Rare mycoses of the oral cavity: a literature epidemiologic review

Vol. 108 No. 5 November 2009

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE Editors: F. John Firriolo and Nelson I. Rhodus

Rare mycoses of the oral cavity: a literature epidemiologic review Roberta Iatta,a Christian Napoli,a Elisa Borghi,b and Maria Teresa Montagna,a Bari and Milan, Italy UNIVERSITY OF BARI AND UNIVERSITY OF MILAN

Stomatologic fungal infections display different etiologies, pathogenesis, and clinical presentations. The incidence of rare mycoses of oral cavity is very low. These infections can involve both immunocompromised and immmunocompetent patients with common predisposing factors, such as diabetes or suffering from diseases causing immune system impairment. Oral mycoses can cause acute, chronic, and mucocutaneous lesions. Candidiasis is the most common mouth mycosis. Although occasionally primary mouth pathogens, Cryptococcus spp. or filamentous fungi (Aspergillus spp. and zygomycetes) can cause oral mycoses, with the oral localization more commonly secondary to a more serious systemic infection. The diagnosis of oral mycoses is based on clinical examination; for yeasts, culture is necessary to identify the etiologic agents; for filamentous fungi, in particular for zygomycetes and dimorphic, a definitive diagnosis can be made by histologic examination and pertinent stains with or without isolation of the fungus from the same site. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:647-655)

The oral cavity is a primary target for some opportunistic infections that are common among the immunocompromised hosts and elderly, resulting in significant morbidity including oral pain and burning, altered taste sensation, and nutritional impairment. In particular, oral candidiasis (OC) is one of the earliest manifestations in HIV-infected individuals but it can also be observed in other individuals, such as cancer or leukemia patients, denture wearers, and diabetics.1-5 Denture stomatitis is a disease of fungal and bacterial origin.6 Many factors can influence its onset and severity, including salivary flow, denture cleanliness, denture base material, age of denture, denture trauma, continuous denture wearing, smoking, dietary factors,

a

Department of Biomedical Science and Human Oncology, University of Bari. b Department of Public Health, Microbiology, and Virology, University of Milan. Received for publication Feb 24, 2009; returned for revision Jul 8, 2009; accepted for publication Jul 8, 2009. 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.tripleo.2009.07.010

and denture plaque pH.7,8 Nowadays, other rare stomatologic mycoses can be observed, especially in immunocompromised individuals. These are mainly caused by microorganisms that are widespread in nature, yeasts such as Cryptococcus spp. or filamentous fungi such as Aspergillus spp., zygomycetes, and dimorphic fungi (Histoplasma, Blastomyces, Coccidioides). The bases of these organisms’ emergence are multifactorial, involving the more intense immunosuppression therapy adopted, the prolonged survival of patients, the selective pressure of broad-spectrum antibiotics and corticosteroid agents, or the large diffusion of infective causes (HIV, above all). Some rare fungi previously geographically restricted (particularly dimorphic agents) with globalization and travels are now described worldwide. Rare mycoses of the oral cavity are classified according to their clinical and etiopathogenetic characteristics. They may have a primary oral localization (zygomycosis) or a secondary in more severe forms (aspergillosis), or they can be disseminated such as those provoked by Cryptococcus neoformans or by dimorphic fungi. This review details the possible etiologic agents that can cause rare oral mycosis, focusing on their epidemiology, manifestations, and management. 647

