Candidiasis: Pathogenesis, Clinical Characteristics, and Treatment

Candida organisms live on the skin and mucous membranes of up to 75 percent of the population. They can live commensally without causing harm or can change to an aggressive form and invade tissue, causing both acute and chronic disease in the host. Oropharyngeal candidiasis manifests clinically as acute pseudomembranous, acute atrophic, chronic atrophic, chronic hypertrophic/hyperplastic, and angular cheilitis. Systemic infection leading to candidemia can be devastating and cause up to a 60 percent mortality rate in medical or post-surgical intensive care wards. Oral nystatin, clotrimazole, and fluconazole usually provide appropriate therapy; although resistance to medications is increasing, particularly in immunocompromised hosts.

Candida organisms are fungi that normally inhabit the oral cavity, gastrointestinal tract, other mucous membranes, and skin. In most humans, this is a commensal relationship; and only a few Candida carriers actually go on to develop clinical signs of candidiasis because yeast growth and colonization are impaired by the resistance of the host.¹ When changes occur in the host environment causing imbalance of the flora or a decrease in resistance, Candida becomes an opportunistic pathogen. Clinical problems range from relatively mild candidiasis to chronic recurrent candidiasis and life-threatening disseminated infections. These problems are growing, and Candida has been called the most important fungal pathogen in humans.² It has been listed as the fourth most common isolate recovered from blood cultures in the United States³ among patients with severe infection acquired while in the hospital. This review will discuss the pathogenesis of candidiasis, the clinical characteristics of oral infection, local and systemic factors that predispose to infection, and treatment.

Candida Microbiology and Pathogenesis

Though dentists commonly treat the oropharyngeal signs of Candida infection and colonization such as denture stomatitis, angular cheilitis, and thrush, they must realize that when dissemination and invasion of internal organs occur, Candida becomes life-threatening.² This has become exceedingly important in recent years as the dental patient pool has expanded to include more of the elderly, with an additional increase in organ transplant, immunocompromised, AIDS, chemotherapeutic, and antibiotic- or steroid-laden patients.

Candida is a human fungal pathogen that grows as a round yeast and replicates by budding. Of the 150 fungal species of Candida, about seven are known to be medically important pathogens: C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. kefyr, C. glabrata, and C. guilliermondii.¹ Other species have been isolated from humans but are considered opportunistic in immunocompromised patients. C. albicans is by far the most prevalent pathogenic fungal species found in the human body, yet C. dubliniensis has been found primarily in the oral cavities of immune-suppressed individuals;^4,5 and although it is a low-level constituent of the human oral flora, it has the potential to cause oral candidiasis.^6,7 C. albicans and C. dubliniensis as well as other Candida species can be differentiated from one another by polymerase chain reaction techniques that are being developed to aid in diagnosis.⁸

Though C. albicans can exist in several forms, from the yeast to the hyphal, the yeast form is commensal and relatively harmless, while the hyphal form is invasive, pathogenic, and the cause of clinical candidiasis. Hyphae are not always seen in lesions, but this could reflect a sampling error.^1,9,10 Studies indicate that when the yeast forms grow hyphae, they then act like adherent filaments to spread across, attach, and burrow between and into epithelial cells. This is commonly seen in the more serious tissue invasion and especially in immunocompromised hosts.¹¹

Adherence by the hyphae to oral keratinocytes may be partially due to a protein called Hwp1, which is present in Candida filaments but not in the yeast form. This protein forms a covalent and permanent bond to epithelial cells with the help of the enzyme transglutaminase. Without Hwp1, the adherence to human oral mucosal cells is reduced 80 percent. Mice infected with Candida strains containing Hwp1 develop more severe disease than those infected with Hwp1-free Candida.¹¹

C. albicans also has the ability to produce secreted aspartyl proteinases that degrade many human proteins found at lesion sites. The proteins affected include albumin, hemoglobin, keratin, collagen, mucin, and secretory immunoglobulin A . Nine secreted aspartyl proteinase genes have been identified in Candida, and laboratory studies have evaluated the regulation of secreted aspartyl proteinase expression through analysis of mRNA and protein synthesis. In vivo studies indicate that secreted aspartyl proteinase 1, 2, and 3 are expressed by yeast cells. Only secreted aspartyl proteinase 4, 5, and 6 expression is seen in C. albicans when it is undergoing transition from yeast form to hyphal form. In patients with oral candidiasis, the hyphal forms with increased adherence have been found to express secreted aspartyl proteinase 4, 5, and 6. Interestingly, in vivo studies have now found that yeast cells, normally thought to be non-invasive, may at times express secreted aspartyl proteinase 4, 5, 6, and 7.¹² Additionally, the fact that secreted aspartyl proteinase genes are each expressed differently in the mouth may in time help to explain the variety of clinical candidiasis that is commonly seen (i.e., pseudomembranous, erythematous, atrophic, and hyperplastic).¹³

