1665CHAPTER 214 Blastomycosis

certain places, such as Vilas County, Wisconsin, and Kenora, Ontario,

blastomycosis is hyperendemic, with annual incidence rates ranging

from 40 to 117 cases/100,000 persons. Incidence data likely underestimate the true burden of infection because they are limited to persons

with clinically apparent infection. Patients with asymptomatic or subclinical infections are undercounted.

Most Blastomyces infections are sporadic and can occur in either

rural or urban areas. There have been at least 20 outbreaks of blastomycosis in the United States since the mid-1950s. Wisconsin, Minnesota,

and North Carolina have had multiple outbreaks. The majority of

outbreaks have been in rural areas, but several have occurred in urban

settings. Activities associated with outbreaks include construction (of

homes, cabins, factories, and roads), excavation of dirt, participation in

water sports (canoeing, tubing on a river, and fishing), and exposure to

a community compost pile or to beaver dams. Blastomyces infection is

typically acquired from disturbed soil, which liberates infectious particles that are then inhaled into the lungs.

An investigation of a blastomycosis outbreak in Marathon County,

Wisconsin (2009–2010) found that 45% of patients were of Hmong

ethnicity. A retrospective study from the Marshfield Clinic in Wisconsin

(1999–2014) found that 14.4% of patients with blastomycosis were

of Asian ethnicity—a figure higher than was anticipated given that

<2.5% of the population within the catchment area is Asian, including

a large Hmong population. These findings suggest that persons of

Hmong ethnicity have an increased risk of acquiring blastomycosis.

A combination of whole-genome sequencing and immunologic analyses indicated that polymorphisms in the interleukin 6 (IL-6) gene in

the Hmong population result in decreased IL-6 production, which in

turn impairs development of IL-17-producing CD4+ T lymphocytes.

IL-17 is a critical cytokine for recruitment and activation of innate

immune cells such as neutrophils and macrophages active against

Blastomyces. Thus, alterations in IL-6 production may be responsible

for the increased risk of blastomycosis in the Hmong population.

Although data are limited, persons of Hmong ethnicity do not appear

to be at increased risk for disseminated blastomycosis. Increased incidence rates of blastomycosis have also been reported in indigenous

people of Canada and the United States. Compared with Caucasians,

Asian and indigenous persons with blastomycosis tend to have fewer

underlying medical conditions and to be younger.

■ PATHOGENESIS

A defining feature of the Blastomyces species complex is the ability

to respond to shifts in temperature by switching between hyphal and

yeast forms. In the soil, Blastomyces grows as mold cells with hyphae

that produce conidia. Hyphal growth promotes environmental survival, genetic diversity through mating, and production of infectious

conidia that facilitate transmission of Blastomyces from the environment to mammals, including humans. At 37o

C (the core temperature

of mammals), Blastomyces hyphae and conidia convert into pathogenic yeast that upregulate yeast phase–specific virulence factors and

downregulate host immune defenses, thereby facilitating infection.

Virulence traits that Blastomyces shares with Histoplasma, Coccidioides,

Sporothrix, and Paracoccidioides are thermotolerance at 37o

C, intracellular survival, and capacity to cause infection in persons with either

healthy or impaired immune defenses. Although Emergomyces and

Talaromyces marneffei (formerly Penicillium marneffei) exhibit thermal

dimorphism, growth as yeast at 37o

C, and intracellular survival, these

dimorphic fungi tend to cause infection primarily in immunocompromised persons.

The morphologic switch from hyphae to yeast at 37o

C is driven chiefly

by temperature and is coupled with the uptake of exogenous cysteine.

Cysteine uptake is required to complete the transition to the yeast

form because it helps restart mitochondrial respiration, which ceases

during the morphologic switch. Over the past two decades, knowledge about the genetic mechanisms that promote the temperaturedependent transition between hyphae and yeast has substantially

increased. The discovery of dimorphism-regulating kinase 1 (DRK1),

which encodes a group III hybrid histidine kinase that is part of the

high-osmolarity glycerol (HOG) signaling pathway, provided genetic

proof that that the transition to yeast is essential for virulence of the

thermally dimorphic fungi. Disruption of DRK1 by gene deletion or

RNA interference resulted in Blastomyces cells that grew as hyphae at

37o

C instead of yeast. Although viable at 37o

C, these cells had altered

cell-wall composition, failed to upregulate the Blastomyces adhesin

1 (BAD1, formerly WI-1) virulence factor, and were avirulent in a

mouse model of lethal pulmonary infection. Subsequent studies of

Histoplasma and Talaromyces demonstrated that the function of DRK1

is conserved with regard to thermal dimorphism and virulence.

