Hippocrates is credited with first describing oral thrush in debilitated individuals. Nineteenth-century authorities rec- ognized that thrush invariably arose as a consequence of pre- existing illness. The initial discovery of the organism causing thrush was not made until 1839, when Langenbeck described a fungus in buccal aphthae in a case of typhus [71], but it was left to Berg in 1846 to establish a cause–effect relationship between the fungus and oral lesions [72]. The taxonomic confusion continued until 1933 when Berkhout proposed the genus name Candida, separating this genus from the univer- sal Monilia genus that affects fruit and vegetables [1].
Oropharyngeal candidiasis (OPC) is considered an oppor- tunistic infection caused by a ubiquitous fungal organism that is routinely seen as normal oral flora. The transition from commensal to invasive infection of the oral mucosa is caused by local changes in the microflora or by an inefficient host response system which results in the overgrowth and inva- sion of Candida spp. The prevalence of OPC remains high and continues to increase, because the population of compro- mised hosts continues to expand [73]. Underlying conditions associated with a greater prevalence of OPC include prema- turity, ill-fitting dentures, xerostomia, radiation of the head and neck, uncontrolled diabetes mellitus, hematologic and solid organ malignancies, oral or inhaled corticosteroid use, antimicrobial therapy, and HIV infection [74].
Persistent OPC in infants may be the first manifestation of childhood AIDS or chronic mucocutaneous candidiasis. One group of investigators reported that 28% of cancer patients not receiving antifungal prophylaxis developed OPC [75], and another group observed OPC in 57% of immunocompro- mised patients [76]. Patients at greatest risk of developing OPC include those receiving corticosteroids and with pro- longed neutropenia who are colonized with a Candida species [76]. Approximately 80–90% of patients with HIV-infection will develop OPC [77]. In one study, 60% of untreated
172 J.A. Vazquez and J.D. Sobel
patients developed an AIDS-related infection or Kaposi’s sarcoma within 2 years of the appearance of OPC [78].
Candida albicans remains the most common species responsible for OPC, accounting for 80–90% of cases. The ability of C. albicans to adhere to buccal epithelial cells is critical in establishing oral colonization; C. albicans adheres better to epithelial cells than non-albicans Candida species.
Pulsed-field gel electrophoresis of Candida strains obtained from HIV-positive patients with OPC compared with isolates recovered from healthy individuals indicate an identical strain distribution frequency, suggesting that HIV-associated can- didiasis is not caused by unique or more virulent strains of Candida, but from defects in host defenses [79]. Immune defenses against Candida depend on appropriate host recogni- tion, followed by activation of antifungal mechanisms in effec- tor cells through pattern-recognition receptors on host cells.
This recognition induces intracellular signaling pathways that modulate protective and inflammatory responses, such as expression of costimulatory molecules, release of proinflam- matory cytokines and modulation of acquired immunity [80].
Mercante et al. examined the impact of viral load and CD4 cell count on the occurrence of OPC in 160 HIV-positive patients [81], and they identified low HIV viral load (<10,000 copies/mL) as the most important co-variate associated with absence of OPC. Other important variables associated with OPC included age, antiretroviral therapy, and low CD4 cell counts, but only in subjects with HIV viral loads >10,000 copies/mL. In a study comparing current OPC epidemiology from that noted in the pre-HAART era [82], similar epide- miologic findings were noted. Similar to the pre-HAART era, they found a frequency of Candida colonization of approximately 50% along with a similar species distribution with C. albicans about 85%. As in prior studies, detectable HIV RNA and CD4 count <200 cells/mL were significantly associated with Candida colonization of the oral cavity.
