Vol 5, No 1 (2017) ISSN 2167-8677 (online) DOI 10.5195/d3000.2017.74

Oral candidiasis: relation to systemic diseases and medications Xiaozhu Chu1

1University of Pisburgh, School of Dental Medicine Citaon: Chu, X. (2017) Oral candidiasis: relaon Abstract to systemic diseases and medicaons. Denstry 3000. 1:a001 doi:10.5195/d3000.2017.74 Background: Oral candidiasis is by far the most common oral fungal infecon in humans. It is caused by the fungal or- Received: May 5, 2017 ganism Candida albicans. When the host is debilitated by other diseases and condions, C. albicans, which is usually a Accepted: May 26, 2017 part of the normal oral flora, can turn pathogenic and invade the host ssue to cause the infecon. The purpose of Published: June 19, 2017 this paper is to invesgate the role of systemic diseases and medicaons in the development of oral candidiasis. Copyright: ©2017 Chu, X. This is an open access Methods: A total of 12 cases with code indicang oral candidiasis were collected from the University of Pisburgh arcle licensed under a Creave Commons School of Dental Medicine Dental Registry and DNA Repository. The systemic diseases and medicaons were descrip- A!ribuon Work 4.0 United States License. vely analyzed. Results: 50% of the subjects had more than two systemic diseases. The most prevalent diseases were Email: xic81@pi.edu mental illnesses (50%), cardiovascular diseases (41.7%), and respiratory system diseases (33.3%). 50% of subjects were on polypharmacy therapies and 75% of subjects were taking medicaons that may contribute to oral candidiasis. Among the medicaons, andepressants and inhalaonal corcosteroids may have strong potenals to cause oral candidiasis. Conclusion: Oral candidiasis is associated with having systemic diseases and intake of medicaon, espe- cially with those medicaons can cause xerostomia. As the number of systemic diseases and medicaons increases, the risk of developing oral candidiasis may increase too.

Introduction result of complex host and organ- γT (RORγT), produce interleukin ism interaction, a large percentage (IL)-17, which has an essential role Candidiasis is by far the of patients with candidal infection in defensing against candidal in- most common oral fungal infec- are still individuals who are debili- fections in humans. Four genetic tion in humans and has a variety tated by another diseases and etiologies, AR IL-17 receptor A, IL- of clinical manifestations. It is the conditions. Many risk factors can 17 receptor C and ACT1 deficien- infection caused by the yeast-like modify an individual’s susceptibil- cies, and AD IL-17F deficiency, are fungal organism Candida albicans. ity to oral candidiasis, including identified as underlying risk fac- As many other pathogenic fungi, compromised autoimmunity, to- tors for chronic mucocutaneous C. albicans can exist in two bacco consumption, hyposaliva- candidiasis. Each of these gene forms—the yeast form and the tion, denture wearing, systemic defects has a direct negative effect hyphal form. The hyphal form is disease, and medication. on IL-17 signaling. Patients with believed to be able to invade the these gene defects may have se- host tissue and cause the infec- Compromised autoimmunity verely reduced frequencies of cir- tion. [1] C. albicans is considered culating IL-17-producing T cells. Or as part of the normal oral flora T-cell immunity has a criti- cal role in host defense against they may produce neutralizing au- and the prevalence of oral Can- toantibodies against IL-17. As a dida carriage in the healthy popu- candidal infection. Chronic muco- cutaneous candidiasis (including result, the ability of neutrophil lation has been estimated to range cells to kill C. albicans is impaired from 23% to 68%. [2] Candidiasis oral candidiasis) is an infectious phenotype in patients with inher- and chronic mucocutaneous can- used to be considered as only an didiasis may develop. [3] opportunistic infection but it has ited or acquired T-cell deficiency. been recognized that people who Studies have shown that Th17 cell, Tobacco consumption are otherwise healthy can develop as well as other cell expressing ret- oral candidiasis too. However, as a inoic acid-related orphan receptor

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Vol 5, No 1 (2017) DOI 10.5195/d3000.2017.73