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CRYPTOCOCCOSIS The Cryptococcus genus includes spherical opportunist yeasts that generally lack a mycelium but have a polysaccharide capsule (⬍2 ␮m) as the main virulent factor.9 The onset of the infection follows inhalation of the spores, with a primary localization in lungs from which they spread through the bloodstream to the central nervous system (CNS), causing meningitis. Etiology Two Cryptococcus species can cause diseases in humans (C. neoformans and C. gattii), with 5 different serotypes, namely C. neoformans var. neoformans (serotypes D and AD), C. neoformans var. grubii (serotypes A), and C. gattii (serotypes B and C).10,11 Cryptococcus neoformans is a ubiquitously distributed microorganism. It has been isolated in the soil and in the feces of birds, such as pigeons (Columbia livia), canaries, and parrots.12,13 Because in feces it is protected from the sun’s rays and high temperatures, the microorganism can survive for a long time, resistant even to natural drying of the vector matter. Subsequent airborne dispersion of the particles released from the biologic substrate facilitates the spread of the microorganism and its inhalation by humans. In contrast, the natural reservoir of C. gattii is the koala bear (Phascolarctos cinereus), and it is endemic in Australia and temperate zones, where it is also frequently found on trees of the Eucalyptus genus.14,15 Recently, some clinical cases due to minor species, such as Cryptococcus laurentii and Cryptococcus albidus, have also been reported.16,17 Epidemiology Clinical concern about this microorganism has dramatically increased since the AIDS advent. Before 1981, cases of cryptococcosis were rare, but since 1990 the first epidemics have been recorded, including one in New York in which about 1,200 cases of cryptococcal meningitis were reported in HIV-positive subjects.18 To date, cryptococcosis remains one of the most common life-threatening systemic fungal infection in HIVinfected patients. Although its incidence has greatly decreased in Europe since the introduction of highly active antiretroviral therapy (HAART),19-21 it is still high in developing countries22 and represents the main cause of meningitis in Africa.23 Recently, the interest in the primary pathogenic form of C. gattii has increased owing to an outbreak infection on Vancouver Island in Canada. Since 1999, more than 66 human cases, with at least 4 fatalities, have been reported in otherwise healthy individuals and are attributable to infection with serotype B.24 The emergence of C. gattii, usually a tropical pathogen, high-

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lights its capacity to infect immunocompetent individuals and the changing of this genotype’s geographic distribution. Pathogenesis and clinical aspects Cryptococcus neoformans infection generally affects immunocompromised hosts, whereas C. gattii is more often isolated in immunocompetent subjects.25 In AIDS patients, C. neoformans–induced meningoencephalitis is the most frequent opportunistic mycosis reported (80%). It shows a mortality rate of 30%-40%, particularly due to the difficulty in eradicating the pathogen, to the frequent recurrences, and to systemic spread often associated with other infective complications.26 Primary cutaneous and mucocutaneous forms are relatively rare, and secondary forms account for 15% of disseminated infections.25-28 Gastrointestinal cryptococcosis can be observed in absence of CNS or respiratory tract infections in patients undergoing steroid therapy or affected by chronic liver disease and in splenectomized patients. There have been only sporadic reports of oral manifestations. A case of cryptococcosis of the parotid gland is described in the literature in a patient wearing dentures who was infected by contaminated soil after oral cavity trauma.8 The invasive infection is always fatal without treatment. Therefore, rapid diagnosis and treatment is required to decrease mortality. Combination of amphotericin-B and flucytosine is the treatment of choice for the first 2 weeks, followed by fluconazole maintenance therapy.29 Diagnostic tests A microbiologic diagnosis of cryptococcosis is made by isolating the microorganism in sputum samples or bronchoalveolar lavage for pulmonary infection, in cerebrospinal fluid (CSF) and blood for disseminated forms, and in biopsy samples for cutaneous or subcutaneous diseases. The ink test on CSF and the search for circulating antigens on serum and/or CSF samples represent highly valid laboratory tests for a rapid and accurate diagnosis.27 ZYGOMYCOSIS Zygomycoses are caused by filamentous fungi, generally saprophytic, characterized by large coenocytic hyphae that grow rapidly and are widely distributed in nature. They are commonly considered to be opportunistic pathogens, although such clinical manifestations are no longer regarded to be unusual, owing to their increase in diabetic subjects and in those receiving immunosuppressive therapies. Two orders are of clinical concern: Mucorales and Entomophthorales.