The temperature-dependent transition in the other direction—from

yeast to hyphae—is regulated in part by a GATA-transcription factor

encoded by siderophore biosynthesis repressor in Blastomyces (SREB),

which influences neutral lipid metabolism. In addition, sensing of

chitin by NGT1 and NGT2 N-acetylglucosamine transporters accelerates the conversion to hyphae following a drop in temperature from

37o

C to 22o

C. These two mechanisms are conserved in Histoplasma

capsulatum.

As a primary fungal pathogen, Blastomyces is one of the few fungi

that can infect immunocompetent persons. In its yeast form, Blastomyces evades and modulates immune defenses. Following disruption of

soil, conidia that are aerosolized and inhaled into the lungs are phagocytosed by pulmonary macrophages, in which a subset of the conidia

germinate as yeast and replicate during the early phases of infection.

Blastomyces is also capable of replicating outside of macrophages. Upon

conversion to the yeast phase, an essential virulence factor encoded

by BAD1 is upregulated. BAD1 encodes a multifunctional 120-KDa

cell-surface protein that facilitates yeast adherence to lung epithelial

cells via interaction with heparin sulfate, attachment to host immune

cells by binding to CR3 and CD14 complement receptors, and downregulation of tumor necrosis factor alpha (TNF-α) in macrophages and

neutrophils. In addition, the BAD1 protein impairs activation of CD4+

T lymphocytes, thereby decreasing the production of IL-17 and interferon gamma (IFN-γ). In vivo transcriptional profiling of B. dermatitidis yeast during pulmonary infection demonstrated that BAD1 is the

most highly upregulated gene. Deletion of BAD1 renders B. dermatitidis avirulent in a murine model of pulmonary infection. Thus, BAD-1

is essential for virulence in B. dermatitidis and likely in B. gilchristii

as well. In contrast, BAD1 is absent from the sequenced genomes of

B. helicus, B. parvus, B. silverae, B. percursus, and B. emzantsi.

Additional factors that contribute to the virulence of Blastomyces

yeast include relative resistance to oxidative stress, upregulation of

catalase and superoxide dismutase during infection, active uptake of

zinc by a PRA1-encoded zincophore and transmembrane transporter

(ZRT1), and cleavage of granulocyte-macrophage colony-stimulating

factor by dipeptidyl peptidase IVA, which blocks activation of innate

immune cells (macrophages, neutrophils) and their recruitment to the

lung.

APPROACH TO THE PATIENT

Blastomycosis

On the basis of outbreak investigations, it is estimated that 50%

of persons exposed to Blastomyces develop symptomatic infection

after a 3-week to 3-month incubation period. The relatively long

incubation period means that patients can be diagnosed with blastomycosis throughout the year. Blastomycosis has been referred to

as the “the great pretender” because it can mimic infectious and

noninfectious diseases. Blastomycotic pneumonia clinically and

radiographically resembles community-acquired bacterial pneumonia, viral pneumonia, tuberculosis, and lung cancer. Patients

often receive two or three courses of antibiotics before pulmonary

blastomycosis is diagnosed. Without fungal stain and culture, cutaneous lesions can mimic skin cancer, sarcoidosis, and pyoderma

gangrenosum. Rarely, blastomycosis can mimic laryngeal cancer.

The most important aspect of the approach to a patient with a

compatible illness is the consideration of Blastomyces as an etiologic

agent in the differential diagnosis. This awareness facilitates early

1666 PART 5 Infectious Diseases

diagnosis and treatment, enhancing the potential for improved

clinical outcomes. Clinical clues to blastomycosis, especially in

persons who reside in or visit endemic regions, include pneumonia

that does not improve with antibiotic treatment, pneumonia with

extrapulmonary manifestations (e.g., skin lesions, osteomyelitis,

central nervous system [CNS] involvement), and skin ulcers that

do not respond to standard therapy. Blastomycosis should also be

considered in persons from an endemic area who have unexplained

respiratory failure or acute respiratory distress syndrome (ARDS).

In addition, a detailed exposure history can elevate blastomycosis

in the differential diagnosis. This history includes inquiries about a

pet or family member with blastomycosis; these factors have been

reported in 7.7–10% and 4–9% of patients, respectively.

