Abstract
Background:
With the emergence and spread of coronavirus disease 2019 (COVID-19) globally, health care systems have faced the biggest challenge in recent decades.Objectives:
The present study aimed to identify risk factors associated with oropharyngeal candidiasis (OPC) in COVID-19 patients.Methods:
The total number of confirmed COVID-19 patients was 218 (105 cases with OPC and 113 controls without OPC). The questionnaire used in this study consisted of demographic data, treatment strategy, clinical and laboratory data, and underlying diseases collected from the onset of clinical OPC until the end of hospitalization.Results:
Pseudomembranous candidiasis (77/105, 73.3%) was the most prevalent form of OPC in case patients. The majority of the cases (58.1%) and controls (58.4%) were males. Increasing age (P = 0.03) and hospitalization length (P = 0.016) were significantly associated with OPC in COVID-19 patients. Diabetes (P = 0.003), solid tumor (P = 0.019), and hypertension (P = 0.000) were the most common underlying conditions. The use of dentures (P = 0.003) and poor oral hygiene (P = 0.000) were related to OPC in the case group. Therapy with chloroquine (P = 0.012), IVIG (P = 0.001), diuretics (P = 0.000), and corticosteroid pulse therapy (P = 0.000) were significantly associated with developing OPC in case patients.Conclusions:
Old age, hospitalization length, poor oral hygiene, corticosteroids use, diabetes, solid tumor, and hypertension may predispose COVID-19 patients to develop OPC.Keywords
1. Background
With the emergence and spread of coronavirus disease 2019 (COVID-19) globally, health care systems have faced the biggest challenge in recent decades (1). When we wrote this article, the prevalence of COVID-19 infection was still increasing worldwide. Bacterial or fungal co-infections in COVID-19 patients have been reported around the world. However, risk factors associated with the development of these infections have been poorly studied (2). Most published studies on fungal infections in COVID-19 are related to invasive pulmonary aspergillosis (3-8). Like influenza patients, acute respiratory distress syndrome (ARDS) is a risk factor for the development of Aspergillus infections in hospitalized COVID-19 patients (3). The disease severity, the lack of treatment, use of corticosteroid therapy, and intubation of critical patients are considered risk factors for oropharyngeal candidiasis (OPC) in COVID-19 patients (9). Besides, OPC is the most common opportunistic infection in HIV patients (10). Oral candidiasis has several risk factors in HIV patients, including age, sex, xerostomia, antibiotic usage, alcohol consumption, smoking, CD4 counts, and advanced HIV clinical stage (AIDS) (11). However, Candida spp. as fungal pathogens have been poorly investigated in COVID-19 patients. As known, OPC caused by fluconazole-resistance Candida species can spread systematically in immunocompromised patients through the bloodstream or upper gastrointestinal tract, leading to candidemia with significant morbidity and mortality (12). However, risk factors associated with OPC in COVID-19 patients have not yet been precisely investigated.
2. Objectives
The present study aimed to identify risk factors of OPC in COVID-19 patients in a multi-center evaluation in Tehran, Iran.
3. Methods
3.1. Study Design and Participants
A prospective case-control study was conducted in five COVID-19 clinical centers in Tehran, Iran, between June 1, 2020, and July 1, 2020. In this study, 218 COVID-19 patients were divided into two groups (105 participants as cases and 113 participants as controls). All patients had laboratory-confirmed COVID-19 infection with positive SARS-CoV-2 RT-PCR from nasopharyngeal swabs or respiratory secretions and were hospitalized at Imam Khomeini Hospital Complex, Ziaeian hospital, Valiasr hospital, Labbafinezhad hospital, Emam Ali hospital, and Loghman Hakim hospital. Inclusion criteria were hospitalized adult COVID-19 patients with OPC diagnosed based on clinical presentations and laboratory features. Sampling was done from individual lesions using sterile swabs. The diagnosis was confirmed by the presence of budding yeast and pseudohyphae in KOH 10% preparation and culture. The swabs were streaked on Sabouraud dextrose agar (Difco Laboratories, Detroit, Mich) plates on the bedside. Plates were incubated at 37°C for 48 h and checked morphologically. After identifying Candida species, the isolates were confirmed based on a three-step 21-plex PCR method. Also, the control group was selected randomly from adult COVID-19 patients who had no evidence of OPC during hospitalization. The forms were completed at the time of discharge or death.
