CHAPTER 3 Nonbacterial Microbiology of the Head, Neck, and Orofacial Region 1

Yeast
of Candida, epithelial cells, leukocytes, bacteria, and
Candida Species focal debris. The patches are removable by scraping and
leaving a raw, bleeding, and painful surface. Patients
Candida organisms are yeast because they are fungi that
with chronic mucocutaneous candidiasis commonly have
are present in a unicellular form. They are small (4 to 6
a dysfunction of the lymphocytic system that places
μm), thin-walled, ovoid cells that reproduce by budding.
the patient at risk of Candida infection. Patients with
They are recovered from soil, animals, the hospital
AIDS are also highly
environment, and food. They are normal commensals of
humans and are com- monly found on the skin, in the
gastrointestinal and female genital tracts, and in the
urine of patients with indwelling Foley catheters.
Clinical Manifestations
The most common candida involving the head and neck
is Candida albicans. The defense mechanism of intact
integu- ment is of importance in maintaining resistance
to cutane- ous candidiasis.

Pseudomembranous Candidiasis
Oral thrush was first described at the time of
Hippocrates and Galen. Berg in 1841 established the
fungal cause of thrush in newborn (Figure 3-12).
Candida species form smooth, creamy white patches on
the tongue and soft or hard palate. The patches are a • Figure 3-12 Oral thrush. (From Goldman L, Schafer AI: Goldman’s
pseudomembrane consisting Cecil medicine, ed 24, Philadelphia, 2012, Saunders.)

TABLE
Summary of Common Fungal Infections Involving the Head and Neck
3-1

Fungal Type Infection site Diagnosis Treatment

Candida Budding Pseudomembranous angular cheilitis KOH, routine culture Topical, systemic azole
yeast Leukoplakia
Atrophic candidiasis
Histoplasma Yeast Ulcerative lesions on the tongue GMS stain on biopsy, Itraconazole, IV amphotericin
capsulatum histoplasma antigen
Cryptococcus Yeast Gingivitis GMS stain on biopsy, Fluconazole, IV amphotericin
neoformans Sinusitis culture, cryptococcal +/- flucytosine
Salivary gland antigen
Coccidioides Yeast Cervical lymphadenopathy GMS stain of tissue, Self-limited, fluconazole, IV
immitis Nodular lesion of the nasolabial fold anticoccidioidal antibodies amphotericin
Paracoccidioides Yeast Ulcerative/granulomatous lesions GMS stain of tissue Sulfonamide, IV amphotericin,
brasiliensis of the mouth, larynx, and pharynx ketoconazole, itraconazole,
posaconazole
Penicillium Yeast Ulcerative or nodular lesions on skin, Identification of organism IV amphotericin ± flucytosine
marneffei larynx, and pharynx
Fusarium spp. Yeast Sinusitis GMS stain of tissue, IV amphotericin, caspofungin,
culture of tissue voriconazole, posaconazole
Aspergillus spp. Mold Allergic sinusitis GMS stain of tissue, Supportive, surgery, voricon-
Fungus ball culture of tissue azole, IV amphotericin,
Mycetoma echinocandin
Invasive sinusitis
Otitis
Oral
Mucor spp. Mold Rhinocerebral GMS stain of tissue, Surgery, IV amphotericin,
Oral culture of tissue posaconazole

GMS, Gomori methenamine silver; IV, intravenous; KOH, potassium hydroxide.

 • Figure 3-15 Candida in yeast form and pseudohyphae. (From Zitelli
• Figure3-13 Angular cheilitis. (From Neville BW, Damm DD, Allen CM, BJ, McIntire SC, Nowalk AJ: Zitelli and Davis’ atlas of pediatric physical
et al: Oral and maxillofacial pathology, ed 4, St Louis, 2016, Saun- diagnosis, ed 6, Philadelphia, 2012, Saunders.)
ders.)

Diagnosis
The yeast form, pseudohyphae, and hyphae stain
positive with a Gram stain. Identification is also
facilitated by 10% potassium hydroxide. Candida grows
well in routine blood culture bottles and on agar plates,
and they do not require special fungal media for
cultivation (Figure 3-15).
Treatment
The treatment of oral candidiasis includes topical agents,
such as mycostatin or clotrimazole, or systemic azole
agents, such as fluconazole, ketoconazole, or itraconazole.
If there is no response to treatment in an
immunocompromised host, the possibility of Candida
glabrata infection should be con- sidered because it may
not be susceptible to fluconazole.