Denture wearing

Denture stomatitis is con- sidered to be a form of erythema- tous candidiasis and it’s a common inflammatory lesion of the oral mucosa covered by denture. Epi- demiological studies show a prevalence of denture stomatitis among denture wearers from 15% to over 70%. Etiological factors include poor denture hygiene, continual and nighttime wearing of removable dentures, accumula- tion of denture plaque, and bacte- Tobacco smoking has been Adequate salivation is es- rial and yeast contamination of considered as one of the many sential for oral health, since it pro- denture surface. All together, the- factors that can predispose indi- vides support for the microbial se factors may increase the ability viduals to oral candidiasis. Litera- population of the mouth, while at of C. albicans to colonize both tures revealed that the rate of oral the same time containing antimi- denture and oral mucosal surfac- candidal carriage in tobacco crobial products that control these es, exerting its pathogenic effort. smokers is significantly higher microbial populations. Histatin 5 [6] than in non-smokers. Besides C. (Hst 5) is an important salivary an- Systemic diseases Many systemic albicans, the oral carriage of other timicrobial protein. It has been diseases have been associated species such as C. glabrata, C. shown that Hst 5 has potent and with oral candidiasis. The primary dubliniensis and C. tropicalis are selective antifungal activity. After cause is attributed to the de- also associated with smoking. The coupling with the carrier molecule creased salivary secretion, leading observation is even more striking spermidine, Hst 5 significantly en- to the reduced concentration of in HIV-infected individuals. It has hances the killing of C. albicans. immunoglobulin in the saliva and been reported that HIV-positive [5] Reduced salivary secretion, as less efficient humoral-mediated smokers are 50 times more likely occurred in patients with Sjögren's host defense against C. albicans. to be oral candidal infection posi- syndrome, can re- tive compared to HIV-infected sult in a significant non-smokers. It has not been increase in oral cleared yet that why tobacco con- candidal carriage. sumption can increase candidal The prevalence of carriage. However, there are stud- oral candidal car- ies suggesting that smoking may riage among lead to localized epithelial altera- Sjögren's syndrome tions, which facilitate candidal patients is estimat- colonization. Another hypothesis ed to range from is that cigarette smoke may con- 68% to 100%, com- tain nutritional factors for C. albi- pared to the range cans. [4] from 23% to 68% in normal population Hyposalivation [2].

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Vol 5, No 1 (2017) DOI 10.5195/d3000.2017.73

used for academic research pur- pose. 12 cases with codes indicat- ing oral candidiasis were collected from the 5,869 subjects. Com- pared to the estimated prevalence of oral candidal carriage, which ranges from 23% to 68% in the normal population [2], the number 12 in 5,869 subjects (0.2%) seems to be unreasonably small. This can be a result of the inconsistent re- port of the oral lesions by clinical faculty members and student den- tists. For the 12 cases with oral candidiasis, the data on current (i.e. time of examination) systemic For patients with diabetes melli- oral candidiasis by directly reduc- diseases/medical conditions, daily tus, besides the reduced salivary ing the salivary flow. [8] intake of prescribed or OTC medi- flow, the high level of blood glu- cations were obtained from the cose also plays a significant role. It It appears that the associa- registry. The total number of sys- is associated with reduced salivary tion between oral candidiasis and temic diseases and medical condi- pH and facilitates oral candidal systemic diseases, intake of medi- tions were counted. All medica- overgrowth and colonization. [7] cations has been well established. tions were categorized by using As an opportunistic infection, oral The purpose of this study is to the internationally approved Ana- candidiasis is also associated with analyze the 12 cases collected tomical Therapeutic Chemical a wide spectrum of systemic dis- from the University of Pittsburgh (ATC) classification system. And eases that suppress the host auto- School of Dental Medicine Dental their impacts on oral hygiene and immunity [8]. Registry and DNA Repository, and dental treatment were obtained further investigate which systemic from the website Lexicomp Online Medication diseases and medications may be for Dentistry potent and contribute to the de- (http://www.wolterskluwercdi.co Several drugs may cause velopment of oral candidiasis. the development of oral candidia- m/online-for-dentistry/). All data sis by many mechanisms. The Methods then were descriptively analyzed. pharmacological action of the Results broad-spectrum group of antibiot- By the time of the study started, ics may break the balance within 5,869 subjects from the University Characteristics of the 12 study the normal oral flora, resulting in of Pittsburgh School of Dental samples are presented in Table 1. the overgrowth of C. albicans. Medicine Dental Registry and DNA Among the 12 cases, only one par- Drugs such as corticosteroids may Repository were available for ticipant (8.3%) did not report any suppress either the nonspecific analysis. Since the September of systemic disease or medical condi- inflammatory response or the T- 2006, the registry invited all pa- tion. For the other 11 cases, the cell-mediated immunity, which tients who seek treatment at the number of systemic diseas- can in turn predispose individuals University of Pittsburgh School of es/medical conditions reported by to oral candidiasis. Drugs that Dental Medicine to participate and the participants varied from 1 to 8 have xerogenic effects can cause give written consent to authorize (33.3% reporting more than four their clinical information to be diseases). The highest scores by