3.2. Variables and Data Sources
The questionnaire used in this study consisted of demographic data, treatment strategy, clinical and laboratory features, and underlying diseases. After a questionnaire was completed, it was checked by the expert team to verify the data. The COVID-19 cases that complained of oropharyngeal symptoms were examined, and the patients with a clinically confirmed diagnosis of OPC were included in the case group. Those without clinical features and complaints of OPC on admission were included as the control group. Levels of oxygen support were categorized as a nasal cannula, simple mask, non-invasive ventilation (NIV), mechanical ventilation (MV), or none. Lung involvement in chest CT was identified as less than 25%, 25 - 50%, 50 - 75%, or more than 75%. The variables obtained from the case and control groups were age, sex, hospitalization duration, past medical history, underlying diseases, COVID-19 clinical manifestations, pulmonary involvement, preliminary laboratory tests on admission, type of oxygen support, presence of oral lesions, time of presentation, and recovery period (poor oral hygiene determined by tooth decays, periodontal tissue inflammation, secretion, bleeding or swollen gums, and loose teeth), COVID-19 treatment strategy (pulse therapy methylprednisolone ≥ 250 mg daily, corticosteroids other than pulse: dexamethasone 4 - 8 mg/daily, prednisolone 1 mg /daily/PO, and/or methylprednisolone < 250 mg/daily), antifungal therapy, and four weeks’ outcome.
3.3. Statistical Analysis
All data were analyzed using SPSS 19 (SPSS Iberica, Madrid, Spain). Descriptive analysis was used for demographic and clinical characteristics. Clinical and laboratory data were compared between the case and control groups. Bivariate analysis was performed on all study variables using the Chi-square test. A P value of less than 0.05 was considered significant.
3.4. Ethical Clearance
The study protocol was in line with the principles of the Helsinki Declaration and was approved by the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.VCR.REC.1399.058). Written informed consent was obtained from all participants.
4. Results
4.1. Characteristics of Patients
A total of 218 COVID-19 patients were included in this study (Imam Khomeini Hospital Complex n = 108 (49.5%; 53 cases and 55 controls), Ziaeian hospital n = 38 (17.4%; 15 cases and 23 controls), Imam Ali hospital n = 23 (10.6%; eight cases and 15 controls), Labbafinezhad hospital n = 9 (4.1%; four cases and five controls), Valiasr hospital n = 10 (4.6%; nine cases and one control), and Loghman Hakim hospital n = 30 (13.8%; 16 cases and 14 controls). The majority of the cases (58.1%) and controls (58.4%) were males. Furthermore, the mean age in the case and control groups was 61.17 ± 14.8 and 55.13 ± 15.1, respectively (P = 0.967). Pseudomembranous candidiasis (77/105, 73.3%) was the most prevalent form of OPC, followed by erythematous candidiasis (22/105, 21%), angular cheilitis (10/105, 9.5%), hyperplastic candidiasis (9/105, 8.6%), median rhomboid glossitis (10/105, 9.5%), denture stomatitis (1/105, 1%), chips in tongue (34/105, 32.4%), and glossitis (29/105, 27.6%).
4.2. Risk Factors Associated with Oral Pharyngeal Candidiasis in COVID-19
The analysis of variables showed several risk factors statistically significantly associated with OPC in COVID-19 patients (Table 1). Increasing age (P = 0.03), the length of hospitalization (P = 0.016), lung involvement level in chest CT scan (P = 0.001), and diabetes (P = 0.003) were significantly associated with OPC in COVID-19 patients. Medications significantly associated with OPC were chloroquine (P = 0.012), IVIG (P = 0.001), diuretics (P = 0.000), and corticosteroid pulse therapy (P = 0.000). The type of oxygen support was also associated with OPC (P = 0.041). Furthermore, dentures (P = 0.003) and poor oral hygiene (P = 0.000) were related to OPC in the case group (Table 2).
