used systemic steroids. In patients with oral candidosis lesions classified as ≥ grade 2, the prevalence of Candida albicans (C. albicans) was 100%, and C. glabrata was found in 18.8% of patients, often in combination with C. albicans. This study did not detect non-albicans in the oral cavities of patients with extensive, severe oral lesions. The presence of oral candida was not associated with age, PS ≥ 4, usage of systemic antibiotics or corticosteroids, chemotherapy or radiation therapy within four weeks, or the degree of oral moisture level. However, extensive oral cavity lesions were associated with poor oral intake, systemic corticosteroid use, and the presence of C. albicans of Candida species. (Table 2) Of the 108 patients with oral candidosis, C. albicans was found in 60.8% of cases, while non-C. albicans species were found in 18.5% of cases. The study also found that C. tropicalis was associated with a lower degree of oral mucosal moisture level. (Table 3)

Table 1

**Clinical characteristics of the participants with or without oral candidosis**
	Oral candidosis
	All	Negative culture	Positive culture	P value
	(N = 142)	(n = 34)	(n = 108)	P value
Systematic
Age, years	77 [68–84]	78.5 [72–85]	76 [67–83]	0.25
Sex, female	52.8	50.0	53.7	0.84
ECOG PS ≥ 4 ^a	26.8	26.5	26.9	> 0.99
Cancer primary location
Gastrointestinal	26.8	32.4	25.0	0.48
Lung	16.2	17.6	15.7
Head & neck	3.5	5.9	2.8
Others ^b	53.5	44.1	56.5
Poor dietary intake ^c	44.3	44.1	44.3	> 0.99
Enteral tube feeding	1.4	0.0	1.9	> 0.99
Oxygen administration use	21.1	20.6	21.3	> 0.99
Medications
Current
Systematic steroids	59.9	47.1	63.9	0.11
Inhaled steroids	2.1	0.0	2.8	> 0.99
Antibacterial drugs	16.2	23.5	13.9	0.19
Opioid	59.2	58.8	59.3	> 0.99
Prior
antifungals in the last 4 weeks	2.8	2.9	2.8	> 0.99
chemotherapy in the last 4 weeks	9.9	5.9	11.1	0.52
Radiation
Head and neck	3.5	5.9	2.8	0.59
Brain in the last 4 weeks	4.9	5.9	4.6	0.67
Oral
Degree of oral moisture
Buccal mucosa	28.9 [26.0-30.3]	29.1 [27.5–30.7]	28.7 [25.6–30.1]	0.14
Tongue	25.7 [15.5–28.6]	24.5 [8.0-28.6]	25.8 [16.8–28.6]	0.82
Candida species
C. albicans	61.3	-	80.6	NA
C. glabrata	21.8	-	28.7	NA
C. tropicalis	4.2	-	5.6	NA
C. krusei	2.8	-	3.7	NA
C. parapsilosis	2.1	-	2.8	NA
Median [25%, 75%] or %.
^a ECOG PS Eastern Cooperative Oncology Group Performance Status.
^b Others includes breast, gynecological, hematological, hepatic, biliary, pancreas, neurological and urological.
^c Poor dietary intake as defined < 30% of daily oral intake.