Profound differences exist between HIV-positive and neg- ative patients with regard to natural history, diagnosis and management of OPC [83] including an increase in non-albi- cans Candida species recovered from HIV-positive individu- als [84]. HIV-positive patients experience recurrent episodes of OPC and esophageal candidiasis as immunodeficiency progresses; these patients may also receive multiple courses of antifungal drugs contributing to antifungal resistance. In these patients, antifungal agents are also less efficacious and take longer to achieve a clinical response. In a prospective study evaluating tissue-associated immune dysfunction in HIV-positive patients with OPC, patients with asymptomatic Candida colonization of the oral mucosa and reduced CD4+ cell counts had higher numbers of CD8+ cells throughout the tissue and had normal E-cadherin expression [85]. In con- trast, in patients with active OPC, the CD8+ cells tended to accumulate around the epithelial-lamina propria junction with reduced E-cadherin expression. After the resolution of
the OPC, the CD8+ cells returned and the E-cadherin expression returned to normal.
Symptoms of oral thrush include a painful mouth, burning tongue and dysphagia. Patients with severe objective intraoral lesions may be asymptomatic. Signs include diffuse ery- thema with white patches that appear as discrete lesions on the surfaces of the buccal mucosa, palate, oropharynx, tongue, and gums. With some difficulty, the plaques can be wiped off revealing a raw, erythematous and sometimes bleeding base. Constitutional signs of infection are absent.
Oropharyngeal candidiasis can impair the quality of life by reduction in fluid or food intake. The most commonly identi- fied form of OPC is termed acute pseudomembranous can- didiasis. This form is seen frequently in HIV-positive persons and presents with a whitish-yellow thick curd–like exudate on mucosal surfaces (Fig. 1a). Plaques may be small and dis- crete or confluent, involving the entire oral mucosa; they consist of necrotic material and desquamated epithelial cells, penetrated by hyphae and yeast cells [86].
Chronic atrophic stomatitis, or denture stomatitis, is the second most common form of OPC. It is frequently asymp- tomatic, but may be associated with chronic soreness and burning of the mouth. Diffuse erythema and edema of the portion of the palate in contact with dentures is evident (Fig. 1b). The lower denture is rarely involved. Chronic atro- phic stomatitis was recorded in 24–60% of denture wearers and is several-fold more frequent in women than in men [87].
Candida is detected by culture or microscopy in over 90% of symptomatic subjects. Even in the absence of signs or symp- toms, the prevalence of yeast is higher in denture wearers.
Maximum concentrations of yeast are found on the denture fitting surface. Candida species readily adhere to plastic objects including orthodontic appliances.
Angular cheilitis, or perleche is characterized by sore- ness, erythema, and fissuring at the corners of the mouth (Fig. 1c). Cheilitis can accompany oral thrush or denture stomatitis, or can appear in the absence of oral disease.
Vitamin deficiency and iron-deficiency anemia are also asso- ciated with cheilitis, with Candida as a secondary colonizer.
Chronic hyperplastic candidiasis or Candida leukoplakia is a term used to describe discrete, transparent to whitish raised lesions of variable sizes found on the inner surface of the cheeks and less frequently on the tongue. These lesions are found predominantly in men and are highly associated with smoking. Most leukoplakia lesions are not related to Candida infection and may be premalignant. Importantly, there is no known association between Candida and either dysplasia or malignancy. Biopsy of Candida-related leuko- plakia lesions reveals parakeratosis and epithelial hyperplasia with Candida invasion. Midline glossitis (median rhomboid glossitis, acute atrophic stomatitis) manifests as symmetrical lesions in the center dorsum of the tongue with erythema and loss of papillae [88].
173 Candidiasis
Candida species have also been incriminated in an oral
“burning mouth” syndrome, characterized by a raw or sore tongue, especially following antibiotic administration. This self-limiting entity, although common, has not been shown to be due to primary or secondary Candida infection. Positive smears or cultures for Candida can be expected in 20–50% of asymptomatic patients, but these do not prove causality. The etiology of this syndrome is probably multifactorial [79].
Physical signs of OPC are insufficient to allow a reliable diagnosis. Oral lesions resembling candidiasis can occur with severe mucositis accompanying chemotherapy, and can reflect tissue necrosis, viral, or bacterial infections. On the other hand, OPC can complicate herpes simplex virus infec-
tions or leukoplakia. Diagnosis requires mycological confir- mation, achieved by 10% potassium hydroxide or normal saline microscopic examination. Cultures are not essential for diagnosis and do not distinguish colonization from infection.