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Etiology The order of Mucorales includes the genera most often implicated in human pathologies: Rhizopus, Mucor, Absidia, Cunninghamella.30,31 These microorganisms are responsible for acute deep mycoses with a rapidly fatal evolution that generally affect immunocompromised patients, although some cases have been recorded even in healthy subjects.32,33 The most common species are Rhizopus oryzae, Rhizopus microsporus and Rhizomucor pussillus. In contrast, the order of Entomophthorales is of limited concern in immunocompromised hosts, causing infection mainly in immunocompetent subjects after trauma, and do not present the same degree of invasiveness as Mucorales. Two genera are known to be implicated in human disease: Conidiobolus and Basidiobolus, responsible for subcutaneous infections and, less frequently, for disseminated forms.33 Epidemiology These molds can be found, worldwide, in soil, decomposing plants, and dejections of insects, reptiles, and amphibia. Although zygomycetes are very common in nature, disease episodes are often confined among inhabitants of tropical areas, especially in Africa. Active population-based surveillance in San Francisco, California, during 1992-1993 revealed an incidence of zygomycosis of 1.7 cases per million persons per year.34 An Italian study conducted on 391 hematologic patients showed that 45 patients (11.5%) were infected by Mucorales.35 Furthermore, a study involving organ transplant recipients showed that zygomycoses accounted for 5.7% of all opportunistic mold infections in these patients.36 Regarding oral zygomycoses, only sporadic cases are reported, and no epidemiologic data are provided on their distribution. Pathogenesis and clinical aspects Disease onset occurs after inhaling a high infective dose of spores, usually in immunocompromised subjects (organ transplant or neutropenic patients) or with an underlying disease (diabetes or acidosis).37 The infection is initially localized in the paranasal sinuses, but can often evolve in a fatal outcome after spreading to the brain (62%). Pulmonary zygomycosis generally affects hematologic or severely neutropenic patients, whereas a skin infection typically progress after skin trauma or burns.38,39 In the literature, cases of oral zygomycosis have most often been described in patients with leukemia or diabetes, with a primary localization on the palate or on mouth soft tissues, or a secondary localization following pulmonary infection.38,40-42 An unusual literature case report is represented by a tongue mucormycosis in

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a child affected by Down syndrome hospitalized for acute gastroenteritis. The infection was thought to have been caused by a wooden tongue depressor used during the medical examination.43 Other cases usually involve deep hard palate ulcers or maxillary necrosis due to mucormycosis in diabetic patients.40,44 In the Auluck case report,40 the intraoral examination showed a necrotic bone of about 1 cm diameter in the right maxillary molar region; maxillary molars were missing, and surrounding soft tissues were normal. Hard tissue specimen along with the adjacent soft tissue was excised and sent for histopathologic examination. The hematoxylin and eosin stain readily showed nonseptate hyphae suggestive of mucormycosis. Grocott modified silver methenamine special staining technique further identified these nonseptate branching hyphae as zygomycetes. The patient was administered amphotericin-B 0.8 mg/kg/day intravenously for 2 weeks. After that, the area started healing.40 Amphotericin-B is the recommended antifungal drug for zygomycosis treatment. In refractory cases, posaconazole may have a useful role. Early clinical diagnosis and treatment with surgical debridement of infected tissue combined with antifungal therapy represent the best management.38,42 Diagnostic tests A definitive diagnosis of zygomycosis is obtained by histology with or without isolation of the microorganism in culture, bearing in mind the known growth difficulties. The characteristic hyphae are better evident with Gomori-Grocott staining than periodic acid–Schiff (PAS) or calcofluor white.31,42 ASPERGILLOSIS The term aspergillosis covers different clinical pictures caused by fungi belonging to the Aspergillus genus. The disease course depends on the type of infection, the amount of inhaled conides, and the general conditions of the host. It can manifest as an “opportunistic” form, localized in various organs and apparatuses of immunocompromised hosts undergoing prolonged immunosuppressive or chemoantibiotic treatment, or of those affected by severe debilitating disease, as well as patients who have undergone bone marrow or solid organ transplants.45-47 The type of infection depends on the subject’s overall conditions and the fungal species involved. Etiology The Aspergillus genus includes ⬎180 species, about 20 of which are responsible for clinical manifestations. The main species is A. fumigatus, followed by A. flavus, A. niger, A. nidulans, and A. versicolor.

