Fungal Infections of the Oral Mucosa

Etiology

Oral Candidiasis

Candida albicans causes around 95% of oral candidiasis infections.[5] Up to 80% of the general population are asymptomatic carriers of Candida albicans, and simple carriage does not predictably lead to infection.[5] However, infections caused by antifungal-resistant, nonalbicans species have increased in recent years, possibly due to age, malignancy, use of polyenes and azoles, indwelling catheters, and more advanced diagnostic methods.[6] 

Nonalbicans species include Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida dubliniensis, Candida guilliermondii, Candida krusei, and Candida kefyr. Besides C albicans, C glabrata and C dubliniensis are most commonly isolated from oral lesions in HIV patients.[7] Candida auris is an emerging, multidrug-resistant strain causing outbreaks in healthcare settings, particularly among post-COVID-19 patients.[8]

Aspergillosis

Aspergillosis is caused by Aspergillus species, saprophytes that grow on dead and decaying matter. Aspergillus fumigatus is the most common cause of invasive disease since the size of its conidia favors penetration into alveoli, promoting establishment in host tissues even in the absence of severe local trauma.[9][10] Aspergillus flavus can cause infections limited to the paranasal sinuses, which may extend to adjacent oral tissues.[11] 

Mucormycosis

Mucormycosis, otherwise known as zygomycosis, is caused by fungi of the order Mucorales, primarily the genera Rhizopus, Mucor, and Rhizomucor. Other clinically relevant organisms within the order Mucorales include: Actinomucor, Apophysomyces, Cunninghamella, Lichtheimia (previously named Absidia), Saksenaea, and Syncephalastrum.[12] Rhizopus accounts for 90% of rhinocerebral mucormycosis,[13] a rare opportunistic infection involving the brain, nasal cavity, oral cavity, and paranasal sinuses.[14] Rhizopus oryzae, Rhizopus microsporus, and Absidia corymbifera are the commonly isolated species in patients with mucormycosis.[15]

Histoplasmosis

Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic environmental fungus that thrives in soil contaminated with bat or bird excreta.[16] The 2 clinical entities of histoplasmosis in humans: the infection caused by H capsulatum var capsulatum, known as Darling disease, small-form histoplasmosis, or American histoplasmosis; and the infection caused by H capsulatum var duboisii, referred to as large-form histoplasmosis or African histoplasmosis.[17]

Blastomycosis

Blastomyces dermatitidis, a spore-forming dimorphic fungus, causes blastomycosis.[18] B dermatitidis organisms live in acidic, moist, and sandy soil. Blastomyces helicus and Blastomyces percursus are the other species recognized in blastomycosis.

Cryptococcosis

Cryptococcus neoformans var grubii, Cryptococcus neoformans var neoformans, Cryptococcus gattii, Cryptococcus bacillisporus, Cryptococcus deuterogattii, Cryptococcus tetragattii, and Cryptococcus decagattii are the Cryptococcus species known to be pathogenic. Cryptococcus neoformans is found in the excreta of birds, eg, pigeons, in the environment, eg, in amoeba nests, and in tree hollows.[19] Cryptococcus gattii is frequently associated with various eucalyptus species, particularly in tropical and subtropical regions.[20]

Paracoccidioidomycosis

Paracoccidioidomycosis or South American blastomycosis is caused by the thermodimorphic fungus Paracoccidioides brasiliensis complex, which comprises Paracoccidioides brasiliensis, Paracoccidioides americana, Paracoccidioides restrepiensis, and Paracoccidioides venezuelensis or Paracoccidioides lutzii.[21]

Geotrichosis

Geotrichosis is a rare opportunistic fungal infection caused by Geotrichum candidum. Species, eg, Geotrichum capitatum and Geotrichum clavatum, can affect the lungs.[22]

Epidemiology

Oral Candidiasis

Oral candidiasis is the most common oral fungal infection and is associated with extremes of age, particularly in newborns and older adults. Almost 5% to 7% of infants develop oral candidiasis.[23] Other risk factors include, but are not limited to, oral immunosuppression, diabetes mellitus, malnourishment, long-term steroid treatment, antibiotic treatment, and denture use.[24] The prevalence increases in patients with AIDS, cancer, and those undergoing radiotherapy or chemotherapy.[5]

Aspergillosis

Aspergillosis is the second most common oral mycosis after candidiasis, with a higher prevalence in males. Though primary invasive aspergillosis is uncommon in the oral cavity, dissemination from the nose or sinuses can result in oral aspergillosis.[25] Aspergillosis frequently occurs in patients with uncontrolled diabetes mellitus, immunocompromising conditions, and those undergoing chemotherapy.[26] The gingiva is the most commonly affected area, followed by the hard palate and maxillary sinus.