Esophageal Candidiasis
The prevalence of Candida esophagitis has increased because of AIDS, as well as the increased number of trans- plant recipients, patients with cancer, and other severely
Fig. 1 Oropharyngeal candidiasis demonstrating (a) pseudomembranous type, (b) atrophic erythematous type associated with denture use, and (c) angular cheilitis
174 J.A. Vazquez and J.D. Sobel
immunocompromised patients. Candida are frequently recovered from the esophageal surface and reach the esopha- gus in oral secretions. Little is known about host and yeast factors operative in the pathogenesis of esophageal candidia- sis (EC) and experimental models have not been established.
Predisposing factors include exposure to local irradiation, recent cytotoxic chemotherapy, antibiotics, corticosteroids, and neutropenia [79]. The high prevalence of EC in patients with AIDS indicates the critical role of cell mediated immu- nity. Esophageal candidiasis in an HIV-positive patient may be the first manifestation of AIDS, typically occurring at CD4 counts <100 cells/mL [89].
EC presents with odynophagia, dysphagia, and retroster- nal pain. Constitutional findings, such as fever and malaise, occasionally occur. Rarely, epigastric pain is the dominant symptom. Although EC may arise as an extension of OPC, in some series, the esophagus was the only site involved in two- thirds of patients. EC usually occurs in the distal 2/3 of the esophagus. EC in patients with AIDS may be entirely asymp- tomatic, in spite of extensive esophageal involvement [90].
Esophagitis is classified on the basis of endoscopic appear- ance: Type I, a few white or beige plagues, up to 2 mm in diameter; Type II, plaques are more numerous, larger than 2 mm in diameter; Type III, confluent, linear and nodular elevated plaques with hyperemia and frank ulceration (Fig. 2) and Type IV, similar to Type III but with increased mucosal friability and occasional narrowing of the lumen [91].
Uncommon complications of esophagitis include perfora- tion, aortic-esophageal fistula, and rarely, extensive necrosis destroying the entire esophageal mucosa. In neutropenic patients, bacteremia and candidemia may arise from EC.
Antifungal therapy is frequently initiated empirically in high-risk patients. A reliable diagnosis of EC can only be
made by histological evidence of tissue invasion in biopsy material. The finding of Candida within an esophageal lesion by smear or culture or in esophageal brushings does not allow distinction between colonization and infection. Positive esophageal brushings are highly sensitive but nonspecific in the diagnosis of EC. A barium contrast swallow study may reveal shaggy mucosal irregularities and nodular filling defects, but this method of diagnosis has been replaced by endoscopy, which not only provides a rapid and highly sensi- tive method of diagnosis, but is also the only reliable method of differentiating among the various other causes of esophagi- tis [89]. The characteristic endoscopic appearance of EC is described as yellow-white plaques on an erythematous back- ground, with varying degrees of ulceration.
In patients with AIDS and Candida esophagitis, gastric involvement is not uncommon and can be manifested by epi- gastric pain, nausea and vomiting. Most patients are asymp- tomatic [74, 83]. There is scant information about the need for or efficacy of antifungal therapy.
Cutaneous Candidiasis
Candida can invade any body surface and cause superficial infection of the skin, hair, and nails. Symptomatic mucocuta- neous candidiasis will occur if dysfunction or local reduction in host resistance promotes an overgrowth of indigenous flora and there is a breach in the anatomical barriers. Dry intact skin is a potent barrier to fungal invasion, and hydra- tion of the epidermis decreases resistance.
Candida albicans and C. tropicalis are the most common causes of superficial infections of the skin and the nails.
These organisms favor growth in warm, moist areas such as the skin folds of obese individuals, between the fingers and toes, perineal areas, and genitocrural folds. Infections in these areas occur with much greater frequency in HIV- positive and diabetic patients and are exacerbated by occlu- sion, moisture, epidermal barrier dysfunction, hormonal manipulation, antibiotic use, and immunosuppression.