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Epidemiology Aspergillus is a ubiquitous fungus capable of producing diverse clinical entities with varying severity. An important United States study demonstrated a high incidence increase from the 1970s, and in 1996 the estimated aspergillosisrelated hospitalizations were 10,190/yr.48 Aspergillus fumigatus is the species most often implicated in human diseases (50%-70%).49 Another review on representative cases of invasive aspergillosis (IA) on 595 patients, showed that 56% of them presented pulmonary disease and 19% a disseminated infection. The major risk factors for aspergillosis were bone marrow transplantation (32%) and hematologic malignancy (29%), but other underlying conditions were reported, including solid organ transplants (9%), AIDS (8%), and pulmonary diseases (9%).47 In a 10-year Italian retrospective analysis on infections caused by filamentous fungi in 391 patients with hematologic malignancies, Aspergillus spp. represented the main cause (75.7%) and A. fumigatus was the most representative species (36.5%).35 Pathogenesis and clinical aspects Although Aspergillus conidia inhalation is very common, the disease is rare in healthy subjects. Clinical forms include colonization, invasive infections, and allergic forms. The worst form is the invasive, especially in immunocompromised subjects, with either pulmonary or extrapulmonary localization. Cases of paranasal sinuses invasion (often in association with other mycetes) or of allergic bronchopulmonary aspergillosis are by no means rare in these subjects. Instead, oral aspergillosis is rare and mainly affects hosts at particular risk or with an impaired immune system. A case of jawbone infection by Aspergillus spp. has been reported after tooth extraction in a diabetic patient50 and gum involvement has been documented in a neutropenic patient affected by leukemia.51 In the first case, after extraction of a posterior tooth the patient began to suffer from facial pain. The pain worsened despite antibiotic treatment. Six months after the onset, serum tests and biopsy diagnosed an invasive aspergillosis of the left masticator space including the mandibular bone. The infection responded to itraconazole treatment.50 Another case of acute lymphoblastic leukemia patient with hard palate perforation due to invasive aspergillosis is described. Two months after the appearance of the fungal lesions, perforation of the hard palate was seen despite amphotericin-B and itraconazole regimen. After necrotic tissue debridement, the patient was followed-up for 6 months for spontaneous closure, but the fistula persisted despite the infection disappearance. The palatal fistula was then surgically

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closed, and there was no recurrence in 6 months of follow up.52 A case report of a patient with Castleman disease, suffering of a mixed infection by Aspergillus spp. and Mucor spp. at the orosinus level, is also reported. Ulceration processes progressively involved the palatal mucosa and bone tissue, the paranasal sinuses, and the orbits. At clinical examination, there was prominent tumefaction of the right hemiface, involving the periorbital, zygomatic, and maxillary areas, nasosinusal congestion, and diffuse ulcerative lesions of the palatal and cheek mucosa. Intraoral examination disclosed a 3 ⫻ 3 cm painful palatal lump, with black central crusting and prominent edematous-erythematous changes of the surrounding tissues. An incisional biopsy was performed, and the histologic exam was mainly composed of PAS-positive elongated fungal hyphae stained light blue with the Giemsa stain and dark brown to black with both the Lugol solution and the Grocott-Gomori silver methenamine method.49 Some authors described, in two young healthy female patients, an unusual case of aspergillosis of the maxillary sinus in association with overextension of root canal fillings with certain root canal cements. It has been suggested that zinc oxide– based root canal cements might promote infection with the Aspergillus species, in particular A. fumigatus.53 In most of these case reports, the antifungal treatment with oral itraconazole alone or in association with amphotericin-B has been effective.50,52 Diagnostic tests Because Aspergillus conidia are normally present in the environment, laboratory data are often insufficient to make a definite diagnosis. In some cases, particularly for invasive aspergillosis, the finding of circulating antigen, galactomannan (GM) and 1,3-beta-glucan (BG), and/or specific antibodies in the serum can support the diagnosis. The GM and BG assays may be useful diagnostic tools, but their sensitivities are variable. This variability may be due to different host-related factors and to human exposure to antifungal agents. However, the performance of GM-based diagnosis appears to be more efficient in detecting infections caused by non-fumigatus Aspergillus spp. The diagnostic BG marker was shown to have a higher sensitivity than that of GM in detecting IA and other mold infections in hematologic malignancy patients.54 In those forms involving the oral cavity and paranasal sinuses, only a biopsy can provide a definite diagnosis. MYCOSES DUE TO DIMORPHIC FUNGI Dimorphic fungi are microorganisms that can grow either in mycelial morphology in the external environ-