Mucormycosis

Mucormycosis is the third most common oral mycosis and can potentially become a fatal opportunistic fungal infection in individuals with diabetes mellitus, hematological malignancies, or undergoing deferoxamine therapy.[27] Mucormycosis rarely occurs in healthy individuals. The incidence of rhinomaxillary mucormycosis in COVID-19 patients has risen due to poorly controlled diabetes, prolonged use of corticosteroids, cytokine storms, lymphopenia, endothelial damage, and iron dysregulation.[28] Oral mucormycosis commonly occurs in the fourth to sixth decade of life.[29] Moreover, up to half of the patients with mucormycosis have diabetes, and this condition is the most prominent underlying medical comorbidity in infected patients.[30][31]

Histoplasmosis

Histoplasmosis is the most common systemic fungal infection in the United States and is more prevalent in men.[32] Histoplasmosis capsulatum has a worldwide distribution, with the highest prevalence in the central United States. In West Africa, however, Histoplasma duboisii is more common.[17] Histoplasmosis predominantly affects adults and is more frequently reported in individuals with underlying immunocompromising conditions, including HIV/AIDS, hematologic malignancies, organ transplantation, and the use of tumor necrosis factor-α inhibitors.[33] The lungs are the primary site of infection, while oral involvement is relatively uncommon. Disseminated histoplasmosis can affect the oral cavity as part of the initial presentation of a disseminated form, as a localized lesion, or as the only manifestation. Oral histoplasmosis most frequently occurs in the tongue, palate, and lips.[34]

Blastomycosis

Blastomycosis is endemic in Central and Southern North America. Sporadic cases of blastomycosis in humans have also been documented outside endemic regions, including Hawaii, Israel, India, Africa, and parts of Central and South America.[35] Unlike histoplasmosis, blastomycosis frequently affects immunocompetent individuals, and there is no reliable way to screen for exposure to the fungus. Oral lesions present as a result of dissemination or local inoculation.[36] Blastomycosis is prevalent in men aged 20 to 50 years who work outdoors.

Cryptococcosis

Cryptococcus neoformans causes infection in both immunocompromised and immunocompetent individuals, but Cryptococcus gattii infects immunocompetent hosts. C neoformans causes 95% of cryptococcal infections, whereas only 4% to 5% are caused by C gattii.[19] HIV patients account for more than 80% of cryptococcosis cases.[19] The central nervous system and lungs are the most frequently affected areas; oral lesions occur rarely.

Paracoccidioidomycosis

Paracoccidiomycosis is endemic in Latin America, with higher prevalence among males aged 30 to 60.[37][38] The beta-estradiol in female hormones prevents the conversion of hyphae to yeast form, resulting in a lower prevalence in females.[39]

Geotrichosis

Geotrichosis is rare in the nails, skin, and oral cavity. Pulmonary infection is the most common form of the disease.[40] Most cases occur in adults, with a slight female predominance. Individuals with underlying conditions, eg, tuberculosis, diabetes mellitus, lymphoma, leukemia, HIV/AIDS, or those receiving immunosuppressive therapy are at increased risk of infection.[40]

Pathophysiology

Oral Candidiasis

Candida albicans is a commensal fungus in the oral cavity. Commensal microorganisms reside on the external surface of the body or mucosa without adversely affecting human health. However, they may become pathogenic under certain conditions, causing superficial to invasive disseminated infections. Candida reversibly adheres to the oral epithelial cells through electrostatic interactions in its commensal yeast state.[5] Cell-wall receptors, eg, the agglutinin-like sequence family of glycoproteins, mediate attachment.[5]

When host defence mechanisms are impaired, the yeast undergoes a morphological transition to the filamentous hyphal form, a process known as phenotypic switching, which is critical for invasion of host tissues.[5] Host defence against C albicans is primarily mediated by cell-mediated immunity and Th17-associated cytokines; disruption of these mechanisms predisposes to mucocutaneous candidiasis.[41] Extracellular hydrolytic enzymes, eg, secreted aspartyl proteinases and secreted phospholipases produced by C albicans, facilitate host tissue destruction and subsequent invasion.[5] In addition, C albicans can form biofilms on denture bases, increasing virulence and reducing susceptibility to antifungal agents.[42]

Aspergillosis

The infectious mechanism of aspergillosis involves the fungal conidia entering the respiratory tract by inhalation. In healthy individuals, these spores are effectively cleared by innate immune mechanisms, primarily alveolar macrophages. Neutrophils encounter conidia that escape macrophage surveillance, and in patients with underlying risk factors, the conidia germinate and disseminate by angioinvasion, spreading to the skin, orbits, and palate.

