eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Noncandidal Fungal Infections of the Mouth

Author: Crispian Scully, MD, PhD, DSc, FRCPath, MRCS, CBE, MDS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FMedSci, FHEA, FUCL,DSc, DChD, DMed(HC), Dr hc., Professor, Director of Special Projects, Eastman Dental Institute for Oral Health Care Sciences; Professor, Special Needs Dentistry, University College; Professor, Oral Medicine, Pathology and Microbiology, University of London
Coauthor(s): Maria Regina Sposto, DDS, PhD, MDSc(Dental Science), PhD(Dentistry), Associate Professor of Oral Diagnosis and Oral Medicine, Consulting Staff, Department of Oral Surgery and Diagnosis, Faculdade de Odontologia de Araraquara, UNESP-Universidade Estadual Paulista, Brazil
Contributor Information and Disclosures

Updated: Sep 23, 2008

Introduction

Background

Candidiasis is the most common fungal infection of the mouth. This article, however, focuses on noncandidal oral fungal infections. A few eMedicine articles on candidiasis include Candidiasis, Chronic Mucocutaneous; Candidiasis, Mucosal; and Candidiasis, Cutaneous.

This article discusses 6 noncandidal oral infections: aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, and mucormycosis. Although these noncandidal fungal infections are considerably less common than oral candidiasis, they commonly produce subclinical infection, especially pulmonary infections.

In rare cases, these infections can produce clinical disease in healthy persons. Systemic mycoses in healthy individuals are more common in endemic areas than elsewhere, and they are often asymptomatic and may spontaneously resolve. In otherwise healthy persons, acute pulmonary and primary mucocutaneous symptomatic lesions may resolve without treatment. However, chronic pulmonary infection tends to progress and disseminated infections can be fatal. Immunocompromised persons are at particular risk from these mycoses, and clinical manifestations of infection by these organisms often suggest impaired immune competence.¹ Patients at greatest risk include those with leukemia, leukopenia, solid tumors, transplants,² or HIV disease.^3,4 Also at risk are premature infants.

Noncandidal fungal infections have the potential for serious injury to the oral cavity and sometimes also the paranasal sinuses, the orbit, and the cranial base. Orofacial lesions caused by the main systemic mycoses may occasionally be seen in isolation, but they are typically associated with lesions elsewhere, often in the respiratory tract. The oral lesions associated with these deep fungal infections are chronic, may mimic neoplasms, and progress to form solitary, chronic deep ulcers with the potential for local destruction and invasion and systemic dissemination.

Chronic oral ulceration, chronic maxillary sinus infection, or bizarre mouth lesions, especially in patients with HIV disease, those with lymphoproliferative disorders, persons with diabetes mellitus, or those who have been in endemic areas, may suggest the diagnosis and patients should be treated in consultation with a physician with appropriate expertise.

Most of these mycoses are diagnosed on the basis of a history of foreign travel or an immunocompromised state. Investigations include smears, biopsy, staining with periodic acid-Schiff (PAS) or Gomori methenamine silver, culture of the affected tissues, serodiagnosis (sometimes), physical examination, and chest radiography. Unfortunately, specific immunostaining for an accurate diagnosis of most mycoses is available only in a few laboratories.

Definitive diagnosis is achieved by means of microbiologic or histologic identification and serodiagnosis. DNA probes are available for several species. Prompt identification and treatment, usually with systemic antifungal drugs, are essential; delayed treatment or no treatment can result in considerable orofacial destruction, systemic dissemination, or death.

Most systemic mycoses can be treated with systemic amphotericin. Azoles are often considered better, but their cost is prohibitive where they are most needed, that is, in the developing world.

The Medscape Immune Reconstitution Resource Center and Emerging and Reemerging Infectious Diseases Resource Center may be of interest.

Pathophysiology

Aspergillosis

More than 160 species and variants of Aspergillus organisms have been discovered, although only 10 are pathogenic in humans. Aspergillus fumigatus is the most common pathogen, but Aspergillus flavus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus terreus, Aspergillus repens, Aspergillus parasiticus, and Aspergillus niger are also encountered. A flavus is the most virulent.