Generalized cutaneous candidiasis is a rare form of can- didiasis that manifests as a diffuse eruption over the trunk and extremities. Patients have a history of generalized pruri- tus, with increased severity in the genitocrural folds, anal region, axillae, hands, and feet. Examination reveals a wide- spread rash that begins as individual vesicles that evolve into large confluent areas [92].
Intertrigo is the most common skin infection due to Candida, affecting sites in which skin surfaces are in close proximity providing a warm and moist environment. Infection begins with a vesiculopustular pruritic rash that enlarges and frequently progresses to maceration and erythema. The involved area has a scalloped border with a white rim
Fig. 2 Type III esophageal candidiasis with confluent plaques
175 Candidiasis
consisting of necrotic epidermis that surrounds the erythematous macerated base. Satellite lesions are frequently found and may coalesce and extend into larger lesions. Erosio interdigitalis blastomycetica is a form of intertrigo that occurs in the areas between the fingers and toes and mani- fests as an erythematous painful rash. The affected skin reveals a tender, erythematous area of erosion, that can extend onto the sides of the digits and can be surrounded by maceration [93]. Candida folliculitis is predominantly found in the hair follicles and rarely becomes extensive; it should be differentiated from more common bacterial folliculitis.
Candida paronychia and onychomycosis are seen typi- cally in patients with prolonged immersion of extremities in water and in patients with diabetes mellitus. Nail plate infec- tion is generally not due to Candida species unless it is asso- ciated with congenital candidiasis or chronic mucocutaneous candidiasis [94]. Candida paronychia tends to be chronic, presenting as a painful erythematous area around and under- neath the nail and nailfold. Physical examination reveals an area of inflammation that is warm, glistening, tense, ery- thematous, and extends underneath the nail. Chronic mani- festations of this infection include loss of seal of the proximal nailfold, nail thickening, ridging, discoloration, and occa- sional nail loss.
Chronic Mucocutaneous Candidiasis
This syndrome involves multiple superficial sites, primarily the mouth, facial skin, hair and nails, which are simultane- ously infected with Candida over a prolonged period of time.
Chronic mucocutaneous candidiasis (CMC) is not a single disease entity, and is a consequence of multiple defects in host defenses against Candida. The final outcome is a chronic, superficial Candida infection at sites where Candida normally resides as a commensal organism [95]. Chronic mucocutaneous candidiasis is a rare entity; links between increased incidence of CMC and families of Iranian, Jewish or Finnish descent are described [96, 97]. Most CMC infec- tions begin in infancy or the first two decades of life; onset after 30 years of age is rare. Chronic and recurrent infections frequently result in a disfiguring form of CMC called Candida granuloma. Most patients with CMC rarely experi- ence visceral or disseminated fungal infections. The most common cause of death is bacterial sepsis.
A wide spectrum of CMC clinical syndromes have been described, based on inheritance as well as clinical factors [95, 98]. Group 1 is chronic oral candidiasis associated with HIV, inhaled steroids and denture-stomatitis. Group 2 comprises CMC associated with endocrinopathy (autosomal recessive) and has also been called “Candida endocrinopathy syndrome” or “autoimmune polyendocrinopathy candidiasis
syndrome.” It is now known to be due to mutations in the autoimmune regulator (AIRE) gene. Group 3 is localized CMC that is characterized by hyperkeratosis and cutaneous horn formation that affects both hands. This group is not associated with endocrine dysfunction. Group 4 is diffuse CMC, and includes patients who have widespread and severe infections and in whom familial factors are unknown or obscure. Group 5 includes CMC associated with thymoma, and usually manifests during the third decade of life. In addition, Group 5 CMC is also associated with myasthenia gravis, hypogammaglobulinemia, red cell aplasia, aplastic anemia, and neutropenia. Group 6 is CMC associated with interstitial keratitis [99]. Group 7 is CMC associated with keratitis, icthyosis, and deafness (KID syndrome).