After Aspergillus has inoculated the oral cavity, it can invade the host tissues by releasing toxins, eg, aflatoxin, proteases, phospholipases, hemolysin, gliotoxin, and phthalic acid.[25] Spores can also enter the sinuses during dental procedures, eg, root canal procedures or tooth extractions.[43] In hospital settings, exposure to decaying organic matter or inadequate dust control may increase the risk of aspergillosis in vulnerable patients.[44] The infection's clinical manifestation depends on the organism's pathogenicity and the host's immune response.

Mucormycosis

Fungal spores can gain entry into the host through inhalation into the respiratory tract, direct inoculation at sites of skin trauma, or ingestion through the gastrointestinal tract.[45] Neutrophils and phagocytes play a central role in host defense, explaining the increased susceptibility to mucormycosis in patients with diabetes mellitus, neutropenia, or those receiving deferoxamine therapy. The infection usually starts in the nasal cavity, where the humid environment favors fungal growth. Oral infection usually spreads through the paranasal sinuses via the nose or direct wound contamination.

The palate is affected if the infection spreads through the sinuses. Wound contamination can affect any part of the oral cavity. Implantation of the organism into the maxilla can occur during any oral surgical procedure.[29] The fungi exhibit angioinvasion, invading small blood vessels and forming intravascular thrombi, thereby reducing tissue perfusion and resulting in extensive necrosis. In diabetic ketoacidosis, acidosis promotes the release of iron from iron-binding proteins, eg, transferrin, increasing serum iron availability; fungal hyphae produce rhizoferrin, which chelates iron and facilitates fungal iron uptake, thereby enhancing growth and tissue invasion.[46]

Histoplasmosis

Histoplasma capsulatum is a thermally dimorphic fungus that exists as a mycelial form in soil enriched with bird or bat guano and converts to a yeast form after inhalation into the host.[32] After passing through the mucosal barriers in the terminal passage of the lungs, the yeasts are phagocytosed by macrophages, and the host defense mechanism usually destroys them, as Dectin-1 is a macrophage receptor that recognizes β-glucan present in the cell wall of Histoplasma. The organism evades immune recognition by masking β-glucan with α-linked glucan and by expressing heat shock protein 60 on its cell surface, which binds to the complement receptor 3 (CR3) on host macrophages and facilitates cellular entry without triggering a significant inflammatory response.

In immunocompetent individuals, cell-mediated immunity leads to granuloma formation and containment of infection, whereas impaired immunity permits intracellular proliferation and hematogenous dissemination to reticuloendothelial organs and occasionally the oral mucosa. The most common pathological findings include pulmonary granulomas and intracellular yeast forms within macrophages.[16]

Blastomycosis

Following inhalation, Blastomyces dermatitidis conidia are phagocytosed by alveolar macrophages, neutrophils, and monocytes. Conidia that survive phagocytosis undergo a morphological shift to the yeast form, which is resistant to phagocytosis due to a thick capsule.[18] The conversion of conidia to yeast form in response to a change in temperature from 71.6 °F (22 °C) to 98.6 °F (37 °C) is essential for its pathogenicity, which is mediated by the virulence factors dimorphism-regulating kinase-1 and blastomyces adhesion-1 (BAD1).

Cryptococcosis

The infectious mechanism of cryptococcosis is characterized by inhaled spores entering the lungs and activating alveolar macrophages. The macrophages, in turn, recruit other immune cells to elicit helper T-cell responses with cytokines including TNF, interferon-γ, and IL-2, causing granulomatous inflammation.[47] The yeast can remain latent within phagolysosomes in thoracic lymph nodes for many years.

The prominent mucopolysaccharide capsule and other virulence factors (eg, melanin production, phospholipase, and urease activity) protect the fungi against host defenses, enabling them to survive within macrophages. The fungi produce mucin, causing macrophages to burst and leading to granulomatous inflammation.[48] The infection may become symptomatic or disseminated without a granulomatous reaction. In immunodeficient states, the yeast proliferates and spreads through the blood to the brain by crossing the blood-brain barrier.[49]

Paracoccidioidomycosis

Paracoccidioides enters the lungs through inhalation. Here, the infected micronidia reach the lower airway, transform into yeast, and then spread to other organs via lymphohaematogenous dissemination.[38] The organism can sometimes enter the mucosa without affecting the lungs.[21]

Geotrichosis

Geotrichum is a part of the normal oral flora and is not pathogenic in immunocompetent individuals.[40]

History and Physical

The diagnosis of oral fungal infection is mainly based on clinical presentation and histopathology of the lesional tissue. Characteristic features can vary depending on the fungal organism.