Table 2

**Baseline characteristics of participants categorized according to the extent of oral candida.**
	Classification
	No extent	Grade 1	≥ Grade2	P for trend/ P
	(n = 61)	(n = 31)	(n = 16)	P for trend/ P
Systematic
Age, years	80 [68–86]	77 [66-83.5]	72.5 [65–76]	0.07
Sex, female	52.5	51.6	62.5	0.38
ECOG PS ≥ 4 ^a	26.2	22.6	37.5	0.62
Cancer primary location
Gastrointestinal	26.2	12.9	43.8	0.21 ^d
Lung	18.0	16.1	6.2
Head & neck	4.9	0.0	0.0
Others ^b	50.8	71.0	50.0
Poor dietary intake ^c	48.3	26.7	62.5	0.87
Enteral tube feeding	1.6	3.2	0.0	0.90
Oxygen administration use	19.7	19.4	31.2	0.51
Medications
Current
Systematic steroids	54.1	71.0	87.5	0.01*
Inhaled steroids	2.2	0.0	1.0	0.31
Antibacterial drugs	14.8	9.7	18.8	0.84
Opioid	0.0	0.0	0.0
Prior
antifungals in the last 4 weeks	57.4	54.8	75.0	0.43
chemotherapy in the last 4 weeks	11.5	9.7	12.5	0.92
Radiation
Head and neck	4.9	3.2	0.0	0.57
Brain in the last 4 weeks	3.3	3.2	0.0	0.24
Oral
Degree of oral moisture
Buccal mucosa	29.0 [26.3–30.1]	28.7 [25.6–30.2]	26.3 [24.7–29.7]	0.16
Tongue	26.7 [18.6–28.8]	25.1 [8.7–28.8]	20.5 [5.2–26.1]	0.06
Candida species
C. albicans	70.5	90.3	100.0	< 0.01*
C. glabrata	34.4	22.6	18.8	0.18
C. tropicalis	4.9	9.7	0.0	0.82
C. krusei	3.3	6.5	0.0	0.85
C. parapsilosis	3.3	3.2	0.0	0.57
Median [25%, 75%] or %.
^a ECOG PS Eastern Cooperative Oncology Group Performance Status.
^b Others includes breast, gynecological, hematological, hepatic, biliary, pancreas, neurological and urological.
^c Poor dietary intake as defined < 30% of daily oral intake.
^d Fisher's exact test

Table 3

**Clinical characteristics of the participants according to the** Candida species
	C. albicans		C. glabrata		C. Tropicalis		C. krusei		C. parapsilosis
	negative	positive	negative	positive	negative	positive	negative	positive	negative	positive
	(n = 55)	(n = 87)	(n = 111)	(n = 31)	(n = 136)	(n = 6)	(n = 138)	(n = 4)	(n = 139)	(n = 3)
Systematic
Age, years	78 [69.5–84]	76 [67–84]	77 [68–84]	79 [68–86]	76.5 [68–84]	80.5 [79–83]	77 [68–84]	77 [76–77]	77 [68–84]	78 [64–86]
Sex, female	47.3	56.3	52.3	54.8	54.4	16.7	52.9	50.0	52.5	66.7
ECOG PS ≥ 4 ^a	25.5	27.6	25.2	32.3	25.7	50.0	26.8	25.0	26.6	33.3
Cancer primary location
Gastrointestinal	30.9	24.1	22.5	41.9	27.9	0.0	27.5	0.0	26.6	33.3
Lung	16.4	16.1	17.1	12.9	15.4	33.3	16.7	0.0	16.5	0.0
Head & neck	5.5	2.3	3.6	3.2	3.7	0.0	3.6	0.0	3.6	0.0
Others ^b	47.3	57.5	56.8	41.9	52.9	66.7	52.2	100.0	53.2	66.7
Poor dietary intake ^c	49.1	41.2	41.8	51.6	42.5	83.3	44.9	25.0	43.8	66.7
Enteral tube feeding	0.0	2.3	1.8	0.0	1.5	0.0	1.4	0.0	1.4	0.0
Oxygen administration use	23.6	19.5	20.5	22.6	20.6	33.3	21.7	0.0	20.9	33.3
Medications
Current
Systematic steroids	54.5	63.2	61.3	54.8	59.6	66.7	60.9	25.0	60.4	33.3
Inhaled steroids	1.8	2.3	0.9	6.5	2.2	0.0	2.2	0.0	2.2	0.0
Antibacterial drugs	18.2	14.9	17.1	12.9	16.2	16.7	16.7	0.0	15.8	33.3
Opioid	58.2	59.8	59.5	58.1	59.6	50.0	60.9	0.0*	59.0	66.7
Prior
antifungals in the last 4 weeks	3.6	2.3	2.7	3.2	3.0	0.0	2.9	0.0	2.9	0.0
chemotherapy in the last 4 weeks	9.1	10.3	11.7	3.2	10.3	0.0	8.7	50.0*	10.1	0.0
Radiation
Head and neck	5.5	2.3	3.6	3.2	2.9	16.7	2.9	25.0	3.6	0.0
Brain in the last 4 weeks	7.3	3.4	4.5	6.5	5.1	0.0	4.3	25.0	5.0	0.0
Oral
Degree of oral moisture
Buccal mucosa	29.1 [27.2–30.7]	28.6 [25.6–30.1]	28.9 [25.9–30.4]	28.6 [26.4–29.7]	29.0 [26.3–30.3]	23.5 [18.5–28.0]	28.9 [26.3–30.3]	24.6 [18.1–28.2]	28.9 [26.1–30.3]	27.8 [22.9–29.3]
Tongue	25.9 [11.0-28.4]	25.5 [17.3–28.7]	25.4 [13.8–28.7]	26.4 [17.7–28.5]	25.9 [17.4–28.7]	7.5 [0.5–15.5]*	25.7 [15.5–28.6]	25.7 [19.2–26.9]	25.6 [16.0-28.6]	28.2 [14.1–28.8]
Candida species
C. albicans	-	-	62.2	58.1	63.2*	16.7	61.6	50.0	61.2	66.7
C. glabrata	23.6	20.7	-	-	22.8	0.0	22.5	0.0	20.9	66.7
C. tropicalis	9.1*	1.1	5.4	0.0	-	-	3.6	25.0	4.3	0.0
C. krusei	3.6	2.3	3.6	0.0	2.2	16.7	-	-	2.9	0.0
C. parapsilosis	1.8	2.3	0.9	6.5	2.2	0.0	2.2	0.0	-	-
Median [25%, 75%] or %. * P < 0.05.
^a ECOG PS Eastern Cooperative Oncology Group Performance Status.
^b Others includes breast, gynecological, hematological, hepatic, biliary, pancreas, neurological and urological.
^c Poor dietary intake as defined < 30% of daily oral intake.