Characteristics, Underlying Diseases, and Risk Factors in COVID-19 Patients with and Without Oral Candidiasis a
| Variables | Cases (n = 105) | Controls (n = 113) | P Value |
|---|---|---|---|
| Age (Mean ± SD) | 61.2 ± 4.8 | 55.1 ± 5.1 | 0.003 b |
| Sex | 0.967 | ||
| Male | 61 (58.1) | 66 (58.4) | |
| Female | 43 (41) | 46 (40.7) | |
| Hospital ward | 0.343 | ||
| ICU | 16 (15.2) | 14 (12.4) | |
| Non-ICU | 89 (84.8) | 99 (87.6) | |
| Length of hospitalization (days) | 0 - 9.2 | 0 - 7.7 | 0.016 b |
| Underlying disease | |||
| Lung disease | 11 (10.5) | 7 (6.2) | 0.251 |
| Cardiovascular disease | 24 (22.9) | 16 (14.2) | 0.097 |
| Diabetes | 49 (44.8) | 27 (25.7) | 0.003 b |
| Liver cirrhosis | 1 (1) | 1 (0.9) | 0.958 |
| Chronic kidney disease | 5 (4.8) | 6 (5.3) | 0.854 |
| Sepsis | 0 (0) | 1 (0.9) | 0.334 |
| Hematological malignancy c | 2 (1.9) | 2 (1.8) | 0.941 |
| Solid tumor d | 5 (4.8) | 0 (0) | 0.019 b |
| Organ transplant | 3 (2.9) | 1 (0.9) | 0.278 |
| HIV | 0 (0) | 1 (0.9) | 0.334 |
| Hypertension | 48 (45.7) | 26 (23) | 0.000b |
| Hypothyroidism | 3 (2.9) | 6 (5.3) | 0.363 |
| Risk factors | |||
| Central venous catheter | 2 (1.9) | 0 (0) | 0.141 |
| Smoking | 11 (10.5) | 12 (10.6) | 0.973 |
| Antibiotics | 23 (21.9) | 26 (23) | 0.845 |
| Dentures | 25 (23.8) | 10 (8.8) | 0.003 b |
| Poor oral hygiene | 30 (28.6) | 10 (8.8) | 0.000 b |
| Hemodialysis | 1 (1) | 1 (0.9) | 0.958 |
| Foley catheter | 28 (26.7) | 18 (15.9) | 0.052 |
| Mechanical ventilation | 4 (3.8) | 0 (0) | 0.036 b |
| Endotracheal tube | 3 (2.8) | 0 (0) | 0.041 b |
| Corticosteroids | 18 (17.1) | 11 (9.7) | 0.019 b |
| COVID-19 clinical signs | |||
| Fever | 75 (71.4) | 62 (54.9) | 0.011 b |
| Cough | 76 (72.4) | 67 (59.3) | 0.042 b |
| Dyspnea | 82 (78.1) | 80 (70.8) | 0.218 |
| Diarrhea | 12 (11.4) | 19 (16.8) | 0.255 |
| Myalgia | 65 (61.9) | 66 (58.4) | 0.598 |
| Headache | 20 (19) | 25 (22.1) | 0.575 |
| Skin lesions | 1 (1) | 0 (0) | 0.298 |
| Nausea | 17 (16.2) | 25 (22.1) | 0.267 |
Laboratory and Clinical Data in COVID-19 Patients with and Without Oral Candidiasis by Bivariate Analysis a
| Variables | Cases (n = 105) | Controls (n = 113) | P Value |
|---|---|---|---|
| Laboratory results at baseline | |||
| WBC | 10493.9 | 9055.4 | 0.494 |
| Lymphocyte count | 879.1 | 1091.7 | 0.274 |
| HB | 13.2 | 14.5 | 0.374 |
| PLT | 226058.2 | 225657.6 | 0.975 |
| ESR | 65.3 | 63.5 | 0.200 |
| CRP | 54.9 | 58.4 | 0.440 |
| Ferritin | 1107.4 | 572.4 | 0.188 |
| D-Dimer | 559.1 | 400.4 | 0.311 |
| Cr | 1.3 | 1.3 | 0.970 |
| Type of O2 received | 0.041 b | ||
| Mask | 79 (75.2) | 71 (62.8) | |
| Nasal | 14 (13.3) | 24 (21.2) | |
| NIIV | 4 (3.8) | 2 (1.8) | |
| Intubation | 2 (1.9) | 0 (0) | |
| Non | 6 (5.7) | 16 (14.2) | |
| Medication | |||
| Chloroquine | 75 (71.4) | 62 (54.9) | 0.012 b |
| Naproxen | 13 (12.4) | 14 (12.4) | 0.998 |
| Acetaminophen | 14 (13.3) | 21 (18.6) | 0.291 |
| Kaletra | 27 (25.7) | 29 (25.7) | 0.993 |
| Interferon | 63 (60) | 56 (49.6) | 0.122 |
| IVIG | 12 (11.4) | 1 (0.9) | 0.001 b |
| Atazanavir | 63 (60) | 61 (54) | 0.370 |
| Antibiotics | 44 (41.9) | 38 (33.6) | 0.208 |
| Vitamin C | 14 (13.3) | 10 (8.8) | 0.291 |
| Benzodiazepine | 0 (0) | 1 (0.9) | 0.334 |