Oral Candidiasis

Patients with oral candidiasis often complain of a burning sensation or an unpleasant taste that lasts weeks, months, or even years. Several clinical forms of oral candidiasis have been identified.[23] Pseudomembranous candidiasis, commonly known as thrush, presents with white plaques in the buccal mucosa, tongue, and palate, which can be removed by scraping or rubbing, revealing an underlying erythematous mucosa. The acute form is commonly observed in infants due to their underdeveloped immune systems. Steroid inhalers, rinses, gels, and ointments can predispose patients to developing these types of fungal infections. Xerostomia may also be a contributing factor.[24] Erythematous candidiasis manifests as erythematous areas with depapillation on the dorsum of the tongue.[23] The acute form of erythematous candidiasis, previously known as "antibiotic sore mouth," occurs due to the long-term use of broad-spectrum antibiotics. A chronic, atrophic form of erythematous candidiasis is common in the palate in HIV patients.

Candida-associated lesions are angular cheilitis, denture stomatitis, and median rhomboid glossitis. Denture stomatitis is a form of chronic atrophic erythematous candidiasis commonly seen in the palate of denture-wearers as erythema.[50] Irregularities in acrylic denture base and denture-relining materials serve as reservoirs for Candida species. Angular cheilitis presents as erythema, fissuring, and crusting of the oral commissures and is common in denture-wearers with decreased vertical occlusal dimension. Angular cheilitis may also be associated with denture stomatitis.[51] Median rhomboid glossitis or central papillary atrophy presents as an erythematous area in the midline of the posterior dorsum of the tongue.[51]

Chronic hyperplastic candidiasis, or candidal leukoplakia, presents as nonscrapable white plaques, mainly in the buccal mucosa, and has the potential for malignant transformation.[50] Chronic mucocutaneous candidiasis is seen in a rare group of immunologic disorders. Patients may present with candida infections of the oral cavity, skin, and nails during the first few years of life. Autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) syndrome is characterized by the development of chronic mucocutaneous candidiasis, adrenocortical failure (ie, Addison disease), and hypoparathyroidism. APECED syndrome is an inherited disorder caused by autoimmune regulator (AIRE) gene mutations. Typically, patients with APECED syndrome have multi-organ autoimmunity and ectodermal dystrophy and develop endocrine disturbances, eg, Addison disease, hypoparathyroidism, hypothyroidism, and diabetes mellitus months or years after the onset of candidiasis. Enamel defects can also be observed in these patients.[52] These patients also have an increased propensity to develop oral squamous cell carcinoma.

Aspergillosis

The clinical presentation of aspergillosis depends on the patient's immune status. Noninvasive infection can occur in an immunocompetent host and may present as allergic sinusitis.[53] A low-grade, noninvasive infection of the maxillary sinus is called aspergilloma. Tissue damage following extraction or endodontic treatment of posterior maxillary teeth predisposes the sinus to infection, presenting as pain and nasal discharge. Oral aspergillosis presents as painful gingival ulcers with diffuse swelling, which may undergo necrosis. Invasive aspergillosis can affect the paranasal sinuses of immunocompromised individuals. Dissemination is common in the lungs.[26] Invasive aspergillosis in the oral cavity presents as a painful necrotic lesion covered by a yellow slough.[25]

Mucormycosis

The 6 clinical variants of mucormycosis are rhinocerebral, pulmonary, gastrointestinal, cutaneous, disseminated, and uncommon site infections. Rhinocerebral is the most common form, which manifests clinically as nasal obstruction, nasal discharge, facial pain, and swelling. A fatal rhino-orbito-cerebral form, which typically occurs when spores are inhaled into the sinuses, or a less fatal rhino-maxillary form may also occur. In the oral cavity, the palate is commonly affected due to involvement of the sphenopalatine and greater palatine arteries, leading to turbinate and palatal thrombosis and necrosis. Initially, intra-oral swelling of the maxilla is evident, which may later present as a black necrotic ulcer and palatal perforation.[54]

Histoplasmosis

Three clinical forms of histoplasmosis exist: primary acute pulmonary, chronic pulmonary, and disseminated. Patients with acute histoplasmosis are usually asymptomatic but may present with pulmonary symptoms, eg, a nonproductive cough accompanied by fever, headache, chest discomfort, and malaise. The chronic form is common in immunocompromised individuals. Oral lesions are frequently associated with chronic disseminated histoplasmosis and typically present as painful ulcers with rolled margins and irregular surfaces.[55] Oral histoplasmosis may also manifest as vegetative, granulomatous, or plaque-like lesions.[34]