Oral Candidiasis, Candidemia, and Invasive Disease

Candida is present in the mouths of 25 percent to 75 percent of the population, depending on the study and sampling techniques. Current large-scale sampling methods such as saliva sampling or oral rinse procedures may identify the presence of yeast but do not diagnose clinical candidiasis or colonization. Patients who have intraoral candidiasis have been found to have greater than 400 colony-forming units per ml of saliva while carriers of C. albicans had less than this amount.¹⁴ High levels may thus suggest the possibility of systemic candidiasis, particularly in the immunocompromised patient, but do not prove deep-seated infection. This is particularly true in the hospital setting in that the problem of candidiasis is clear, but there are difficulties in establishing an early or even specific diagnosis. In hospital-acquired infections, Candida isolates from blood have become a common finding in the United States;³ similarly instances of candidemia have increased in Europe. Usually one-half of these occur in surgical intensive care units, while the other half occur in medical units. In these settings, the mortality rates attributable to candidemia range from 40 percent to 60 percent.^15,16

Antibodies against C. albicans or Candida-derived molecules in the sera of a patient may point to deep-seated infection. Investigations to detect C. albicans proteins,^17-19 metabolites,²⁰ DNA,^21-23 and polysaccharides are being done. For example, studies looking at mannans, which are a major component of C. albicans’ cell wall structure, may help determine the presence of C. albicans systemically by evaluating the antibody reaction to the organism. Thus, enzyme immunoassays for sensitive detection of circulating C. albicans mannan and antimannan antibodies look promising in the diagnosis of systemic candidiasis.²⁴

Predisposing Factors for Oral Candidiasis

A decreased amount of saliva has been related to a possible increase in Candida organisms and intraoral candidiasis in some but not all studies. Increased C. albicans carriage has been reported with decreased salivary flow in patients with salivary gland dysfunction^14,25-29 or Sjögren’s syndrome^30-34 and secondary to radiation therapy and anticholinergic drug use.^{14,25-27,32,34,35} Glossodynia has also been associated with C. albicans carriage.^{14,25-27,32,34,35} Other studies show no increase in C. albicans carriage with hyposalivation due to medicines and primary or secondary Sjögren’s syndrome.³⁶ In one study, C. albicans was detected in only a few subjects with hyposalivation³⁷ (see the article by Daniels in this issue).

Of interest is one recent study of primary and secondary Sjögren patients treated only with pilocarpine hydrochloride to increase salivary flow. At the start of the study, 75 percent of the subjects were positive for Candida, and 75 percent had clinical manifestations of infection. After one year of treatment with pilocarpine hydrochloride (5 mg, t.i.d.), 75 percent of the subjects presented with no cultivable Candida and no clinical manifestations.³⁸

In another study, decrease in whole salivary flow rate was correlated with an increase in C. albicans counts.²⁹ In fact, several have concluded that susceptibility to oral C. albicans infection is partially predicted by the whole unstimulated salivary flow rate.^29,38,39 It appears that low salivary flow rates do not necessarily predict the entrance of C. albicans, but in patients who already have C. albicans commensally, diminished flow rates may help increase the quantity of C. albicans, its colonization, and the emergence of clinical signs of disease. Efforts to increase the salivary flow rate may thus be an important part of antifungal therapy.

Hyposalivation occurs in the presence of numerous drugs such as sedatives, hypnotics, antidepressants, psychotropics, pain medications, and antihistamines. One study has shown a decrease of 60 percent in the flow rate of patients taking two or more hyposalivatory drugs.⁴⁰ The evaluation of the medications taken by patients who have oral candidiasis and hyposalivation should be considered a part of antifungal therapy.

Antimicrobial properties are known to be present in saliva and are important in the defense against C. albicans.^40-42 This is partially due to lysozymes, histatins, lactoperoxidase, immunoglobulins, lactoferrin, and salivary IgA.^43,44 Each of these plays a particular role. For example, the sensitivity of Candida species to lysozymes is rated in decreasing order: C. krusei (most susceptible), C. parapsilosis, C. tropicalis, C. guilliermondii, C. albicans. and C. glabrata.⁴¹ This helps to explain the high intraoral carriage rates of C. albicans and the increase in the other species seen in some saliva-deficient or immune-deficient patients. Therapy directed at increasing the immune status should be considered in the treatment of patients with recalcitrant candidiasis.