Aspergillus species are the most common environmental fungi, being prolific saprophytes in soil and decaying vegetation. Inhalation of the conidia is very likely extremely common, but, unless the inhalation is massive or unless the host is immunocompromised, clinical disease is rare. Nevertheless, aspergillosis is found worldwide. Its prevalence is increasing, and this is the most prevalent mycosis second only to candidosis.

The organisms exist as prolific saprophytes in soil and decaying vegetation. Inhalation of the organisms allows for their germination and colonization in the mucosa of the respiratory tract, including the mouth. Lesions may be established primarily in the oral mucosa, but they more commonly begin in the mucosa of the maxillary sinus. They may appear in the oral cavity after local invasion and/or destruction of the surrounding structures. Inhalation of the spores is common, although clinical disease is rare unless the individual is immunocompromised by medication (eg, chemotherapy,⁵ organ transplantation immunosuppression) or disease (eg, HIV infection, leukemia, lymphoma).

Blastomycosis

Blastomycosis is a term sometimes used to include a range of granulomatous systemic mycoses, including North American blastomycosis (Gilchrist disease), South American blastomycosis (paracoccidioidomycosis or Almeida disease), coccidioidomycosis, and cryptococcosis. However, the nomenclature is now restricted mainly to the North American and South American forms of blastomycosis, which involve the viscera, lymph nodes, and mucocutaneous tissues.

Blastomyces dermatitidis causes the North American form, whereas Paracoccidioides brasiliensis causes the South American form. As expected, North American blastomycosis is seen predominantly in North America, in the Mississippi, Missouri, and Ohio River valleys in the United States and in southern Canada. However, it is also seen in Africa, India, the Middle East, and Australia.

B dermatitidis, which is found in soil and spores, may be inhaled to produce respiratory tract and sometimes disseminated disease. Serotype 1 is seen in North America, and serotype 2 is seen in Africa. Outdoor workers are particularly affected, but blastomycosis is increasingly recognized in persons with HIV disease.

Coccidioidomycosis

Coccidioidomycosis is seen mainly in arid parts of the Western hemisphere, such as the southwestern United States, Mexico, Central America, and parts of South America. Inhalation of spores of Coccidioides immitis, found in soil, produces subclinical infection in up to 90% of the population in such areas.

Cryptococcosis

Cryptococcosis is seen worldwide in humans and animals. Aspiration of Basidiobolus spores, mainly capsular serotype A but sometimes serotype D of Cryptococcus neoformans (a ubiquitous yeast found especially in pigeon feces and present in soil), may lead to infection. Two varieties have been described, which are C neoformans var neoformans (synonymous with capsular serotypes A, D, and AD) and the less common C neoformans var gattii (synonymous with capsular serotypes B and C). C neoformans var neoformans is found in excreta from pigeons, canaries, parrots, and budgerigars and in rotting fruit and vegetables. C neoformans var gattii is associated with a particular tree, the Red River gum tree (Eucalyptus camaldulensis).

Histoplasmosis

Histoplasmosis is the most frequently diagnosed systemic mycosis in the United States and has now been reported in approximately 30 countries worldwide. Histoplasma capsulatum, the causal organism, is a soil saprophyte found particularly in northeastern and central states such as Missouri, Kentucky, Tennessee, Illinois, Indiana, and Ohio (mainly in the Ohio and Mississippi valleys). The organism has also been found in Latin America, India, the Far East, and Australia. H capsulatum var duboisii is the type mainly found in equatorial Africa.

Histoplasma species are commonly found in bird and bat feces. In endemic areas, the organism is a soil saprophyte, and more than 70% of adults appear to be infected, typically with subclinical manifestations, as a result of inhaling spores.

Mucormycosis⁶

Mucor and Rhizopus species are the most common agents to cause zygomycosis. Fungi of the order Mucorales (of the class Zygomycetes) are responsible for most mucormycosis. However, in addition to Mucor and Rhizopus species, organisms from the genera Absidia, Apophysomyces, Mortierella, Saksenaea, Rhizomucor, and Cunninghamella may also be involved. Therefore, the condition is probably better termed zygomycosis.

These fungi are ubiquitous worldwide in soil, manure, and decaying organic matter. Classic zygomycosis occurs worldwide. In some warmer regions, other Zygomycetes such as Conidiobolus coronatus infect a range of animals and can also occasionally cause rhinofacial zygomycosis in humans. Most human cases have been recorded from the Caribbean, Latin America, and Central and West Africa.