Blastomycosis

Pulmonary infection is the most common manifestation, and can be asymptomatic or symptomatic with fever, malaise, hemoptysis, cough, chest pain, and dyspnea. Blastomyces can disseminate to virtually any organ system. Clinical evidence of extrapulmonary spread is observed in approximately 25% to 40% of cases.[56] Blastomycosis in the oral cavity manifests as intraoral pain, progressively growing verrucous or papular growth, or ulcers with rolled borders. These lesions may develop in any area of the oral cavity.[55] The ulcers mimic squamous cell carcinoma.[55] Bone involvement may present as nonhealing extraction sockets. Osteomyelitis results from the direct spread of infection from contiguous sites. These lesions may develop in any area of the oral cavity.[55] But the gingiva, alveolar mucosa, and buccal mucosa are most commonly affected.[36]

Cryptococcosis

Cryptococcosis infection is usually asymptomatic in immunocompetent individuals. Meningoencephalitis may present with headache and fever; pulmonary cryptococcosis may present with symptoms of pneumonia, including productive cough, chest pain, weight loss, and fever. Clinical features of oral cryptococcosis include a nonhealing ulcer that usually develops on the palate, gingiva, or tonsillar pillar, and draining sinuses, erythematous plaques, or granulomas; however, these are rare compared to symptoms seen in the eye, prostate, and CNS.[2][55]

Paracoccidioidomycosis

Paracoccidioidomycosis can be either acute or chronic. The acute form accounts for 3% to 5% of cases and presents with superficial lymph node enlargement, digestive, and cutaneous symptoms. Chronic, which forms the remaining 95%, presents as weakness, weight loss, cough, and dyspnea. The oral cavity may be the first site of manifestation, presenting as mulberry-like ulcers with a granular appearance.[57] Extrapulmonary sites can present as pain on mastication, sialorrhea, and odynophagia.[38] Patients may also report tooth softening, clinically seen as periodontal injuries.[58]

Geotrichosis

The clinical manifestations of oral geotrichosis are similar to those of oral candidiasis, with pseudomembranous white plaques on the tongue, soft palate, buccal mucosa, and sometimes the angle of the mouth.[59] Hyperplastic lesions, or palatal ulcers, are observed in a second form that resembles mucormycosis or aspergillosis.[40][59]

Evaluation

Candidiasis

Identifying the predisposing factor is essential in patients with suspected oral candidiasis. Predisposing factors can be local (eg, topical steroid use, salivary hypofunction, uninterrupted denture use, and tobacco abuse) or systemic (immunodeficiency, nutritional deficiency, and chronic corticosteroid or antibiotic therapy).[23] The diagnosis of oral candidiasis is mainly based on clinical features. A swab or smear obtained from the lesion may reveal Candida hyphae when stained with the periodic acid-Schiff method. A biopsy is required in cases of chronic hyperplastic candidiasis to rule out malignancy.[50]

Histopathology of the lesional tissue reveals the increased thickness of the parakeratin layer with embedded candidal hyphae, microabscesses in the superficial spinous cell layer, and elongated rete ridges. The underlying connective tissue contains a chronic inflammatory infiltrate.[60] Antifungal susceptibility testing is essential in patients who relapse or do not respond to conventional antifungals.[6] CHROMagar culture media can be used to isolate and identify Candida species. Production of germ tubes in the germ tube test indicates the presence of C albicans or C dubliniensis. Immunological methods to detect mannan antigen and anti-mannan antibodies, antimycelial antibodies, or β-D-glucan can be employed in immunocompromised patients when obtaining deep samples is challenging. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry reduces culture time and is helpful for identifying Candida species.[61]

Aspergillosis

Diagnosis is primarily based on clinical, microbiological, and histopathological features. A characteristic histopathologic finding of aspergillosis is septate hyphae, 3 to 4 µm in size, branching at acute angles.[62] In addition to necrosis, granulomatous inflammation is noted in immunocompetent individuals. Histopathology of aspergilloma reveals a tangled mass of hyphae without any evidence of tissue invasion. However, findings consistent with allergic sinusitis typically demonstrate pools of eosinophils and lymphocytes.[63]

Microbiological confirmation can be achieved through fungal culture of biopsy specimens or sinus aspirates, allowing for species identification. Radiographic imaging, such as computed tomography of the paranasal sinuses, can be used to assess sinus involvement, bone destruction, and disease extent, whereas magnetic resonance imaging is reserved for suspected soft-tissue or orbital invasion. Special stains, such as Grocott-Gomori methenamine silver and galactomannan, can be used to confirm the diagnosis. Galactomannan is a fungal cell wall marker relatively specific for Aspergillus and can be detected in serum.[27]

Mucormycosis

Mucormycosis is an opportunistic infection in patients with underlying diseases, eg, uncontrolled diabetes mellitus, AIDS, leukemia, and lymphoma. Other systemic risk factors include burns, bone marrow transplant patients, and those taking deferoxamine. A history of tooth extraction, periodontal surgery, and abscess drainage can be local risk factors for mucormycosis. For mucormycosis, early diagnosis is critical to ensure appropriate therapy is delivered effectively to improve patient outcomes. 