| Diuretic | 22 (21) | 2 (1.8) | 0.000 b |
| Corticosteroids | 50 (47.6) | 56 (49.6) | 0.775 |
| Corticosteroid pulse therapy | 45 (42.9) | 13 (11.5) | 0.000 b |
| Clinical signs at baseline | |||
| SO2 | 85.16 | 87.26 | 0.019 b |
| RR | 26.10 | 21.81 | 0.039 b |
| PR | 87.37 | 88.38 | 0.716 |
| BP/S | 126.32 | 125.89 | 0.878 |
| BP/D | 73.33 | 75.70 | 0.154 |
| Temperature | 37.38 | 37.12 | 0.185 |
| Outcome after 2 weeks | 0.004b | ||
| Discharge from the hospital | 60 (57.1) | 62 (54.9) | |
| Hospitalized in the ward | 34 (32.3) | 49 (43.3) | |
| Expired | 11 (10.5) | 2 (1.8) | |
| Chest CT | 0.001 b | ||
| Less than 25% | 12 (11.4) | 17 (15) | |
| 25 - 50% | 30 (28.6) | 54 (47.8) | |
| 50 - 75% | 40 (38.1) | 36 (31.9) | |
| More than 75% | 23 (21.9) | 6 (5.3) |
4.3. Treatment and Outcome of Oral Candidiasis
Fluconazole (86 patients, 81.9%) and nystatin (40 patients, 38.1%) were considered the antifungal drugs of choice for OPC treatment. In 71 (67.6%) cases, oral lesions were utterly recovered and not recovered in 34 (32.4%) cases at discharge.
5. Discussion
A significant percentage of patients with severe COVID-19 are susceptible to fungal infections such as OPC (1). The treatment of COVID-19 patients with secondary fungal infections is complicated (9). Besides, OPC develops when local host defense is weakened, permitting the fungus to invade and damage oral epithelial cells, such as in HIV-positive patients with several risk factors (13).
Our previous study revealed that several underlying diseases such as cardiovascular and diabetes were more frequent in COVID-19 patients with OPC (9). Therefore, in the present study, we conducted a comparative case-control study for finding risk factors associated with OPC in COVID-19 patients. Numerous factors were analyzed in both case and control groups. We found that several factors were significantly associated with OPC in COVID-19 patients. The age (61.17 ± 14.8 vs. 55.13 ± 15.1, P = 0.03) was a statistically significant risk factor when comparing the case and control groups. A significant reduction in innate salivary defense occurs with aging (14), and several studies showed a relationship between age and OPC in HIV patients (11, 15-17). The length of hospitalization (9.2 days) in the case group had a significant association with OPC in COVID-19 participants (P = 0.016). Patients with a more extended hospital stay may have a higher risk of OPC as they receive more antibiotics and corticosteroids.
The study by Salehi et al. reported that OPC occurs in COVID-19 patients more frequently among cases with eight days’ hospitalization on average (9). In the present study, among the risk factors investigated, dentures (P = 0.003), poor oral hygiene (P = 0.000), and MV (P = 0.036) were statistically significantly related to OPC. Dentures can act as a suitable microenvironment for adherence and overgrowth of the Candida yeast in the mouth, leading to oral candidiasis (18). Endotracheal intubation and MV can cause several complications, such as bacterial and fungal infections (19). Intubation impairs the host's natural defense against infections, and Candida yeast and bacteria can produce biofilms that adhere to the plastic tube (20).