AIDS patients with candidiasis are easily treated initially with azole antifungals; however, as the disease progresses, failure of these medications is becoming more common. In one study of 921 oral specimens taken from HIV-positive patients with oral candidiasis, 95 yielded non-albicans species, mainly from patients with low CD4 lymphocyte counts and extensive previous azole exposure. Eighty-five of these were resistant to fluconazole.⁴⁵ The need for a new generation of antifungal medications is imminent.

The tongue is the primary oral reservoir, particularly the midline of the dorsal surface. This is followed by the cheek and the palate.⁴⁶ Acrylic in dental prostheses should also be considered a reservoir. Dentures have been implicated as a reason for increased levels of oral yeasts. In denture stomatitis, counts of C. albicans and C. glabrata are substantially higher than in non-stomatitis denture-wearing subjects. In patients who have denture stomatitis, the counts of C. albicans and C. glabrata are higher on the denture-bearing areas that do not show signs of stomatitis.⁴⁰ Patients with denture stomatitis thus need treatment of all denture-bearing surfaces. Additionally, the appliances should be thoroughly scrubbed along with the denture container at least daily. This is often overlooked in the care of disabled or bedridden patients and those in a rest home or even a retirement center. Soaking dental prostheses in chlorhexidine is also recommended.

Clinical Manifestations

Five specific clinical oral manifestations of candidiasis have been described: pseudomembranous, acute atrophic/erythematous, chronic atrophic, angular cheilitis, and chronic hypertrophic/hyperplastic. The clinical presentation may include more than one of these manifestations but usually one is predominant.

Acute pseudomembranous candidiasis (Figure 1): The lesions are superficial curd-like white patches that wipe off, leaving an erythematous base. They are located on any or all mucosal surfaces, particularly the buccal mucosa, mucobuccal folds, oropharynx, and dorsal tongue. Infants and the elderly are predilected. Predisposing factors include a history of broad-spectrum antibiotics, steroids, nutritional deficiency, diabetes, malignancy, chemotherapy, radiation therapy, and cell-mediated immunity dysfunction including HIV infection.

Acute atrophic candidiasis (Figure 2): Loss of the Candida organism pseudomembrane causes small to generalized large red lesions with inflammation of surrounding tissues. The tongue typically shows depapillation and dekeratinization. Atrophic lesions are most often seen on the tongue and palate. Predisposing factors include broad-spectrum antibiotics and corticosteroid aerosols as may be used by asthmatics.

Chronic atrophic candidiasis (Figures 3a through c): The lesions are chronic showing erythema and edema with a slight velvety/pebbly surface. Small erosions may also be seen. The lesions are located on the palate and upper and lower edentulous ridges, and are frequently encountered under dentures. Predisposing factors include ill-fitting or poorly cleaned dentures, as well as those enumerated for the other forms of candidiasis

Angular cheilitis (perleche) (Figure 4): Angular cheilitis is the same as intraoral chronic atrophic candidiasis, just in a different location. Clinically, there are fissures at the commissural angles that allow pooling of saliva and incubation of yeast forms, crusting with underlying erythema. The lesions are localized to the corners of mouth. Predisposing factors include ill-fitting dentures with overclosure, drooling at corners of mouth, lip-licking habits, and thumb/digit-sucking habits.

Chronic hypertrophic/hyperplastic candidiasis (Candida leukoplakia) (Figures 5a and b): Chronic nodular hard lesions appear white, cream-colored, or red. These hypertrophic lesions are located on the surface of tongue, buccal mucosa, palate, denture-bearing areas, central dorsum of tongue (median rhomboid glossitis), as papillary nodules on palate usually under dentures (papillary hyperplasia), and in areas of epithelial hyperplasia (pre-existing leukoplakias and keratotic papillomas). Predisposing factors include cellular hyperplasia, oral precancerous lesions, smoking, and denture wearing.

There is a generalized mucocutaneous form of candidiasis that presents as chronic infection of the oral mucosa, nails, skin, and vaginal mucosa. Resistance to therapy is common. This is usually initiated by pseudomembranous candidiasis and then proceeds to a chronic form. A familial form, possibly autosomal recessive, also exists, with about half of the patients presenting with associated endocrinopathy (hypoparathyroidism, Addison’s disease, hypothyroidism, or diabetes mellitus). Other familial forms are associated with abnormalities of iron metabolism or cell-mediated immunity.⁴⁷

Treatment

The first line of treatment in most cases of Candida infection is the use of frequent normal saline rinses, which can be found in all hospitals for bedside use or can be mixed at home using 1/2 teaspoon of salt in 1 quart of water. This helps to decrease the fungal counts and is soothing to the mucous membranes. The temperature of the rinse should be adjusted for comfort. If the epithelium is intact and not sloughing, the patient should gently swab or brush the mouth and use a tongue scraper.