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ment or in yeast-like form in the host tissues. The morphologic transformation from mold to yeast confers virulence to these microorganisms. For these reasons, they are retained primary pathogens, being able to cause disease even in immunocompetent subjects. The severity of the resulting infection depends on the inhaled spores load, the duration of exposure, and the host immune status.55 Etiology This geographic distribution of this fungal group is well defined, and they are confined to circumscribed area, generally representing endemic mycoses: in particular, Blastomyces dermatitidis and Histoplasma capsulatum var. capsulatum are frequent in North America, Histoplasma capsulatum var. duboisii in Africa, Coccidioides immitis in California, C. posadasii in Texas, Arizona, and countries in Latin America, Paracoccidioides brasiliensis in Brazil and some other areas in Latin America, and Penicillium marneffei in southeast Asia. In contrast, Sporothrix schenckii is geographically much more widespread.56-58 Imported dimorphic mycoses must also be considered in nonendemic areas, because it can easily be misdiagnosed and therefore incorrectly treated.59,60 Epidemiology Histoplasmosis is highly endemic to the Ohio and Mississippi river valleys of the United States. An estimated 40 million people in the US have been infected with H. capsulatum, with 500,000 new cases occurring each year.55 Coccidioidomycosis is a recognized opportunistic infection among HIV-positive persons. The incidence declined dramatically since the advent of potent HAART. It is estimated that upwards of 100,000 primary human coccidioidal infections occur each year in the endemic U.S. areas. In recent years, the incidence of the disease has increased in California and Arizona, which may be partially due to greater migration of Americans to these areas.61 Brazil accounts for 80% of reported cases of Paracoccidioides brasiliensis (⬎5,000), followed by Colombia and Venezuela. This infection is observed only exceptionally in children (3%) and young adults (10%). It is diagnosed more frequently in men between 30 and 50 years old, most of them (70%) being farmers.62 Sporotrichosis has been mainly reported in tropical and temperate zones. In South America, it occurs more frequently in humid autumn or in summer, whereas in Mexico the highest incidence is observed in cold and dry seasons. It can affect all ages.62

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Epidemiological data regarding prevalence and incidence of these diseases are fragmentary or not available, and their true incidence is still unknown. Pathogenesis and clinical aspects All mycoses due to dimorphic fungi can spread to other sites after a first, generally asymptomatic, localization at the pulmonary level. In some cases the lesions may be extrapulmonary, affect the oral cavity or intestine. Blastomycosis (Blastomyces dermatiditis) can cause skeleton and urinary tract pathologies. Primary skin infections are rare.63,64 Histoplasmosis (Histoplasma capsulatum) causes chronic disseminated forms or acute forms with a fatal outcome, especially in newborns or in severely immunocompromised subjects.55 In some cases, the fungus can spread from the lungs to the skin and to the oral cavity. The oral lesions are frequently granulomatous and appear as nodular ulcerative or vegetative lesions that may be painful, localized on the oral mucosa, tongue, hard and/or soft palate, or lips. The ulcers have raised and rolled borders, commonly covered by a yellow or greyish membrane, resembling carcinoma or tuberculosis.65,66 In some cases, the primary manifestation could be observed in the oral cavity, with initial gum lesions, progressing to and damaging hard palate and then extending to the maxillary sinus and nasal cavity. This kind of oral presentation is more often typical of HIV infection.67 In contrast, disseminated histoplasmosis with oral involvement has been rarely described around the world in immunocompetent patients. A case of chronic disseminated histoplasmosis, with the sole lesions in the oral cavity, has been reported in an alcohol-dependent Brazilian patient, HIV negative, without other subjacent underlying disease. The medical examination revealed a hypomobile indurated tongue, with firm consistency and the presence of crater-like ulcers, with inflamed base and irregular borders. This lesion was located in the right margin, extending to the dorsal surface of the tongue. The ulcer border was elevated, white, well demarcated, and hard. It was friable and bled upon scraping and was extremely painful to palpation. Another irregular ulcerated lesion with the same characteristics was observed in the medium lateral portion and dorsal surface of the tongue in the left side. A third lesion with irregular peripheral margin, granular surface, and pain on palpation was presented at the posterior hard palate, extending to the soft palate, tonsil pillar, and uvula. Biopsy was performed on one of the tongue lesions, and palate tissue was excised. Both tissue fragments were submitted to the laboratory for histopathologic and microbiologic examination. Histopathology revealed pseudoepitheliomatous hyperplasia, with granulomatous chronic inflammatory process. Furthermore, H. capsulatum–like yeasts were evident, as demonstrated by PAS and Grocott stains.68