Mucoraceae are commonly cultured from the nose, throat, mouth, and feces of many healthy individuals, but infection is virtually unheard of in otherwise healthy individuals.

Paracoccidioidomycosis

South American blastomycosis (paracoccidioidomycosis or Almeida disease) is found mainly in Colombia, Venezuela, Uruguay, Argentina, and particularly Brazil. In Brazil, the disease is endemic in the states of Sao Paulo, Rio de Janeiro, and Minas Gerais. P brasiliensis is responsible and is presumably being inhaled as spores. Subclinical infection is not uncommon in endemic areas.

Frequency

United States

Because of the ubiquitous presence of these fungi in the environment, exposure is common. However, clinical disease is uncommon except in persons with iatrogenic or pathologic immunosuppression.

International

Because of the ubiquitous presence of these fungi in the environment, exposure is common in endemic areas, and travelers may present with manifestations even years after exposure. However, clinical disease is uncommon except in persons with iatrogenic or pathologic immunosuppression.

Mortality/Morbidity

In a healthy individual, infection is typically self-limited, although latency is commonly established, rather than elimination. Reactivation of latent infection may subsequently occur if the infected individual becomes immunosuppressed.

• Primary infection or reactivation in individuals with impaired immune surveillance presents a different scenario in which the disease may continue as a locally invasive and destructive process. Once the organism breaks through local barriers and enters the blood or lymphoreticular system, dissemination is rapid and difficult to control.
• Untreated, these fungal infections can be fatal, and among patients who are immunosuppressed (eg, those with AIDS, diabetes, leukemia, lymphoma, or iatrogenic immunosuppression as in organ transplantation), death rates dramatically increase.
• Regional destruction of the maxilla by paranasal infections leads to considerable morbidity, including oroantral fistula with oronasopharyngeal insufficiency and orbital invasion, which may result in loss of the eye.

Race

The deep mycoses can affect individuals of all races; no racial predilection is recognized.

Sex

The mycoses affect both sexes equally.

Age

The deep mycoses can affect individuals of all ages, although they are more common in adults than in children. Elderly individuals may be at increased risk, although this is often secondary to impaired immunity.

Clinical

History

The following conditions may predispose individuals to infection. These conditions require an evaluation to determine whenever a deep fungal infection is established.

• Drug use
  • Use of corticosteroids
  • Use of cytotoxic agents
  • Use of immunosuppressants
• Immunodeficiency
  • Due to HIV
  • Due to AIDS
• Endocrinologic condition
  • Poorly controlled diabetes mellitus
  • Ketoacidosis
• Malignancy
  • Leukemia
  • Lymphoma
  • Others
• Other conditions
  • Neutropenia
  • Malnutrition
  • Old age

Physical

Patients with deep mycoses may present with a primary infection of the oral mucosa, but, more commonly, they present with an extension of an established paranasal infection. Therefore, by the time oral lesions are present, considerable destruction of the maxilla and maxillary sinus may have occurred.

In healthy individuals, the disease is usually self-limiting, but in individuals who are immunocompromised, extensive local destruction, fungemia, visceral and cerebral invasion, and death are substantial risks.

The most common presentation of oral deep fungal infection is a chronic, solitary ulcer or nodule. When infection involves the palate, this finding may be only the initial indication of considerable antecedent destruction of the maxilla and maxillary sinus. Extension and/or invasion into the orbital and cranial cavity are not uncommon. The condition may be indistinguishable from other causes of chronic oral ulcers (eg, tuberculosis, malignancy).