Our findings showed that poor oral hygiene was a risk factor of OPC, in line with previous study (21). Brushing the mouth is essential for cleaning the teeth, dentures, buccal cavity, and tongue. Dentures should be cleaned and left out overnight for at least six hours daily (22). These health measures may be recommended for high-risk COVID-19 patients. In the present study, the lymphocyte count was associated with OPC in COVID-19 patients, and the case group had a lower average lymphocyte count (879.10 cells/mm3) than the control group (1091.73 cells/mm3). A previous study (9) reported lymphopenia in 71.7% of COVID-19 patients with a median lymphocyte count of 1000 cells/mm. A low CD4+ T-lymphocyte count is considered the most important risk factor for developing oral candidiasis in HIV patients (11, 16, 21). We recorded all underlying diseases in both groups. Among them, diabetes (P = 0.003), non-hematological malignancy (P = 0.019), and hypertension (P = 0.000) were statistically significantly associated with OPC in COVID-19 participants. Diabetes decreases the function of the cellular immune system, and these patients are susceptible to opportunistic fungal infections, such as OPC (23).
The finding of a single study performed on the prevalence of OPC in COVID-19 patients showed that diabetes (37.7%) was the major underlying condition (9). Several studies showed that oral candidiasis is a common infection in cancer patients (24-26). This is confirmed by our results in which non-hematological malignancy (P = 0.019) was associated with OPC in COVID-19 patients. Interestingly, hypertension (P = 0.000) had a significant association with OPC in COVID-19 participants in our study. Antihypertensive drugs often cause side effects, such as xerostomia, which is a risk factor for OPC (11, 27). Among medications used for treatment of COVID-19 participants, chloroquine (P = 0.012), IVIG (P = 0.001), diuretic (P = 0.000), and corticosteroid pulse therapy (P = 0.000) were significantly associated with OPC. The use of diuretics can lead to salivary gland hypofunction and xerostomia (11, 28). An increased incidence of oral candidiasis following corticosteroids use has been shown in several studies (29, 30). Some studies showed that chloroquine and IVIG had an antifungal effect on Candida spp. However, in the present study, both factors were significantly associated with OPC in COVID-19 participants (31, 32). Fever (P = 0.011) and tachypnea respiratory rate (P = 0.039) were the most important clinical symptoms associated with OPC. The possible reasons for the high rate of OPC associated with fever and tachypnea can be attributed to dehydration caused by fever and a dry mouth due to the high respiratory rate (19). The main limitations of our study were the lack of mycological examinations, Candida species identification, and their antibiotic susceptibility.
In conclusion, it is reasonable to consider that old age, hospitalization length, poor oral hygiene, corticosteroids use, diabetes, solid tumor, and hypertension may predispose COVID-19 patients to develop OPC. There is a need to strengthen the diagnosis and use effective antifungal and prophylaxis treatment strategies in COVID-19 patients. We concluded that many risk factors and medications could affect the development of OPC in COVID-19 patients. Practical strategies for antifungal prophylaxis may help prevent OPC in high-risk COVID-19 patients.
References
-
1.
Phelan AL, Katz R, Gostin LO. The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health Governance. JAMA. 2020;323(8):709-10. [PubMed ID: 31999307]. https://doi.org/10.1001/jama.2020.1097.
-
2.
Zhou P, Liu Z, Chen Y, Xiao Y, Huang X, Fan XG. Bacterial and fungal infections in COVID-19 patients: A matter of concern. Infect Control Hosp Epidemiol. 2020;41(9):1124-5. [PubMed ID: 32317036]. [PubMed Central ID: PMC7184139]. https://doi.org/10.1017/ice.2020.156.
-
3.
Verweij PE, Gangneux JP, Bassetti M, Bruggemann RJM, Cornely OA, Koehler P, et al. Diagnosing COVID-19-associated pulmonary aspergillosis. Lancet Microbe. 2020;1(2):e53-5. [PubMed ID: 32835328]. [PubMed Central ID: PMC7211496]. https://doi.org/10.1016/S2666-5247(20)30027-6.
-
4.
Alanio A, Dellière S, Fodil S, Bretagne S, Mégarbane B. High prevalence of putative invasive pulmonary aspergillosis in critically ill COVID-19 patients. medRxiv. 2020. https://doi.org/10.1101/2020.04.21.20064915.
-
5.
Koehler P, Cornely OA, Bottiger BW, Dusse F, Eichenauer DA, Fuchs F, et al. COVID-19 associated pulmonary aspergillosis. Mycoses. 2020;63(6):528-34. [PubMed ID: 32339350]. [PubMed Central ID: PMC7267243]. https://doi.org/10.1111/myc.13096.
-
6.