A variety of Candida antigen-specific defects have been described in CMC patients. The commonest abnormality is a negative delayed-type skin test reaction to Candida antigen and is evident in 80% of patients tested (controls 16–37%), regardless of the clinical type of CMC. Approximately 70% of patients tested showed defective in vitro lymphocyte blasto- genesis in response to Candida antigen [100]. A sub population of T-suppressor cells that respond to Candida mannoproteins by inhibiting T-helper cell function has been described [101].
These investigators reported a serum inhibitory factor in CMC patients that suppressed T-cell function. The majority of patients with CMC have normal or high serum antibodies to Candida and no consistent B-cell dysfunction has been reported. T-cell dysfunction is often reversible, with improve- ment in immunological parameters following clinical remis- sion achieved by antimycotic therapy.
Chronic mucocutaneous candidiasis is frequently associ- ated with endocrinopathies such as hypoparathyroidism (80%), hypoadrenalism (72%), ovarian failure (60%), growth hormone deficiency, gonad insufficiency (15%), diabetes mellitus (12%), and chronic lymphocytic thyroiditis with hypothyroidism (5%) [98]. Autoimmune antibodies may be found to adrenal, thyroid, and gastric tissues, and melanin- producing cells (vitiligo). Other features include thymomas and dental dysplasias, polyglandular autoimmune diseases, and antibodies. The onset of CMC is usually within the first year of life in nonendocrinopathy cases and within the first decade when associated with endocrinopathies.
Approximately 90% of all cases of CMC have their onset before the age of 20 years, and about 33% of cases are associ- ated with endocrinopathies.
The earliest lesion to appear is chronic pseudomembra- nous oral candidiasis. Angular cheilitis and lip fissures can develop and infection can spread to involve the esophagus and larynx. In postmenarchal females, Candida vaginitis supervenes, but is not a common feature. These superficial infections tend to be severe, chronic and recurrent in nature.
Persistent onychia and paronychia are nearly as common as oral lesions. Lesions of the fingers vary from discoloration
176 J.A. Vazquez and J.D. Sobel
and dystrophy of the nails to crusting and hyperkeratotic horns (Fig.3a). Skin lesions, when present, are found mainly on the face, neck, ears, and shoulders, and less often involve the scalp and groin. In severe forms of CMC, there are hyper- keratotic crusts or Candida granuloma producing severe dis- figurement (Fig. 3b). The latter findings are invariably found in the idiopathic, infant or juvenile-onset cases and rarely in association with endocrinopathy or mature-onset cases. A striking feature of CMC is the lack of invasive candidiasis.
Other associated disorders include autoimmune hepatitis, iron deficiency and malabsorption syndromes, aplastic ane- mia, hemolytic anemia, pernicious anemia, neutropenia, thrombocytopenia, thymomas, oropharyngeal tumors, and ectodermal abnormalities, such as alopecia and dental dys- plasias. Patients with CMC are also prone to superinfections caused by herpes simplex, herpes zoster, bacteremias, dis- seminated Mycobacterium avium infections, dermatophyto- sis, and occasionally invasive fungal infections.
The evaluation of persons suspected of having any form of CMC should include a complete blood count with differential, lymphocyte phenotyping, T-lymphocyte response
to Candida and tetanus, skin testing with Candida, tetanus, and mumps antigens, lymphokine production by antigen or mitogen-stimulated cells, T and B lymphocyte counts, and serum immunoglobulins. In adults, HIV antibody testing and a chest CT scan to rule out a thymoma should be done [95].
Vulvovaginal Candidiasis
In the USA, Candida vaginitis is the second most common vaginal infection. During the childbearing years, 75% of women experience at least one episode of vulvovaginal can- didiasis (VVC), and 40–50% of these women experience a second attack [102]. Candida is isolated from the genital tract of approximately 10–20% of asymptomatic, healthy women of childbearing age. Candida organisms gain access to the vagina from the adjacent perianal area and then adhere to vaginal epithelial cells. Candida albicans adheres to vagi- nal epithelial cells in significantly greater numbers than non- albicans Candida species [103].
Fig. 3 Chronic mucocutaneous candidiasis showing crusted hyperkeratotic lesions on (a) hands and (b) trunk and scalp