• Figure 3-14 Candidal leukoplakia. (From Ibsen O, Phelan J: Oral

pathology for the dental hygienist, ed 6, St Louis, 2014, Saunders.) Histoplasma capsulatum
Histoplasma capsulatum is a dimorphic fungus, first
identi- fied by Darling in 1905 in Panama. 22 It exists as a
mold in soil and as a yeast in humans (Figure 3-16). It
susceptible to oral thrush because of lymphopenia and
causes infec- tions commonly in the Midwestern and
the role of T helper cells, which are essential for
Southeastern United States, specifically from the Ohio
regulation of phagocytosis.21 Other risk factors are
and Mississippi rivers into the Canadian provinces of
diabetes, steroid use, antibiotic use, neutropenia, and
Québec and Ontario. Histoplas- mosis is acquired by
other immunosuppressive conditions.
inhalation of mycelial fragments and microconidia from
Other oral manifestations of Candida infection are the
the soil. It remains a frequent cause of opportunistic
following:
infection in immunocompromised hosts.
• Angular cheilitis, which represents a nonspecific
inflam- matory reaction to the corners of the mouth Clinical Manifestations
because of candida (Figure 3-13). Most oral lesions are ulcerative (Figure 3-17) or nodular
• Candida leukoplakia, which consists of a raised firm and can involve the skin, tongue, palate, or buccal
white plaque of the oral mucosa that cannot be mucosa. They can mimic squamous oral cancer.
removed by scraping, is usually found on the side of
the tongue, and can affect the cheeks (Figure 3-14). Diagnosis
The diagnosis of histoplasmosis requires isolation of the
organism from body fluid or tissue. The antigen
detec- tion and PCR analysis assay, which detects
polysaccha-
• Acute atrophic candidiasis, chronic atrophic candidiasis, or
“denture sore mouth,” which is described as ride antigen in the serum or the urine by enzyme-linked
erythematous tongue, or thinning of the mucous immunosorbent assay, are the mainstays of the diagnosis
membrane. of histoplasmosis.
 • Figure 3-16 Biology of histoplasmosis. (From Centers for Disease Control and Prevention, Atlanta, Ga.)

Cryptococcus neoformans
Cryptococcus comprises 19 species. Cryptococcus
neoformans is an encapsulated oval yeast (4 to 6 μm)
surrounded by a capsule that can measure up to 30 μm.
It is a common opportunistic pathogen worldwide in the
immunosup- pressed host. C. neoformans serotype A is
the most common serotype infecting patients with AIDS.
It is mainly found in the southwest United States and
Central and South Amer- ica. The mode of transmission is
from inhalation of the yeast from the environment, mainly
from soil contaminated by guano from birds; it is also
associated with trees and rotting wood.
• Figure 3-17 Oral lesions of histoplasmosis. (From Regezi JA,
Sciubba JJ, Jordan RCK: Oral pathology: clinical pathologic Clinical Manifestations
correla- tions, ed 6, St Louis, 2012, Saunders.) Cryptococcus species can rarely cause gingivitis,
sinusitis, and salivary gland enlargement. The oral
lesions are craterlike, nonhealing ulcers that are tender to
Histopathologic analysis shows macrophages with palpation or are friable plaques.
bud- ding yeast organisms. Special stains include
periodic acid– Schiff stain, Gomori methenamine silver Diagnosis
(GMS) stain, or Grocott silver stain. Characteristic of C. neoformans is the presence of the
Treatment spheri- cal budding yeast and the organism capsule on
India ink stain (Figure 3-18). C. neoformans grows on
Oral itraconazole and intravenous amphotericin B are laboratory agar media in 48 to 72 hours. Cryptococcal
treat- ment options. antigen in the serum is elevated in cases of disseminated
infection.
• Figure 3-18 India ink demonstrating Cryptococcus neoformans.
(From Murray P: Medical microbiology, ed 5, Philadelphia, 2005,
Mosby.) • Figure 3-20 Spherules with thick capsule and filled with endospores
of Coccidioides spp. by hematoxylin-eosin stain seen in tissue.
(From Kradin RL: Diagnostic pathology of infectious disease,
Philadelphia, 2010, Saunders.)

Diagnosis
Identifying spherules in clinical specimen (Figure 3-
20), detecting serum-specific anticoccidioidal anti-
bodies, or dermal delayed-type hypersensitivity to coc-
cidioidal antigens by skin testing make the diagnosis of
coccidioidomycosis.