■ CLINICAL MANIFESTATIONS

PULMONARY BLASTOMYCOSIS Pulmonary manifestations

occur in 69–93% of patients with symptomatic blastomycosis and are

the most common clinical feature of infection. Signs and symptoms

can include fever, chills, productive or nonproductive cough, shortness

of breath, hemoptysis, malaise, and decreased appetite. Pulmonary

blastomycosis also can manifest as asymptomatic infection, a brief

influenza-like illness, acute pneumonia, chronic pneumonia, or ARDS.

Radiographic findings in the lungs include lobar consolidation, a mass

lesion, interstitial infiltrates, nodule(s), a miliary pattern, cavitary

disease, and diffuse involvement of multiple lobes. Hilar adenopathy,

pleural effusion, and empyema are uncommon. No distinctive features

differentiate blastomycosis from other pulmonary diseases. Diabetes,

receipt of a solid organ transplant, immunosuppression, and multilobar pneumonia are risk factors for severe pulmonary blastomycosis.

Approximately 4–15% of patients with pulmonary blastomycosis

develop ARDS, which is characterized by a fulminant course and high

mortality rates ranging from 40 to 89% in most studies. The mortality

rate in ARDS is increased when the diagnosis is delayed.

DISSEMINATED BLASTOMYCOSIS Disseminated blastomycosis occurs in 15–48% of patients and has the potential to involve

nearly any organ in the body. The most common site of dissemination

is the skin, in which the infection can manifest as papules, ulcers, verrucous lesions, or abscesses. The second most common site is bone,

with consequent osteomyelitis characterized by bone pain, soft tissue

swelling, soft tissue abscess, and sinus tract formation. Typically, a

single bone is involved; however, multifocal osteomyelitis can occur.

The most common sites for osteomyelitis include the spine, long bones,

and ribs. Dissemination to the CNS (e.g., manifesting as meningitis, an

abscess, or a mass lesion), the larynx, or the genitourinary system (e.g.,

to the prostate or epididymis) occurs in fewer than 10%; the majority

of the affected patients have concomitant involvement of other organs,

such as the lung or the skin.

Factors that influence dissemination include the infecting Blastomyces species, the duration of pulmonary symptoms, and concomitant

AIDS. Multiple studies from Wisconsin, a state in which B. dermatitidis

and B. gilchristii are endemic, have demonstrated that B. dermatitidis

is more likely to cause disseminated infection (31.4–47.8% of cases),

whereas B. gilchristii tends to remain localized to the lung (90.7–92.2%).

Surprisingly, immunosuppression has only a minimal influence on dissemination, an observation suggesting that Blastomyces virulence factors have a greater impact than host immune defenses. The frequency

of disseminated blastomycosis among solid organ transplant recipients,

persons receiving cancer chemotherapy, and patients undergoing pharmacologic immunosuppression is similar to that among patients with

intact immune systems. Although patients treated with TNF-α antagonists are considered at risk for blastomycosis, the clinical manifestations

and frequency of disseminated disease are unknown in this group

because of a paucity of published data. Persons with AIDS and CD4+ T

lymphocyte counts of <100/μL are an exception: they are at increased

risk for CNS dissemination. Blastomycosis in pregnancy is uncommon,

is typically diagnosed in the second or third trimester (91%), and most

frequently manifests as pneumonia (74%) or disseminated infection

(48%). Transmission to the neonate by either the transplacental route

or aspiration of infected vaginal secretions is rare. Persons infected

with B. helicus can have localized pulmonary infection or disseminated

disease; they are typically immunosuppressed (e.g., as a result of solid

organ transplantation, chemotherapy, HIV infection, or lupus) and

have a high mortality rate (71.4% in seven patients). In contrast to

B. dermatitidis and B. gilchristii, B. helicus commonly causes fungemia.

Infections with B. percursus and B. emzantsi are often of long duration

(persisting for 4 weeks to 5 years) and can involve the lungs or become

disseminated (skin, bone, brain).

■ DIAGNOSIS

Timely diagnosis of blastomycosis requires a high degree of clinical

suspicion because its clinical and radiographic presentations mimic

more common etiologies, such as community-acquired pneumonia,

malignancy, and tuberculosis. Laboratory findings such as leukocytosis, mild anemia, increased C-reactive protein level, and elevated

erythrocyte sedimentation rate are nonspecific. Once suspected, the

diagnosis of blastomycosis is straightforward and involves microscopic

examination of stained specimens, fungal culture, and antigen testing.