• Aspergillosis^7,8,9
  • Orofacial lesions caused by Aspergillus species include antral aspergilloma, invasive aspergillosis of the antrum, indolent chronic sinusitis, allergic sinusitis, and oral lesions. Aspergilloma of the maxillary antrum is uncommon and typically occurs in a healthy host as a hyphal ball in a chronically obstructed sinus.
  • Invasive sinus aspergillosis is rare and affects mainly immunocompromised hosts, although it is also seen in some apparently healthy individuals, predominantly in subtropical countries with a warm climate (eg, Sudan, Saudi Arabia, India). Patients with leukemia, lymphoma, HIV disease, or iatrogenic immunosuppression (eg, those undergoing bone marrow or renal transplantation) are at particular risk from such invasive sinus aspergillosis. Although A fumigatus is the usual cause of invasive sinus aspergillosis, A flavus appears to predominate in immunocompromised individuals. Rarely, other species (eg, A repens) are encountered, sometimes with other mycoses such as Microascus cinereus.
  • In invasive sinus aspergillosis, the antral wall is destroyed; this damage may be characterized by antral pain, swelling, sequelae from orbital invasion (eg, impaired ocular motility, exophthalmos, or impaired vision), or intracranial extension (eg, headaches, meningism).
  • Chronic sinus aspergillosis is uncommon, and patients present with a diffusely opaque antrum radiographically, sometimes with dense punctate radiopacities. This disease is unresponsive to treatment used for bacterial sinusitis. Allergic fungal sinusitis is also uncommon and is usually due to fungi other than Aspergillus organisms.
  • Interestingly, subclinical defects in cell-mediated immune responses to Aspergillus species have been observed in patients with sinus aspergillosis. Occasional cases of sinus aspergillosis arise as a result of metastasis from pulmonary aspergillosis or iatrogenic factors following dental procedures such as extractions, endodontics, or implants in the maxilla.¹⁰
  • Oral lesions of aspergillosis are seen predominantly in some immunocompromised patients with invasive aspergillosis. Yellow or black necrotic ulcers typically appear on the palate or occasionally on the posterior tongue.
• Blastomycosis
  • Blastomycosis may become disseminated to produce ulcerating lesions that affect the oral mucosa.
  • Mandibular involvement is rare.
  • Cutaneous blastomycosis may spread to affect the lips.
• Coccidioidomycosis
  • Oral lesions from coccidioidomycosis are rare, but when they occur, they typically are reported secondary to lung involvement.
  • They are verrucous lesions, sometimes occurring with infection of the jaw.
  • They have yet to be reported in a patient with HIV disease.
• Cryptococcosis
  • Oral cryptococcal infection manifests mainly as nonhealing extraction wounds or chronic ulceration on the palate or tongue.
  • Several cases of cryptococcal oral lesions have recently been reported in persons infected with HIV. In the past, rare cases have been reported in individuals with leukemia.
• Histoplasmosis
  • Oral lesions of H capsulatum infection have been recorded mainly in persons with pulmonary or disseminated histoplasmosis, especially in patients with HIV infection.¹¹
  • Oral lesions are sometimes isolated and have also been recorded in apparently healthy persons. Oral lesions are usually ulcerative or nodular; have been found on the tongue, palate, buccal mucosa, or gingiva; and rarely invade the mandible or maxilla.
  • Oral lesions in African histoplasmosis are generally localized, affecting the tongue, buccal mucosa, or jaws.
• Paracoccidioidomycosis¹²
  • Oral lesions of paracoccidioidomycosis are chronic, often granular or exophytic, and ulcerated.
  • Antral lesions are rare.
  • Oral lesions of paracoccidioidomycosis appear to be uncommon in persons with HIV disease, although involvement of the submandibular lymph nodes and the presence of lesions outside the head and neck have been reported.
• Rhinosporidiosis: Oral lesions of rhinosporidiosis are usually proliferative lumps, especially affecting the soft palate.
• Zygomycosis
  • Rhinocerebral zygomycosis is usually caused by Rhizopus oryzae or Rhizopus arrhizus. The disease typically commences in the nasal cavity or paranasal sinuses and causes pain, nasal discharge, and fever; the organisms may then invade the palate to produce black, necrotic oral ulcers.
  • Orbital invasion may produce orbital cellulitis, impaired ocular movements, proptosis, and ptosis.
  • Intracranial invasion follows penetration of ophthalmic vessels or the cribriform plate.
  • Zygomycosis occasionally commences in the palate.

Causes

• Aspergillosis -A flavus, A terreus, and A fumigatus
• Cryptococcosis -C neoformans
• Histoplasmosis -H capsulatum
• Blastomycosis -B dermatitidis
• Mucormycosis (zygomycosis) -Mucor species and Rhizopus species
• Paracoccidioidomycosis -P brasiliensis

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