Treatment
The disease is usually self-limited. Treatment option
• Figure 3-19 Skin lesions of coccidiomycosis. (From Fitzpatrick JE: includes fluconazole or amphotericin B.
Dermatology secrets plus, ed 4, Philadelphia, 2011, Mosby. Courtesy
James E. Fitzpatrick.)
Paracoccidioides brasiliensis
Paracoccidioidomycosis is the most important endemic
fun- gal disease; it is reported only in Latin America
Treatment from Mexico to Argentina. Brazil constitutes the center
The treatment of localized disease can be established of the endemic area. Paracoccidioides brasiliensis is a
with fluconazole. Disseminated disease should be treated thermally dimorphic fungus. It appears as an oval-to-
with amphotericin B with or without flucytosine. round yeast with a size of 4 to 40 μm, and surrounded
by a translucent double-con- toured cell wall. It
resembles a mariner’s wheel.
Coccidioides immitis
Coccidioides species is endemic to the soils of certain Clinical Manifestations
regions of the western United States. Coccidioides
immitis is a dimor- phic fungus that appears as either a Paracoccidioidomycosis is a polymorphic, progressive
mycelium or a spher- ule.23 Both forms of growth are dis- ease. Extrapulmonary manifestations involve the
asexual. Infection occurs after inhalation of skin, mucosa, and lymph nodes (mainly cervical nodes).
arthroconidia (Figure 3-19). Painful, mulberry-like ulcerations and granulomatous
lesions with raised border are seen in the mouth, lips,
gingiva, tongue, and palate. On occasion, lesions can be
Clinical Manifestations seen in the nose (Figure 3-21), larynx, and pharynx.25,26
Extrapulmonary dissemination occurs in
immunocompro- mised patients by hematogenous Diagnosis
spread, and can result in cervical lymphadenopathy or
ulcerative nodular skin lesions of the face with Direct microscopy of specimen can identify the fungus
predilection to the nasolabial fold.24 on a wet mount. GMS stain is used to identify fungus on
a tissue
• Figure 3-21 Paracoccidioidomycosis involving the nose. (From
• Figure 3-23 Skin lesions on the face caused by Penicillium marnef-
Marques SA: Paracoccidioidomycosis. Clin Dermatol 30(6): 610-615,
fei. (From Guerrant RL, Walker DH, Weller PF: Tropical infectious dis-
2012.)
eases, ed 3, Edinburgh, 2011, Saunders.)

• Figure 3-22 Paracoccidioides seen in tissue by Gomori methena-

mine silver stain. (From Kradin RL: Diagnostic pathology of
infectious disease, Philadelphia, 2010, Saunders.)

biopsy specimen (Figure 3-22). PCR can also be used on • Figure 3-24 Penicillium marneffei in yeast form by Gomori methena-
both exudate and tissue. Serology detection is helpful for mine silver stain. (From Tille P: Bailey and Scott’s diagnostic microbiol-
diagnosis and follow-up. Skin testing has not been ogy, ed 13, St Louis, 2014, Mosby.)
clinically reliable for diagnosis.
Clinical Manifestations
Treatment
Skin lesions, such as papules, pustules, nodules, ulcers,
Treatment with sulfonamides, amphotericin B, or both is or abscess, can occur on the face (Figure 3-23). In
not always successful. Ketoconazole shows some patients with AIDS, lesions can also be seen on the
treatment success. Other options include itraconazole or palate and pharynx. It can be associated with purulent
posaconazole. discharge, granuloma, or necrosis.

Penicillium marneffei Diagnosis

Penicillium marneffei is a thermally dimorphic fungus Clinical suspicion is raised based on presentation and
that causes life-threatening disseminated infection. The epi- demiologic exposure. The diagnosis is based on
rapid expansion of the AIDS epidemic in Thailand has identifica- tion of the organism on smear,
led to a marked increase in the rate of penicilliosis, but the histopathology, or culture of tissue (Figure 3-24).
disease has been described in both HIV-infected and Microscopic examination reveals yeast forms measuring
uninfected individ- uals. The mode of transmission is 2 to 3 × 2 to 6 μm, both within phagocyte
inhalation of the conidia.
 Molds
Human exposure to fungal elements is inevitable, with
nor- mal respiration routinely depositing fungal hyphae
within the nose and paranasal sinuses. Fungal species
can cause sinonasal disease, with clinical outcomes
ranging from mild symptoms to intracranial invasion
and death. There has been much debate regarding the
precise role of fungal spe- cies in sinonasal disease and
optimal treatment strategies.29 Noninvasive disease
includes asymptomatic fungal colo- nization, fungus
balls, and allergic fungal rhinosinusitis. Invasive disease
includes indolent chronic rhinosinusitis, granulomatous
fungal sinusitis, and acute fulminant fungal
rhinosinusitis.30 A differentiation of these somewhat
• Figure 3-25 Fusarium species shown by Gomori methenamine sil- over- lapping syndromes and the disparate treatment
ver stain. (From Kradin RL: Diagnostic pathology of infectious disease, regimens required for effective management are the focus of
Philadelphia, 2010, Saunders. Courtesy Mirian Sotto, Department
this review.