Medication therapy falls into three basic categories; however, fungal resistance is a growing problem, and a new generation of drugs is needed.⁴⁸ The polyenes, which include amphotericin B and nystatin, help destroy the protein gradient in the cell due to leakage of cellular components. Resistance to amphotericin B is rare except for C. lusitaniae, C. guilliermondii, and Trichosporon beigelli.⁴⁹ It is highly effective when given intravenously but toxicities and renal dysfunction are problematic. Nystatin is easy to use but some dislike the taste. The azoles -- which include ketoconazole, clotrimazole, fluconazole and itraconazole -- inhibit ergosterol biosynthesis.⁴⁸ Fluconazole has been the drug of choice for AIDS-associated fungal infections, but resistance is rapidly becoming a problem, particularly among the non-albicans species (e.g.: C. krusei, C. glabrata, C. lusitaniae, and C. dubliniensis).^4-7,50-53

The third category, 5-Flucytosine, disrupts the DNA and protein synthesis of the cell. It is used in connection with amphotericin B, fluconazole, and itraconazole. The development of resistance to 5-FC is common. The use of multiple agents is necessary in cases of fungal resistance.

For most cases seen in the general dental arena, various forms of nystatin or clotrimazole are sufficient (Table I).

The Internet has many sites that address Candida or candidiasis. Many of these espouse the concept that chronic systemic candidiasis is the cause of multiple symptoms and diseases including constipation, diarrhea, bloating, fatigue, lethargy, poor memory, difficulty focusing, moodiness, numbness, burning, tingling, muscle aches, nasal congestion or discharge, swollen joints, erratic vision, endometriosis, menstrual problems, prostatitis, impotence, chronic fatigue, fibromyalgia, anger, and frustration. Scientific verification of the cause-and-effect relationship is debatable and probably impossible. The recommended treatments also vary widely and include the elimination of specific foods, detoxification, herbal cleansing, multiple vitamins, special diets, colonics, and high enemas. This makes for interesting surfing, but the scientific literature does not support such contentions.

A useful Web site is provided by the Centers for Disease Control and Prevention, which lists health topics from A to Z in a short-form encyclopedia of diseases. The address is www.cdc.gov/health/diseases.htm. Click on Candidiasis. A comprehensive literature search can be performed at www.ncbi.nlm.nih.gov/pubmed/

Author

Stanton S. Appleton, DDS, MPH, MSD, is a professor of oral medicine at Loma Linda University School of Dentistry.

References

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To request a printed copy of this article, please contact/Stanton S. Appleton, DDS, MPH, MSD, LLU School of Dentistry, Loma Linda, CA 912350, or at sappleton@sd.llu.edu

Legends

Figure 1. Acute pseudomembranous candidiasis.

Figure 2. Acute atrophic candidiasis.

Figure 3a. Chronic atrophic candidiasis.

Figure 3b. Chronic atrophic candidiasis.

Figure 3c. Chronic atrophic candidiasis on a finger.

Figure 4. Angular cheilitis.

Figure 5a. Leukoplakia of the soft palate.

Figure 5b. Papillary hyperplasia.

Table I. Drug Regimens Used to Treat Oral Candidiasis

* Nystatin (Mycostatin) oral suspension, 100,000 units/ml, dispense 60 ml. Swish and swallow 2-5 ml four times daily.

* Nystatin cream or ointment. Dispense 15 or 30 g. Apply to corners of mouth four times daily. The cream can also be used as a coating for the denture and then placed in the mouth.

* Nystatin troche 200,000 units to 400,000 units. Dissolve one troche four times daily.

* Nystatin topical powder 15 g. Apply thin layer under the denture after each meal.

* Clotrimazole (Mycelex) troche 10 mg. Dissolve one tab in mouth five times per day

* Clotrimazole cream 15 g, 30 g, 60 g, and 90 g tubes

* Amphotericin B (Fungizone) suspension 100 mg/ml. Swish and swallow 1 ml four times daily.

* Ketoconazole (Nizoral) 200 mg, one to two tabs per day (watch for liver dysfunction).

* Ketoconazole cream 2% 15 g, 30 g, and 60 g tubes (contains sodium sulfite anhydrous, to which some patients have allergic reactions).

* Fluconazole (Diflucan) 50 mg, 100 mg, 150 mg, 200 mg. Take 200 mg on day 1 then 100 mg per day for 14 days.

* 5-Flucytosine (Ancobon) 250 mg, 500 mg caps. Take 50 to 150 mg per kg per day in divided doses every six hours. Used in combination with amphotericin B, fluconazole or itraconazole.

* Itraconazole (Sporanox) 100 mg caps, oral solution 100 mg/10 ml. Dispense 150 ml. Take 200 mg per day. Dose may be increased 100 mg per day to 400 mg per day. Doses greater than 200 mg per day should be given in two divided doses.