The poor sensitivity of complement fixation (9%) and immunodiffusion (28%) renders serologic testing diagnostically dispensable. However, a recently developed serologic test designed to detect antibodies

to BAD1 has a sensitivity of 87% and a specificity of 94–99%. This test

is not yet commercially available.

A presumptive diagnosis of blastomycosis can be made by staining

of clinical specimens and looking for broad-based budding yeast with

a doubly refractile cell wall. Along with the broad-based budding pattern, yeast size (4–29 μm) allows Blastomyces to be distinguished from

other fungi. An exception is B. helicus, which has the potential to be

confused with Histoplasma because of its small-sized yeast. Respiratory

tract specimens such as sputum, tracheal aspirate, and bronchoalveolar

(BAL) fluid can be stained with calcofluor, 10% potassium hydroxide,

or Papanicolaou stain. Purulent drainage can be stained in a similar

manner. The sensitivity of staining of respiratory samples ranges from

50 to 90%. Tissue samples for histopathology should be stained with

Gomori methenamine silver or periodic acid–Schiff stain and assessed

for pyogranulomatous inflammation and broad-based budding yeast.

Traditional stains, such as Gram’s stain or hematoxylin and eosin, do

not permit optimal visualization of Blastomyces yeast.

Growth of Blastomyces in cultures of respiratory tissue or body

fluid samples provides a definitive diagnosis of blastomycosis but

typically requires 5–28 days of incubation. Special media such as

Sabouraud dextrose, potato dextrose, and brain–heart infusion are

required because Blastomyces does not grow well on standard bacteriologic media. Most clinical microbiology laboratories incubate fungal

cultures at 25–30°C, a temperature that results in hyphal growth of

Blastomyces. Unfortunately, Blastomyces hyphae are not morphologically distinct enough to confirm diagnosis. Thus, fungal identification

and diagnosis are commonly confirmed via chemiluminescent DNA

probe or, less commonly, via conversion to yeast upon incubation at

37°C. Diagnosis can also be confirmed by polymerase chain reaction.

Neither the chemiluminescent DNA probe nor morphologic analysis of

yeast by light microscopy differentiates among the different species of

Blastomyces. Moreover, some species, such as B. emzantsi, are difficult

to convert to yeast at 37°C. The species of Blastomyces is not typically

determined because DNA sequencing is required.

An antigen test that detects a conserved galactomannan component

in the Blastomyces cell wall has supplanted serologic testing. This test

can be performed on urine, blood, BAL fluid, and cerebrospinal fluid.

The sensitivity of the antigen test is 85–93% for urine and 57–82% for

serum. Infection burden appears to influence test sensitivity, with a

lower burden of infection resulting in reduced sensitivity. The antigen

test can detect B. dermatitidis, B. gilchristii, and B. helicus; however, its

utility for detection of other Blastomyces species is unknown. Crossreactions in the antigen test occur during infection with other dimorphic fungi, including H. capsulatum (96%), Paracoccidioides species

(100%), and T. marneffei (70%). Among these, only H. capsulatum is

found in the same endemic region as Blastomyces. Rare cross-reactions

1667CHAPTER 214 Blastomycosis

can occur with Aspergillus and Cryptococcus infections. Antigen levels

in urine and blood decline with successful treatment, and their measurement can be used to monitor the response to antifungal therapy.

TREATMENT

Blastomycosis

Guidelines for the treatment of blastomycosis have been published by the Infectious Diseases Society of America, the American

Thoracic Society, and the American Society of Transplantation.

Although there are isolated reports of self-limited pulmonary blastomycosis, there are no criteria to determine which patients will

experience a resolution of infection. Thus, treatment is recommended for all patients with blastomycosis in order to prevent

progressive infection, respiratory failure, and disseminated disease. Antifungal selection is influenced by immune status, CNS

involvement, pregnancy, medical comorbidities (e.g., congestive

heart failure, prolonged QT interval), and drug–drug interactions.

Antifungal drugs active against Blastomyces include amphotericin

B (AmB) formulations and triazoles. The minimal amount of

beta-(1,3)-glucan in the Blastomyces yeast cell wall renders echinocandins ineffective, and they should not be used to treat blastomycosis. Hematologic, hepatic, and renal function should be

assessed prior to initiation of antifungal therapy, and possible drug–

drug interactions should be evaluated. In addition, patients should

be educated about proper administration of triazole antifungals. For

example, itraconazole capsules require an acidic gastric environment for optimal absorption and should be taken with food and an

acidic beverage to improve bioavailability; they cannot be used by

persons taking antacids, H2 antagonists, or proton pump inhibitors.