Aspergillus Species
of Dermatology, Hospital das Clinicas, University of São Paulo, São
Paulo, Brazil.) chromoblastomycosis, and Blastomyces dermatitidis
are uncommon and will not be dis- cussed in this
and extracellular. The extracellular forms may appear in chapter.
a “sausage form” consisting of three cells divided by two
trans- verse septa.

Treatment
The recommended treatment is intravenous amphotericin
B, with or without flucytosine, followed by
itraconazole.27

Fusarium Species
Fusarium species is common in soil. Disease in humans
is rare. The modes of entry are inhalation, ingestion, or
follow- ing a traumatic inoculation of the organism.
Fusariosis has been increasingly described in the bone
marrow transplant patients or prolonged neutropenia,
and it is associated with a high mortality rate. Sinusitis
can precede dissemination.28

Diagnosis
The diagnosis is made by identification of the organism
in the blood or tissue culture growth. Histopathologic
analysis shows septated hyphae of Fusarium species on
GMS stain or periodic acid–Schiff stains (Figure 3-25).

Treatment
Treatment can be established with amphotericin B,
caspo- fungin, voriconazole, or posaconazole.

Other Yeasts
Orofacial infections caused by Pneumocystis jiroveci,
Spo- rothrix schenckii, fungi causing
The genus Aspergillus was first recognized in 1729 by
Micheli, who associated the shape of the sporulating
head of the mold with an aspergillum used to sprinkle
holy water. Aspergillus species are widespread in
nature and ubiquitous, found in soil, in decaying
vegetation, in the air, and in the water supply. There are
more than 180 Aspergillus species, most of which
reproduce asexually. The most common spe- cies
causing invasive disease is Aspergillus fumigatus
(66%). Aspergillus flavus (14%), Aspergillus terreus
(5%), and Asper- gillus niger (5%) are less common.31
The usual route of infection for invasive aspergillosis is
inhalation of Aspergillus conidia. On occasion,
infection follows local tissue invasion after surgery or
contaminated devices.32

Clinical Manifestations
The variety of clinical syndromes associated with
aspergillo- sis range from colonization, to allergic
response to the fun- gus, to invasive disease.
Aspergillus species can be a colonizer of the sinuses
and the ear canal. Aspergillus species occasionally
cause allergic fungal sinusitis in patients with chronic
allergic sinusitis and nasal polyps. In all mycetoma
cases, the active agent was an Aspergillus organism.33
Aspergillus species can also be accompanied by fungus
ball of the sinuses without tissue invasion. Maxillary
sinuses are the most commonly involved in sinus
aspergilloma because of A. fumigatus or A. flavus.34
Otomycosis is a condition of otitis externa with evi-
dence of mold growth clinically. It is usually caused by
A. niger forming a black tuft or A. fumigatus with a
greenish mold.35
Prolonged and profound neutropenia, solid organ or
bone marrow transplant, and steroid and TNF-α
medica- tions increase the risk for invasive
aspergillosis.36 It com- monly manifests as acute
invasive rhinosinusitis. The presence of epistaxis and
an ulcer or eschar should be the clue to invasive fungal
disease. The infection can spread
• Figure 3-26 Conidial head of Aspergillus fumigatus by Gomori
methenamine silver stain. (From Murray PR: Medical microbiology,
ed 7, Philadelphia, Saunders, 2013.)