In addition, we found that patients with severe oral lesions caused by Candida species had a significantly shorter prognosis than those without severe oral lesions, with no difference in prognosis between patients with mild Candida and the no extent group. (Fig. 2, a, b) The study also found that patients detected with C. tropicalis had a significantly shorter prognosis. (Fig. 2, c) Logistical regression analysis showed that the extent of severe candida lesions and the presence of C. tropicalis were independent factors associated with decreased OS of palliative care patients. During the observation period (with a median of 23 days and interquartile range of 0-374 days), multivariate Cox proportional hazards models revealed that the existence of oral lesions of grade 2 or higher (adjusted hazard ratio [aHR] = 2.04; 95% confidence interval [CI]: 1.18–3.54; P = 0.011) and the presence of C. tropicalis (aHR = 2.38; 95% CI: 1.03–5.55; P = 0.044) were predictive factors.

This study presents a novel finding that a larger extent of oral candidosis lesions and the presence of Candida species, specifically C. tropicalis, may act as prognostic markers in patients with end-of-life cancer.

To the best of our knowledge, previous reports on the presence of Candida in patients with advanced cancer have been limited to clinical or microbiological assessments; the extent of Candida lesions has not been examined [3, 4, 11, 17–23]. Few studies suggested that oral Candida infection might indicate impending death based on clinical observations [3, 4]. Despite this, no prior study has established a clear association between oral Candida and prognosis in end-of-life cancer patients. The lack of evaluation of the spread of oral Candida may explain why early reports did not provide a definitive understanding of the relationship between the presence or absence of oral Candida and life prognosis.

Several factors, including systemic corticosteroids and poor oral intake, are significantly associated with the spread of Candida. Poor oral intake, which is an endpoint used in the palliative performance scale (PPS) and a factor associated with prognosis [24], may be related to reduced oral motility and self-cleaning, which may facilitate the growth of Candida, especially in the terminal stage when oral self-care is difficult due to decreased PS. The Candida species most commonly involved in the spread of oral Candida is C. albicans, which is generally thought to be associated with pseudomembranes [25, 26]. However, the presence of non-albicans Candida species cannot be ruled out, particularly if pseudomembranes are not formed, indicating that the prevalence of Candida may be underestimated.