In contrast, itraconazole solution can be given to patients receiving

gastric acid–lowering therapies and should be taken without food.

Treatment for blastomycosis is summarized in Table 214-1. For

immunocompetent patients with pulmonary or disseminated blastomycosis of mild or moderate severity (e.g., treatable in the outpatient

setting), itraconazole therapy for 6 months is recommended. For

severe blastomycosis (e.g., that requiring hospitalization), induction

therapy with lipid AmB for 7–14 days (or until clinical improvement), followed by itraconazole treatment for 6–12 months, is

recommended. Although not well studied, combination antifungal

therapy with lipid AmB and itraconzole can be considered for

patients with severe pulmonary blastomycosis. In patients with

ARDS, prednisone can be considered; however, the benefits of steroids are unclear. Osteomyelitis due to blastomycosis requires at least

12 months of antifungal therapy, and some patients may require surgical debridement. For blastomycosis involving the CNS, lipid AmB

is administered for 4–6 weeks and is followed by treatment with

itraconazole, voriconazole, or fluconazole for at least 12 months.

Although fluconazole has excellent CNS penetration, its MIC against

B. dermatitidis and B. gilchristii is higher than that of either itraconazole or voriconazole.

Immunosuppressed patients should be treated with 7–14 days

of lipid AmB followed by 12 months of itraconazole. For patients

requiring irreversible immunosuppression, indefinite suppressive

azole therapy may be needed; however, in light of the heterogeneity

of this patient population, a decision about suppressive therapy

should be made on a case-by-case basis. The majority of solid organ

transplant recipients do not require lifelong suppression because

rates of relapse are low when treatment guidelines are followed.

For pregnant women, lipid AmB treatment for 6–8 weeks is

recommended because, unlike the triazole antifungals, lipid AmB

is not teratogenic. Fluconazole can cause craniofacial, skeletal, and

cardiac defects in the developing fetus (Antley-Bixler-like syndrome); voriconazole and posaconazole also can result in skeletal

abnormalities. Itraconazole increases the risk of spontaneous abortion. Before starting antifungal therapy, women of childbearing age

with blastomycosis should have a pregnancy test.

Voriconazole, posaconazole, and isavuconazonium sulfate have

potent activity against B. dermatitidis and B. gilchristii and can be

considered as alternatives for persons who cannot tolerate itraconazole. These agents, along with itraconazole and AmB, also

exhibit good activity against newly identified species of Blastomyces, such as B. helicus, B. percursus, and B. emzantsi. Fluconazole

MICs against B. percursus and B. emzantsi are higher than those of

other triazoles. Moreover, fluconazole appears to have poor activity

against B. helicus, B. parvus, and B. silverae.

■ PROGNOSIS

Mortality rates for blastomycosis range from 5 to 13%; most deaths are

associated with respiratory failure due to ARDS. The vast majority of

patients who recover from pulmonary blastomycosis do not experience

TABLE 214-1 Treatment of Blastomycosis

PATIENT POPULATION

SEVERITY OF

INFECTION SITE OF INFECTION THERAPY

Immunocompetent Mild to moderatea Lung Itraconazole for 6–12 monthsb

Disseminated Itraconazole for 6–12 monthsb

 (≥12 months for osteomyelitis)

Severec CNS Lipid AmB (5 mg/kg dailyd,e for 4–6 weeks) followed by itraconazole,b

 fluconazole (800 mg

daily), or voriconazole (200–400 mg bid) for at least 12 months of treatment

Lung Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb

 for 6–12 months

Disseminated Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb

 for 12 months of

treatment (≥12 months for osteomyelitis)

Immunocompromised Any severity CNS Lipid AmB (5 mg/kg dailyd,e for 4–6 weeks) followed by itraconazole,b

 fluconazole (800 mg

daily), or voriconazole (200–400 mg bid) for at least 1 year of treatmentg

Lung or disseminated Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb

 for 12 monthsg

Pregnanth Any severity Any site Lipid AmB (3–5 mg/kg dailye,f for 6–8 weeks), with avoidance of azole antifungals

a

Mild to moderate infections can typically be managed in the outpatient setting. b