• Figure 3-27 Fungus ball on computed tomographic scan of the

sinuses. (From Flint PW, Haughey BH, Robbins KT, et al:
to the paranasal sinuses, palate, orbit, or brain with a Cummings otolaryngology: head and neck surgery, ed 6,
Philadelphia, 2015, Saunders.)
high mortality rate.
Other presentations can manifest as an oral
aspergillo- sis after an endodontic procedure, especially
in the maxil- lary segment. It presents as swelling, pain, by Paltauf in 1885. The Mucorales order is a subset of
and violaceous discoloration of the oral mucosa that can the Zygomycetes (formerly Phycomycetes) class and
progress to a necrotic ulcer. contains the order Mucorales, the family Mucoraceae,
and the genera Absidia, Mucor, and Rhizopus.37
Diagnosis
Aspergillus species are easily cultured. A distinguishing Clinical Manifestations
char- acteristic is their ability to grow at 37° C. Most Mucormycosis refers to several different diseases
strains of A. fumigatus grow at a temperature of 45° C caused by infection with fungi in the order of
and above, which can be used to identify the species. Mucorales. Rhi- zopus species are the most common
A. fumigatus hyphae are hyaline, septated, and usually causative organisms (Figure 3-28). In descending
branched at an acute angle. The conidial head (Figure 3- order, the other genera with mucormycosis-causing
26) is columnar with conidiophores that are smooth- species include Mucor, Cun- ninghamella,
walled and uncolored, or darkened in the upper portion Apophysomyces, Absidia, Saksenaea, and
near the ves- icle. Conidia can appear smooth to rough, Rhizomucor.38,39
measuring 2 to Mucormycosis is a rare fungal infection that affects
3.5 μm in diameter. immunocompromised patients, and the
Computed tomographic (CT) scanning of the sinuses rhinoorbitocerebral presentation is the most common
can be used to confirm fungus ball (Figure 3-27). CT clinical form of the dis- ease, often associated with
scan- ning is also helpful in determining the extent of the diabetes mellitus.
infec- tion in invasive disease. The identification of Various forms of the disease have been described,
Aspergillus species in tissue pathology and not just with the rhinocerebral manifestation being considered
culture is needed to confirm the diagnosis. the most common in large case series. The
rhinocerebral form of the disease can present in two
Treatment distinct patterns: a rapidly progressive form with a high
mortality rate40,41 or the rarer slowly progressive chronic
The treatment consists of voriconazole or amphotericin form of the disease.
B. Surgical debridement might be required. Acute rhinocerebral mucormycosis (ARM) is a well-
described fungal infection that typically develops in a
Mucormycosis rapidly fulminant manner with fever, headache, lethargy,
mucosal necrosis, and ophthalmologic findings such as
Mucormycoses are a group of invasive infections caused pro- ptosis, ptosis, ophthalmoplegia, and visual changes
by filamentous fungi of the Mucoraceae family, first (Figure 3-29). Cranial nerve involvement is often
described present. Maxil- lary sinusitis and oral involvement have
been described. Oral lesions are ulcerative with a
black necrotic surface.
 • Figure 3-30 Broad, nonseptate hyphae seen on tissue is charac-
teristic of Mucor species. (From Klatt EC: Robbins and Cotran atlas of
pathology, ed 3, Philadelphia, 2015, Saunders.)

of the disease. The prognosis of the disease has not been

thoroughly evaluated in the relevant literature, overshad-
owed by the more aggressive acute form of the
disease. The largest series available report an overall
• Figure 3-28 Rhizopus species sporangiospores. (From Jennessen J, survival rate of 83%.42,43
Schnürer J, Olsson J, et al: Morphological characteristics of sporangio-
spores of the tempe fungus Rhizopus oligosporus differentiate it
from other taxa of the R. microsporus group, Mycol Res 112(Pt 5):547- Diagnosis
563, 2008.)
Chronic rhinocerebral mucormycosis is a rare
representa- tion of the mucormycoses group of
infections. The disease can present with atypical
symptoms, and the clinician can be further misled by
coexisting infections. Correct diagnosis requires a high
degree of clinical suspicion, and the presence of
predisposing factors should motivate the clinician
toward the possibility of this disease. Histopathologic
finding of broad nonseptate hyphae confirms the clinical
diagnosis (Figure 3-30).44

Treatment
Appropriate treatment should be started promptly, and
underlying conditions should be controlled for a better
outcome. The treatment is complex, and it involves
surgical debridement and systemic intravenous
amphotericin B fol- lowed by posaconazole.42
• Figure 3-29 Fungal sinusitis caused by Mucor species. (From
Requena L, Sitthinamsuwan P, Santonia C, et al: Cutaneous and
mucosal mucormycosis mimicking pancreatic panniculitis and gouty
panniculitis, J Am Acad Dermatol 66:975-984, 2011.) Parasitic Infections
Myiasis
Massive tissue destruction can occur if there is a delay in
Myiasis is an infestation by the larvae of dipterous flies.
treatment.
Myiasis is induced by flies of the superfamily Oestridae.
ARM usually develops in critically ill patients with
The most common species of botflies are Dermatobia
dia- betic ketoacidosis or immunodeficiency. The
hom- inis and the New World screw-worm Cochliomyia
incidence of ARM has risen in the past several decades,
hom- inivorax. The disease most commonly occurs in
possibly because of the increased use of steroids,
tropical areas like Mexico, South America, Central
cytotoxic drugs, and other immunosuppressive medical
America, and the Caribbean.
therapies (e.g., bone marrow transplant), or simply
Eggs are laid in the soil or on sand floors. When the
because of increased recognition
larvae hatch at night, they seek a blood meal from
sleeping human