On imaging studies of patients with mucormycosis, radiographs reveal opacification of the sinuses and effacement of the sinus walls. However, radiographic findings in mucormycosis are nonspecific and, when considered alone, are inadequate for definitive diagnosis.[64] Scrapings examined with 10% to 20% potassium hydroxide show nonseptate fungal organisms. Diagnostic confirmation is made by pathologic examination, which reveals necrosis and ribbon-like nonseptate fungal hyphae 6 to 30 µm in size, branching at 90 degrees. Culturing on Sabouraud's glucose agar can identify Mucor.[29] Real-time quantitative polymerase chain reaction (PCR) is a rapid, sensitive, and accurate method to detect 18S or 28S ribosomal RNA genes of Mucorales.

Histoplasmosis

While a definitive diagnosis of histoplasmosis requires either culture or histopathologic confirmation, a probable diagnosis can be established in the presence of predisposing host factors (eg, immunocompromising conditions), a compatible clinical presentation, and supportive mycological evidence, including positive antigen testing.[65] Histopathology using the presence of yeast cells can support the diagnosis of histoplasmosis (although not specifically active infections). Yeast cells are ovoid in shape, measuring 2 to 4 µm in size for H capsulatum var capsulatum and 6 to 12 µm for H capsulatum var duboisii have thin nonrefractile cell walls and manifest characteristic narrow-base budding.

Yeast is predominantly found phagocytosed within macrophages and histiocytes, often in clusters of many organisms, but may sometimes be seen in extracellular spaces.[66] The host tissue typically demonstrates a diffuse lymphohistiocytic infiltrate, with fungal elements 1 to 2 µm in diameter within the cytoplasm of histiocytes. A well-formed granuloma with macrophages and multinucleated giant cells is a rare observation. Stains, eg, periodic acid-Schiff and Grocott-Gomori methenamine silver, can be used to highlight the cell wall of H capsulatum. The cytoplasm retracts from the thick cell wall, giving a classic "halo" appearance.[34] Diagnosis by fungal culture is the gold-standard method for identifying the organism and can be employed in chronic pulmonary or disseminated histoplasmosis.

Blastomycosis

Many methods can be used to visualize Blastomyces, including 10% potassium hydroxide, calcofluor white, Gomori methenamine silver, and periodic acid-Schiff. The diagnostic feature of Blastomyces is yeast cells sized 8 to 20 µm with double-refractive capsules and broad bud attachment to the parent cell. Histopathology reveals pseudoepitheliomatous hyperplasia with granulomatous reaction and acute inflammation.[67] Culture can aid in making the definitive diagnosis, but it may take 2 to 3 weeks. An enzyme immunoassay can be used to detect BAD1 protein. No radiographic features are pathognomonic for pulmonary blastomycosis. Imaging findings are nonspecific and may resemble bacterial pneumonia, tuberculosis, or pulmonary malignancy.[68]

Cryptococcosis

India ink is a rapid method to visualize encapsulated yeast cells in cerebrospinal fluid, but false-negative results are common.[48] Cryptococcal polysaccharide antigen can be detected in the serum or cerebrospinal fluid. Histopathology shows granulomatous inflammation with multinucleated giant cells containing 4 to 6 µm organisms surrounded by a clear halo representing the capsule. The capsule can be demonstrated by staining with mucicarmine. Fontana–Masson stain can identify melanin in the cell walls, and Calcofluor can stain fungal chitin.[69] The most common radiologic findings of cryptococcosis include well-defined single or multiple noncalcified nodules and pulmonary infiltrates.[19]

Paracoccidioidomycosis

Histopathology reveals pseudoepitheliomatous hyperplasia associated with connective tissue containing epithelioid macrophages and multinucleated giant cells. The organisms may be seen as parent cells with multiple offshoots (ie, daughter buds) resembling "Mickey Mouse ears," giving a steering-wheel appearance.[70] Immunodiffusion testing with the Ag7 antigen has been shown to have high specificity and sensitivity for the initial diagnosis of paracoccidioidomycosis.[58]

Geotrichosis

Multiple hyphae with rectangular arthroconidia, long with acute inflammatory cells, are characteristic of geotrichosis histopathological sections. Rectangular arthroconidia with rounded borders, called clavata cells in KOH mounts, are also common features. Culture is essential for geotrichosis diagnosis.[71]

Treatment / Management

Oral Candidiasis

Managing candidiasis involves evaluating and correcting predisposing factors, maintaining proper oral and denture hygiene, and selecting an appropriate antifungal agent. Topical antifungal therapy is the first-line treatment for uncomplicated cases of oral candidiasis and should be continued concurrently when systemic treatment is indicated.[50] Topical clotrimazole is the first-line treatment for adult candidiasis. 