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A case imported in Italy was on a 44-year-old Tanzanian immonucompetent male who presented painful lesion of the tongue. He had emigrated from Tanzania to the U.S. and from the U.S. to Italy.69 Another report describes a histoplasmosis presenting as oral ulcer in a non-HIV patient in Malaysia, where the pathology is very rare.70 For the remission of oral lesions the treatment with itraconazole resulted effective.68 Coccidioidomycosis, caused by Coccidioides immitis, can present with different clinical pictures. In about 60% of cases it is asymptomatic, and the remainder are benign syndromes (“valley fever”) or may evolve into pulmonary or extrapulmonary disease.61 Therapy for the more severe forms of coccidioidal infection was once limited to amphotericin-B but now includes azole antifungal agents.61 Paracoccidioidomycosis (Paracoccidioides brasiliensis) is often a subclinical infection but can manifest with a wide spectrum of clinical presentations, frequently involving the mouth. In many cases, the first and main clinical manifestations are oral lesions, and the dental surgeon can play an important role in diagnosis and treatment.58 Usually, the oral lesions are multiple, involving the lip, gingival and buccal mucosa, palate, tongue, and floor of the mouth. Although not common, oral paracoccidioidomycosis can occur in a patient in good general health. In one case,71 the hard and soft palate presented erythematous ulcers with a finely granulated base and irregular, but clearly defined, margins. A perforation (diameter 0.5 cm) of the hard palate was seen in the center of the ulcerated region. Direct examination of 10% KOH– cleared specimens showed typical double-walled multiple budding yeast structures. Paracoccidioidomycosis serologic tests were positive. Hematoxylin and eosin–stained sections of oral lesions showed an ulcer covered by a fibrous leukocytic crust, with a lymphoplasmacytic infiltrate, as well as multinuclear giant cells containing round bodies with a double membrane. Gomori-Grocott staining showed budding and blastoconidia suggestive of mycoses.71 A case of imported paracoccidioidomycosis was described in a 60year-old Dutch man who presented with a painful ulceration in the buccal mandibular vestibular mucosa of 3 months’ duration.60 Paracoccidioides brasiliensis sometimes draws an unusual picture, as in a case of a patient with paracoccidioidomycosis of the larynx that mimicked a carcinoma.72 Amphotericin-B has provided effective therapy. Azole derivatives have also improved prognosis and facilitated therapy. Itraconazole is presently the drug of choice. Sporotrichosis, caused by Sporothrix schenckii, generally manifests at the lymphocutaneous level.62 Penicilliosis, due to Penicillium marneffei, is an important problem in HIV-positive patients. In Thailand, this