In this study, the prevalence of oral Candida was 43.5% after a uniform buccal mucosa swab and culture using CHROMagar. This prevalence was higher than that reported in previous studies, such as the 13% prevalence in a United Kingdom (UK) study that used CHROMagar™ Candida with mouthwash or swabs in 390 patients attending hospice day care centers [4], the 30% prevalence in a UK study that used mouthwash or swabs and sub-low dextrose agar or CHROMagar in 120 palliative care patients [20], and the 34% prevalence in a Norwegian study that used swabs and sub-low dextrose agar in 126 patients admitted to palliative care wards [23]. Possible explanations for this disparity in prevalence rates could include differences in patient characteristics such as PS, ethnicity, healthcare setting (hospital or institution), the medium used for culturing, and collection method (mouthwash or swab).

Studies have reported a correlation between low ECOG PS and an increased prevalence of oral candidosis. In our study, 26.8% of the patients had PS4, whereas, in the study by Davies et al., only 1% of the patients had PS4 [20]. Since many of our patients had a poor general condition, PS may have played a role in the higher prevalence of candidosis observed in our study.

The fungal species that showed an independent association with the spread of oral Candida and its prognosis was C. tropicalis, which was not detected in many Candida cases (5.6%). Although there are no reports on the relationship between oral C. tropicalis infection and prognosis, studies on ICU and HIV patients have shown a link between C. tropicalis as a deep infection and high mortality rates [27]. The mechanisms by which C. tropicalis worsens prognosis include its adhesion behavior, biofilm formation, hemolytic activity, enzyme secretion, and seeding ability [28, 29]. Since this study did not investigate deep C. tropicalis infections, it is unclear whether local oral infections are related to prognosis.

Patients with C. tropicalis infection had significantly lower oral mucosal moisture levels. Although C. tropicalis is resistant to osmotic pressure and can survive at high salt concentrations (unlike other Candida species), this resistance might have contributed to its detection in patients with significantly dry mucous membranes in this study [30].

Strength and limitation

The strength of this study lies in the fact that a highly skilled dentist specialized in palliative oral care made the clinical diagnosis, samples were collected from a fixed site, and bacterial species were identified using Cromoger's medium. However, the study was limited by its single-center nature, small sample size, and limited scope. In addition, systemic candidemia could not be assessed because no blood tests were conducted, which is common in palliative care settings unless there is a compelling reason to do so. Medication history was analyzed for the previous four weeks, and any effects prior to that period were not evaluated.

Implication for practiceThe current study identified a predictive factor in terminally ill cancer patients, namely the visible severe extent of oral candida (OC), with the most frequent type being C. albicans; however, the mere presence of OC was not a significant indicator. In addition, our findings demonstrated that the presence of C. tropicalis was associated with the prognosis, irrespective of the presence of OC lesions. Therefore, palliative care professionals should be aware of the potential presence of C. tropicalis despite the absence of pseudomembranous oral candidosis (thrush).

Oral candidosis is prevalent in palliative care wards, particularly in patients with advanced cancer. The spread of Candida lesions and presence of C. tropicalis indicate poor prognoses. Regular re-evaluation of the replication and fungal species of oral candidosis is essential, as it may serve as an indicator of the patient's end-of-life phase.

Acknowledgments:

The authors would like to thank the palliative care doctors and all the nurses at the Unit of Palliative Care, Kyoto Medical Center.We would like to thank Editage (www.editage.com) for English language editing.

Funding: This study was supported by the Sasakawa Health Foundation of Japan.

Conflicts of interest/Competing interests: No competing financial interests exist.

Authors' contributions: MS designed the study, recruited and cared for the patients, and drafted and revised the manuscript. SK clinically advised patients and revised the manuscript. EY checked the medications. NS analyzed and supervised this study and revised the manuscript.

Ethics approval: The study protocol was approved by the Institutional Review Board of the National Hospital Organization Kyoto Medical Center (Approval ID:) and registered with the UMIN Clinical Trials Registry (UMIN 000026613).

Consent to participate: Informed consent was obtained from all participants included in the study.

Consent to publish: The patients signed an informed consent form for the publication of their data and photographs.

Availability of data and material: The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability: Not applicable

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Oral Candida Lesions and Candida tropicalis: Potential Prognostic Markers in End-of-Life Cancer Patients

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