Nystatin suspension is most commonly used for infants.[72] In disseminated infections, systemic administration of fluconazole or itraconazole may be necessary. Posaconazole oral solution can be used in patients with immunosuppression and drug resistance.[23]

Aspergillosis

Surgical debridement alone is sufficient for treating noninvasive aspergilloma in immunocompetent individuals. However, surgical debridement and corticosteroid therapy are effective treatments for allergic fungal sinusitis. Debridement followed by voriconazole administration is recommended for immunocompetent individuals with localized aspergillosis. Aggressive debridement and systemic antifungal therapy with voriconazole (the first-line drug of choice)/itraconazole, or amphotericin B can be given for immunosuppressed patients with invasive aspergillosis.[73]

Mucormycosis

Management of mucormycosis involves surgical debridement of the necrotic tissue followed by administration of systemic antifungals, eg, liposomal amphotericin B (AmB). Prosthetic obturator, or surgical closure, is recommended in patients with oronasal communication.[74] Posaconazole and isavuconazole are the most effective against mucorales and can either be used in stepdown therapy after successful AmB or in salvage therapy if AmB is unsuccessful on the patient.[75] Supportive measures such as hyperbaric oxygen can promote tissue neovascularization and reduce acidosis. Elimination of predisposing factors should also be attempted. For example, achieving glycemic control in patients with diabetes is an important component of management.[76](B3)

Histoplasmosis

Histoplasmosis is self-limited in immunocompetent patients and in cases of acute pulmonary histoplasmosis. However, intravenous amphotericin B is recommended for the treatment of pulmonary histoplasmosis in immunosuppressed patients. Additionally, itraconazole can be given for localized infection, mild to moderate cases, and relapse prevention.[16](B3)

Blastomycosis

Systemic administration of amphotericin B may be essential only in patients with immunosuppression, in severe cases, or when it involves the central nervous system.[18] Itraconazole is first-line therapy in non–life-threatening conditions, or for step-down therapy after initial amphotericin B treatment.[77](B3)

Cryptococcosis

Localized cryptococcosis infection without underlying systemic immunodeficiency can be treated with oral fluconazole. Cryptococcal meningitis is treated with amphotericin B and flucytosine in 3 phases: induction, consolidation, and maintenance.[78]

Paracoccidioidomycosis

Patients with oral paracoccidioidomycosis are typically treated with oral itraconazole or ketoconazole.[37] Sulfamethoxazole-trimethoprim is an alternative, with amphotericin B reserved for severe cases.[79](B2)

Geotrichosis

Oral geotrichosis treatment recommendations are similar to those for oral candidiasis.[71] Topical agents, eg, 1% gentian violet or nystatin cream or gel, are effective options for the treatment of cutaneous and oral lesions, respectively.[59](B3)

Differential Diagnosis

The various types of fungal infections can mimic several other conditions, depending on the clinical features present.

Oral candidiasis

White-coated tongue, leukoplakia, lichenoid reactions, and secondary syphilis may mimic pseudomembranous candidiasis. The differential diagnosis for erythematous candidiasis includes thermal burns, erythroplakia, anemia, and oral mucositis.[5]

Aspergillosis

Histologically, granulomatous inflammation observed in aspergillosis can be similar to that seen in tuberculosis, syphilis, Wegener's granulomatosis, or leprosy.[80] Neoplastic lesions should also be considered, as well as chemical and physical trauma.[80]

Mucormycosis

Palatal necrosis can be seen in conditions, eg, bacterial infections (eg, actinomycosis), viral infections (eg, herpes zoster), radiation, and trauma. Mucormycosis and aspergillosis often pose diagnostic challenges that can be addressed by evaluating the histopathological appearance of the fungal hyphae.[29] Necrotizing inflammatory conditions, eg, granulomatosis with polyangiitis and midline lethal granuloma, along with malignancies, eg, oral squamous cell carcinoma, should also be included in the differential diagnosis of destructive palatal lesions [81]

Histoplasmosis

Chronic histoplasmosis primarily affects the lungs, causing clinical manifestations similar to tuberculosis, including fever, weight loss, cough, dyspnea, and chest pain. Acute histoplasmosis can also present with symptoms similar to those of blastomycosis, coccidioidomycosis, and pneumonia.[82] Oral histoplasmosis is clinically indistinguishable from malignancy.[34]

Blastomycosis

Blastomycosis lesions resemble oral carcinoma both clinically and histopathologically. Hence, careful histological demonstration of yeasts is essential.[36] The clinical course may also mimic bacterial infections, eg, syphilis, tuberculosis, or actinomycosis, or autoimmune diseases such as Crohn disease and systemic lupus erythematosus.