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disease is the third cause of infection in patients with AIDS, after tuberculosis and cryptococcosis.73 Apart from pulmonary localizations and disseminated forms, the fungus can cause skin lesions that may ulcerate and even affect the bone.74 Oral P. marneffei lesions usually occur in patients with disseminated infections, presenting as shiny papules, as erosions, or as shallow ulcers covered with whitish yellow, necrotic slough which may be found on the palate, gingiva, labial mucosa, tongue, and oropharynx.75-77 Treatment of P. marneffei infection is based on parenteral amphotericin-B and itraconazole. Although amphotericin-B is recommended for seriously ill patients, itraconazole has been suggested as drug of first choice in the treatment of mild to moderately severe P. marneffei infections. Diagnostic tests The isolation of the fungus from clinical specimens is the definite method for establishing a precise etiologic diagnosis. However, a presumptive rapid diagnosis of dimorphic mycoses is possible by direct sample examination with pertinent stains highlighting fungal elements. It is highly recommended to perform cytologic or histologic tests, supported by serologic findings for antibodies and antigen detection, especially in cases of histoplasmosis. DISCUSSION This review has focused on the extremely unusual fungal infections that can occur in the oral cavity of immunocompromised or healthy individuals. Among about 100,000 different species of fungi, only a few are pathogenic for humans, and most of them show distinct geographic distribution. In recent years, the dramatic raise of immunocompromised patients, due to iatrogenic (mostly organ transplantation or immunosuppressive treatments) or infective causes (HIV infection above all), resulted in increasing reports worldwide of systemic fungal infections. With the exception of candidiasis, isolated oral mycotic lesions are occasionally encountered, generally detected in association with respiratory tract or disseminated fungal infections, most of the latter potentially being ominous or lethal for the patient.65 Many authors showed that these fungi very rarely arise in healthy individuals,8,53,68 commonly affecting insulindependent diabetics,40,50 immunocompromised,66,67 or leukemic patients.38,52 Despite the apparent rarity of these kinds of infections, clinicians, microbiologists, and pathologists should be aware of these rare mycoses when cases of oral ulcer are encountered. Knowledge of patients at risk should be important, in particular for the clinicians, to hypothesize and to make an

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accurate and early diagnosis, which often is not easy. Otherwise, these pathogens can disseminate, with a fatal result. Moreover, in view of the risk of dissemination of the etiologic agent to other body sites, of the difficulties of clinical management owing to drug resistance onset, and of the peculiar clinical features of these diseases, a greater attention needs to be paid to the planning of appropriate prevention measures. For microbiologists, it is important to remember that the isolation of etiologic agents represents the best way to make a precise diagnosis, but some of them, particularly dimorphic fungi, represent severe biohazard risk to laboratory personnel because of the highly infectious conidial form. So they must be handled with extreme caution and only within a biologic containment cabinet. Moreover, surgery dental practices can play an important role in this context. The literature reports the occurrence of fungi in water and biofilms present in dental unit waterlines.78,79 Szymanska79 demonstrated that favorable conditions for fungal growth are provided by the biofilm formation on the waterline walls, which is periodically released and may contaminate the water flowing from handpieces. The water in bioaerosol produced during the work of dental handpieces can contain fungi and may be a health threat for both patients and dental staff. Other studies have shown that the environment (water, air, and surfaces) and consequently unsterile dental conditions can represent a potential risk for infection, particularly in patients who are immunocompromised due to drug therapy, alcohol abuse, systemic diseases, and old age.80 Thus, it is necessary to submit the dental unit waterlines to decontamination protocols and routine microbial monitoring to guarantee an appropriate quality of water used in dental treatment. This kind of health care practice could represent an important transmission route of infectious agents such as fungi. The American Centers for Disease Control and Prevention has provided guidelines for infection control in dental care settings. These recommendations regard different aspects, such as sterilization and disinfection of patient-care items, environmental infection control, dental unit waterlines, biofilm, and water quality. They represent a good-practices guide in the management of the dental patients.81 In conclusion, dental physicians’ knowledge concerning fungal infections and practice behaviours are crucial to prevent complications or to make a precise diagnosis of oral mycoses.

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Reprint requests: Roberta Iatta Department of Biomedical Science and Human Oncology University of Bari c/o Policlinico—Piazza Giulio Cesare 11 70124 Bari Italy [email protected]