Arastehfar A, Carvalho A, van de Veerdonk FL, Jenks JD, Koehler P, Krause R, et al. COVID-19 Associated Pulmonary Aspergillosis (CAPA)-From Immunology to Treatment. J Fungi (Basel). 2020;6(2). [PubMed ID: 32599813]. [PubMed Central ID: PMC7346000]. https://doi.org/10.3390/jof6020091.
-
7.
Van Arkel AL, Rijpstra TA, Belderbos HN, Van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19 Associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020;202:132-5. [PubMed ID: 32396381]. [PubMed Central ID: PMC7328331]. https://doi.org/10.1164/rccm.202004-1038LE.
-
8.
Schauwvlieghe A, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6(10):782-92. [PubMed ID: 30076119]. https://doi.org/10.1016/S2213-2600(18)30274-1.
-
9.
Salehi M, Ahmadikia K, Mahmoudi S, Kalantari S, Jamalimoghadamsiahkali S, Izadi A, et al. Oropharyngeal candidiasis in hospitalised COVID-19 patients from Iran: Species identification and antifungal susceptibility pattern. Mycoses. 2020;63(8):771-8. [PubMed ID: 32609906]. [PubMed Central ID: PMC7361944]. https://doi.org/10.1111/myc.13137.
-
10.
Bonafe SM, Caceres NA, Vieira MMC, Vieira IF, Monteleone VF, Neto LJM. Opportunistic Infection in AIDS Patient. iMedPub Journals. 2015;7(5):10.
-
11.
Suryana K, Suharsono H, Antara I. Factors Associated with Oral Candidiasis in People Living with HIV/AIDS: A Case Control Study. HIV AIDS (Auckl). 2020;12:33-9. [PubMed ID: 32021484]. [PubMed Central ID: PMC6969700]. https://doi.org/10.2147/HIV.S236304.
-
12.
Laudenbach JM, Epstein JB. Treatment strategies for oropharyngeal candidiasis. Expert Opin Pharmacother. 2009;10(9):1413-21. [PubMed ID: 19505211]. https://doi.org/10.1517/14656560902952854.
-
13.
Saravani S, Nosratzehi T, Mir S. Oral manifestations and related factors of HIV positive patients in south-east of Iran. J Dent Mater Tech. 2017;6(1):11-8. https://doi.org/10.22038/jdmt.2016.7871.
-
14.
Gasparoto TH, de Oliveira CE, Vieira NA, Porto VC, Gasparoto CT, Campanelli AP, et al. The pattern recognition receptors expressed on neutrophils and the associated cytokine profile from different aged patients with Candida-related denture stomatitis. Exp Gerontol. 2012;47(9):741-8. [PubMed ID: 22796226]. https://doi.org/10.1016/j.exger.2012.07.003.
-
15.
Takahashi Y, Nagata N, Shimbo T, Nishijima T, Watanabe K, Aoki T, et al. Long-Term Trends in Esophageal Candidiasis Prevalence and Associated Risk Factors with or without HIV Infection: Lessons from an Endoscopic Study of 80,219 Patients. PLoS One. 2015;10(7). e0133589. [PubMed ID: 26208220]. [PubMed Central ID: PMC4514810]. https://doi.org/10.1371/journal.pone.0133589.
-
16.
Goulart LS, Souza WWR, Vieira CA, Lima JS, Olinda RA, Araujo C. Oral colonization by Candida species in HIV-positive patients: association and antifungal susceptibility study. Einstein (Sao Paulo). 2018;16(3):eAO4224. [PubMed ID: 30088546]. [PubMed Central ID: PMC6080703]. https://doi.org/10.1590/S1679-45082018AO4224.
-
17.
Owotade FJ, Patel M, Ralephenya T, Vergotine G. Oral Candida colonization in HIV-positive women: associated factors and changes following antiretroviral therapy. J Med Microbiol. 2013;62(Pt 1):126-32. [PubMed ID: 23002070]. https://doi.org/10.1099/jmm.0.047522-0.
-
18.
Webb BC, Thomas CJ, Whittle T. A 2-year study of Candida-associated denture stomatitis treatment in aged care subjects. Gerodontology. 2005;22(3):168-76. [PubMed ID: 16163908]. https://doi.org/10.1111/j.1741-2358.2005.00065.x.
-
19.
Field E, Longman L. Tyldesley's oral medicine. Oxford University Press; 2003.
-
20.
Touman AA, Stratakos GK. Long-Term Complications of Tracheal Intubation. Tracheal Intubation. 2018. https://doi.org/10.5772/intechopen.74160.