Cryptococcosis

Clinically, oral cryptococcosis appears similar to histoplasmosis, paracoccidioidomycosis, tuberculosis, and malignancy.[83] Other deep fungal infections and chronic granulomatous inflammatory conditions may present with similar clinical features.

Paracoccidioidomycosis

The primary differential diagnosis is pulmonary tuberculosis. Oral lesions mimic malignancies and other granulomatous lesions.[37]

Geotrichosis

Oral geotrichosis resembles oral candidiasis.[40]

Prognosis

Oral candidiasis

Oral candidiasis has a good prognosis when treated appropriately.[51] Recurrences may occur due to poor patient compliance or to an unresolved underlying predisposing factor.

Aspergillosis

The prognosis of disseminated aspergillosis is poor for immunocompromised patients.[84] The mortality rate of invasive aspergillosis is almost 58%.[25]

Mucormycosis

Mucormycosis has a poor prognosis and is fatal in almost all cases of immunocompromised patients if dissemination occurs.[84] Early diagnosis is vital for improving outcomes in mucormycosis. Since clinically approved biomarkers are currently lacking, detecting circulating DNA in serum is essential for the early identification and treatment of the disease.[85]

Histoplasmosis

The prognosis depends on the patient's immune status. HIV patients presenting with severe pulmonary and renal impairment have a poor prognosis. Disseminated histoplasmosis can be fatal if not treated.[16]

Blastomycosis

The mortality rate is approximately 2% to 6% and is higher in patients with disseminated disease. Immunocompromised patients have a poor prognosis.[56]

Cryptococcosis

In immunocompetent individuals with localized pulmonary disease, outcomes are generally favorable with appropriate antifungal therapy. Cryptococcosis can be life-threatening in patients with AIDS. Prognosis in HIV patients depends on antiretroviral therapy. Treatment with antiretrovirals during antifungal therapy can cause cryptococcal immune reconstitution inflammatory syndrome (IRIS).[86] Cryptococcal meningitis has a poor prognosis and a high mortality rate.[78]

Paracoccidioidomycosis

The prognosis depends on disease severity.[37]

Geotrichosis

Oral geotrichosis responds well to treatment.[40]

Complications

Oral candidiasis

Complications are rare in a nonimmunocompromised patient. However, if not treated, oral candidiasis can lead to chronic persistent infection, invasive candidiasis, necrotizing ulcerative mucositis, and oropharyngeal and esophageal candidiasis, which is a prevalent complication of oral candidiasis in those with HIV/AIDS. Other complications include bronchitis, pneumonia, and endocarditis.[5]

Aspergillosis

Sinus infection is often invasive, involving the bone. The fungi invade the blood vessel wall, resulting in thrombosis, hemorrhagic necrosis, and fatal bleeding. Hematogenous spread to distant sites, eg, the eyes, brain, skin, and gastrointestinal tract, can occur.[84]

Mucormycosis

The infection from the nasal cavity rapidly spreads to the paranasal sinuses and then to the orbit. Visual impairment and facial paralysis due to cranial nerve involvement can occur. If left untreated, the infection may spread to the brain through the ethmoidal sinuses and orbit, resulting in death.[84]

Histoplasmosis

A pathological fracture can occur as a result of progressive bone destruction. The infection may spread to extrapulmonary sites, eg, the adrenal gland, spleen, liver, lymph nodes, and gastrointestinal tract.[16] Granulomatous mediastinitis and less common mediastinal fibrosis can be complications of pulmonary histoplasmosis.[82]

Blastomycosis

Dissemination commonly occurs on the skin. Other sites include the bone, prostate, testicles, and the central nervous system.[56]

Cryptococcosis

Dissemination is common in immunocompromised patients and can occur in the skin, prostate, eyes, and bone. The infection may rarely spread to the salivary glands.[78] Central nervous system involvement, especially cryptococcal meningitis, represents the most serious complication and is associated with elevated intracranial pressure, neurologic deficits, and significant mortality.[87]

Paracoccidioidomycosis

The oral lesion may precede the pulmonary infection. Therefore, lung evaluation is essential, even in patients without pulmonary symptoms.[70] In severe cases, patients may have difficulty swallowing, CNS involvement, and adrenal gland involvement.[38]