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Vol 5, No 1 (2017) DOI 10.5195/d3000.2017.73 number of diseased individuals systemic hormones, analgesics, oral candidiasis”. The other cate- were found for neurological sys- and agents for obstructive airway gories, which contained medica- tem disease (58.3%, N = 7) includ- diseases predominated. This med- tions that may contribute to oral ing depression, epilepsy, and bipo- ication pattern reflected the dis- candidiasis, included anticonvul- lar disorder, cardiovascular system ease burden among the study sub- sant, antimanic, antiulcer, hypnot- diseases (41.7%, N = 5) including jects. ic and immunosuppressant agents. mainly hypertension, irregular (Figure 3) Among all 12 subjects, 9 heartbeat, and heart failure, and Since intake of medication (75%) were taking medications respiratory system disease (33.3%, is an important risk factor to the that fitting into the “ may contrib- N = 4) including asthma (Figure 1). development of oral candidiasis, ute to oral candidiasis” category. Less frequent diagnosis included all the medications taken by study gastrointestinal tract and metabo- subjects were analyzed by their Discussion and Conclusion impacts on oral cavity environ- lite diseases (liver diseases and In my study, 50% of the diabetes, 25%, N = 3), neoplasms ment and dental treatment. Based on the information obtained from study samples were having three (neuroblastoma and unspecified or more than three systemic dis- throat cancer, 16.7%, N = 2), geni- the website Lexicomp Online for Dentistry, all medications that can eases, which is in agreement with tourinary system diseases (kidney previous observations suggesting disease, 8.3%, N = 1), and muscu- cause xerostomia, change in sali- vation, candidal infection were that having multiple systemic dis- loskeletal system diseases (pros- eases and medical conditions is thetic joint, 8.3%, N =1). labeled as “may contribute to oral candidiasis”. The 63 medications associated with oral candidiasis. All the study subjects had were fitted into 22 categories The most frequent diseases involv- intake of prescribed or OTC (over based on the Anatomical Thera- ing in this study were mental dis- the counter) medications. The peutic Chemical (ATC) classifica- eases including depression and number of medications taken on tion system. Among the predomi- bipolar disorder, and obstructive daily basis varied from 1 to 14. nated categories, antidepressant airway diseases including asthma, Among the 12 cases, three indi- contained 10 medications, all of chronic obstructive pulmonary viduals took only one medication which may contribute to the de- disease, and an unspecified lung (25%), three took 2-4 medications velopment of oral candidiasis. It disease. Those are not diseases (minor polypharmacy, 25%), and had been followed by agents for that directly cause change in sali- six took more than 4 medications obstructive airway diseases and vary secretion and salivary glands (major polypharmacy, 50%). The analgesics, which had 5 out of 9 or those suppress the host auto- distribution of prescribed medica- (55.5%) and 2 out of 7 (28.6%) immunity. Their primary associa- tion (Figure 2) shows that antihy- medications, respectively, fell into tion with the development of oral pertensive agents, antidepressant, the category “may contribute to candidiasis is more attributed to the medications that were taken by subjects to treat the systemic diseases. However, it may not be true for one subject who was di- agnosed as insulin-dependent dia- betes. On the morning the dental examination was performed, the subject reported that her blood glucose level was 235mg/dl. Com- pared with the preferable goal of a good diabetic management, which is close to the 70 to 120mg/dl