-
21.
Ambe NF, Longdoh NA, Tebid P, Bobga TP, Nkfusai CN, Ngwa SB, et al. The prevalence, risk factors and antifungal sensitivity pattern of oral candidiasis in HIV/AIDS patients in Kumba District Hospital, South West Region, Cameroon. Pan Afr Med J. 2020;36:23. [PubMed ID: 32774600]. [PubMed Central ID: PMC7392032]. https://doi.org/10.11604/pamj.2020.36.23.18202.
-
22.
Millsop JW, Fazel N. Oral candidiasis. Clin Dermatol. 2016;34(4):487-94. [PubMed ID: 27343964]. https://doi.org/10.1016/j.clindermatol.2016.02.022.
-
23.
Motta-Silva AC, Aleva NA, Chavasco JK, Armond MC, Franca JP, Pereira LJ. Erythematous oral candidiasis in patients with controlled type II diabetes mellitus and complete dentures. Mycopathologia. 2010;169(3):215-23. [PubMed ID: 19760517]. https://doi.org/10.1007/s11046-009-9240-6.
-
24.
Jayachandran AL, Katragadda R, Thyagarajan R, Vajravelu L, Manikesi S, Kaliappan S, et al. Oral Candidiasis among Cancer Patients Attending a Tertiary Care Hospital in Chennai, South India: An Evaluation of Clinicomycological Association and Antifungal Susceptibility Pattern. Can J Infect Dis Med Microbiol. 2016;2016:8758461. [PubMed ID: 27403171]. [PubMed Central ID: PMC4923570]. https://doi.org/10.1155/2016/8758461.
-
25.
Chung LM, Liang JA, Lin CL, Sun LM, Kao CH. Cancer risk in patients with candidiasis: a nationwide population-based cohort study. Oncotarget. 2017;8(38):63562-73. [PubMed ID: 28969011]. [PubMed Central ID: PMC5609943]. https://doi.org/10.18632/oncotarget.18855.
-
26.
Kharadi U, Kharadi UA, Parkarwar P, Khairnar S, Reddy S, Arur P, et al. Oral Candidiasis Turns to Oral Cancer - A Rare Clinical Presentation. Clin Oncol. 2016;1:1126.
-
27.
Kumar P, Mastan K, Chowdhary R, Shanmugam K. Oral manifestations in hypertensive patients: A clinical study. J Oral Maxillofac Pathol. 2012;16(2):215-21. [PubMed ID: 22923893]. [PubMed Central ID: PMC3424937]. https://doi.org/10.4103/0973-029X.99069.
-
28.
Nadig SD, Ashwathappa DT, Manjunath M, Krishna S, Annaji AG, Shivaprakash PK. A relationship between salivary flow rates and Candida counts in patients with xerostomia. J Oral Maxillofac Pathol. 2017;21(2):316. [PubMed ID: 28932047]. [PubMed Central ID: PMC5596688]. https://doi.org/10.4103/jomfp.JOMFP_231_16.
-
29.
Marable DR, Bowers LM, Stout TL, Stewart CM, Berg KM, Sankar V, et al. Oral candidiasis following steroid therapy for oral lichen planus. Oral Dis. 2016;22(2):140-7. [PubMed ID: 26599999]. https://doi.org/10.1111/odi.12399.
-
30.
Rostaing L, Malvezzi P. Steroid-Based Therapy and Risk of Infectious Complications. PLoS Med. 2016;13(5). e1002025. [PubMed ID: 27218466]. [PubMed Central ID: PMC4878798]. https://doi.org/10.1371/journal.pmed.1002025.
-
31.
Pedraza-Sanchez S, Mendez-Leon JI, Gonzalez Y, Ventura-Ayala ML, Herrera MT, Lezana-Fernandez JL, et al. Oral Administration of Human Polyvalent IgG by Mouthwash as an Adjunctive Treatment of Chronic Oral Candidiasis. Front Immunol. 2018;9:2956. [PubMed ID: 30627128]. [PubMed Central ID: PMC6309162]. https://doi.org/10.3389/fimmu.2018.02956.
-
32.
Li Y, Wan Z, Liu W, Li R. Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species. Antimicrob Agents Chemother. 2015;59(2):1365-9. [PubMed ID: 25512426]. [PubMed Central ID: PMC4335839]. https://doi.org/10.1128/AAC.04417-14.