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Vol 5, No 1 (2017) DOI 10.5195/d3000.2017.73 range, it’s safe to assume the dia- inhaler users to oral candidiasis. 3rd ed. St. Louis: Saunders, betes was not well controlled. Be- [10] In this study, 75% of the study an imprint of Elsevier. 213- sides all other drugs she took, the subjects was on polypharmacy 224 p. level of blood glucose may play an therapies and took medications important role in the development that had xerogenic or immuno- 2. Elucidating of her oral candidiasis. It has been suppressive properties, including the role of hyposalivation a reported that highest rate of C. 10 antidepressants and 2 inhala- nd autoimmunity in oral albicans colonization occurs in di- tional corticosteroids. The finding candidiasis. Billings M, Dye abetic patients with poor glycemic is in line with previous studies in- BA, Iafolla T, Grisius M, Al- control. In addition, subjective oral dicating that intake of medications evizos I. Oral Dis. 2017 dryness is a frequent complaint is an important risk factor for the Apr;23(3):387-394. doi: among diabetic patients. [7] development of oral candidiasis. 10.1111/odi.12626. Epub 2017 Feb 8. PMID: The five most commonly When treating patients 27998016 reported medications included with systemic diseases and taking systemic hormones, antidepres- multiple medications, the dental 3. Chronic mucocutaneous sants, antihypertensive agents, professionals must be able to rec- candidia- agents for obstructive airway dis- ognize the early signs and symp- sis disease associated with eases, and analgesics. Among the toms of oral candidiasis and adjust inborn errors of IL-17 im- five categories, the association the treatment plans to meet the munity. Okada S, Puel A, between antidepressants and oral special needs of those patients Casanova JL, Kobayashi M. candidiasis has been well estab- and prevent the development of Clin Transl Immunology. lished. All salivary secretion is me- oral candidiasis. 2016 Dec 2;5(12):e114. diated by neurotransmitters and doi: 10.1038/cti.2016.71. relies on stimulations from the In conclusion, based on the eCollection 2016 Dec. Re- autonomic nervous system. Stimu- descriptive analysis of 12 cases view. PMID: 28090315 lation of the cholinergic system with oral candidiasis, the findings support the concept that the de- 4. The impact of ciga- leads to secretion of “watery” sali- rette/tobacco smok- va thus anticholinergic drugs re- velopment of oral candidiasis is associated with having multiple ing on oral candidosis: an duce the secretion. Many antide- overview. Soysa pressants have an anticholinergic systemic diseases and intake of medications. NS, Ellepola AN. Oral Dis. effect that blocks the peripheral 2005 Sep;11(5):268-73. cholinergic innervation, resulting Acknowledgements Review. PMID: 16120112 in hyposalivation and xerostomia. [9] Among other agents used to Data from the study was obtained 5. Saliva- manage obstructive airway dis- from the University of Pittsburgh microbe interactions and eases, corticosteroids are widely School of Dental Medicine Dental salivary gland dysfunction. used as oral inhalers due to its an- Registry and DNA Repository, Baker OJ, Edgerton M, ti-inflammatory and immunosup- which is supported by the Univer- Kramer JM, Ruhl S. Adv pressive properties. However, the sity of Pittsburgh School of Dental Dent Res. 2014 repeated use of corticosteroids Medicine. May;26(1):7-14. doi: oral inhalers also suppress an indi- 10.1177/00220345145262 vidual’s resistance to candidal in- References 39. Review. PMID: fection by suppressing either the 1. Neville B, Damm D, Allen C, 24736699 nonspecific inflammatory re- Bouquot J. (2009) Oral and 6. Epidemiology sponse or the T-cell-mediated im- Maxillofacial Pathology. munity, which predispose the oral and etiology of denture

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stomatitis. Gendreau L, Loewy ZG. J Prosthodont. 2011 Jun;20(4):251-60. doi: 10.1111/j.1532- 849X.2011.00698.x. Epub 2011 Apr 4. Review. PMID: 21463383

7. Can- didal overgrowth in diabeti c patients: potential pre- disposing factors. Belazi M, Velegraki A, Fleva A, Gida- rakou I, Papanaum L, Baka D, Daniilidou N, Karamitsos D. Mycoses. 2005 May;48(3):192-6. PMID: 15842336

8. Fungal infections of the oral mucosa. Krish- nan PA. Indian J Dent Res. 2012 Sep-Oct;23(5):650-9. doi: 10.4103/0970- 9290.107384. Review. PMID: 23422613

9. Risks for oral health with the use of antidepressants. Peeters FP, deVries MW, Vissink A. Gen Hosp Psy- chiatry. 1998 May;20(3):150-4. Review. PMID: 9650032

10. Inhalational and topical steroids, and oral candidosis: a mini review. Ellepola AN, Sama- ranayake LP. Oral Dis. 2001 Jul;7(4):211- 6. Review. PMID: 11575870

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