A loading dose of 200 mg PO tid for 3 days followed by 200 mg PO daily or bid, with dosing

based on serum itraconazole levels. The goal for levels of total itraconazole (i.e., itraconazole plus hydroxyitraconazole) is 1–5 μg/mL. Liquid itraconazole has greater

bioavailability than the capsule formulation. Liquid itraconazole and oral capsules are administered differently (see text for details). Serum itraconazole levels should be

measured after steady state has been reached (2 weeks). Because of the drug’s long half-life, blood for serum itraconazole determinations can be drawn regardless of

the time of administration. In contrast, serum drug levels for voriconazole, posaconazole, and isavuconazole should be measured before a dose is administered when

steady state has been reached (~1 week). c

Severe blastomycosis requires hospitalization on a medical ward, an intermediate care unit, or an intensive care unit. d

Lipid

amphotericin B (AmB) is the preferred formulation because it has the best CNS penetration among AmB formulations. For patients with CNS blastomycosis that results

in neurologic dysfunction, surgical intervention should be considered. e

For patients with CNS blastomycosis, severe pulmonary blastomycosis, or severe disseminated

blastomycosis, combination therapy with lipid AmB plus a triazole antifungal can be considered; however, this combination has not been formally studied. For patients with

ARDS, adjunctive steroid therapy with prednisone (40–60 mg daily for 1–2 weeks) can be considered; however, the benefit of steroid administration is not well defined.

f

If lipid AmB is not available, then AmB deoxycholate (0.7–1. 0 mg/kg daily) can be substituted; however, this formulation is associated with higher rates of nephrotoxicity

and infusion reactions than lipid AmB. g

Consider lifelong suppression with itraconazole (200 mg daily) if immunosuppression cannot be reversed. This decision should be

made on a case-by-case basis; not all immunosuppressed patients require lifelong suppressive therapy. In addition, lifelong antifungal suppression can be considered in

patients who experience relapse after appropriate therapy. h

All women of childbearing age should undergo pregnancy testing before initiation of therapy.

1668 PART 5 Infectious Diseases

long-term loss of pulmonary function. Cutaneous blastomycosis typically results in scarring.

■ PREVENTION

Prevention of blastomycosis is challenging because most infections

are sporadic and unpredictably acquired from the environment. However, substantial progress has been made in understanding vaccinemediated immunity conferred by a live, attenuated vaccine strain that

is deficient in BAD1. When injected subcutaneously into mice, the

B. dermatitidis BAD1-null vaccine strain induces sterilizing immunity

by activating TH17 lymphocytes to protect against lethal pulmonary

challenge. Major antigenic components of the vaccine include calnexin

and Blastomyces endoglucanase-2, which may also be conserved in

other pathogenic fungi, including Histoplasma capsulatum, Coccidioides species, Aspergillus species, Fonsecaea pedrosoi, and Pseudogymnoascus destructans. Neither the BAD1-null attenuated vaccine nor

recombinant antigen-based vaccines are commercially available.

■ FURTHER READING

Chapman SW et al: Clinical practice guidelines for the management

of blastomycosis: 2008 update by the Infectious Diseases Society of

America. Clin Infect Dis 46:1801, 2008.

Limper AH et al: An official American Thoracic Society statement:

Treatment of fungal infections in adult pulmonary and critical care

patients. Am J Respir Crit Care Med 183:96, 2011.

Maphanga TG et al: Human blastomycosis in South Africa caused by

Blastomyces percursus and Blastomyces emzantsi sp. Nov. 1967–2014.

J Clin Microbiol 58:e01661, 2020.

■ DEFINITION AND ETIOLOGY

Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of

cryptococcosis. Until recently, cryptococcal strains were separated

into two species, Cryptococcus neoformans and Cryptococcus gattii,

both of which can cause cryptococcosis in humans. The two varieties

of C. neoformans—grubii and neoformans—correlate with serotypes A

and D, respectively. C. gattii, although not divided into varieties, also

is antigenically diverse, encompassing serotypes B and C. However,

genome sequencing studies have now revealed tremendous diversity

among isolates previously assigned to each species, leading to the proposal that each of the prior species classifications includes numerous

new species. Hence, C. neoformans and C. gattii are now considered as

species complexes. However, for clinical purposes, these species complexes cause indistinguishable disease referred to as cryptococcosis.

Consequently, this chapter will continue to use the nomenclature C.

neoformans and C. gattii with the understanding that these terms refer

to species complexes.

■ EPIDEMIOLOGY

Cryptococcosis was first described in the 1890s but remained relatively

rare until the mid-twentieth century, when advances in diagnosis and

increases in the number of immunosuppressed individuals markedly

raised its reported prevalence. Although serologic evidence of cryptococcal infection is common among immunocompetent individuals,

cryptococcal disease (cryptococcosis) is relatively rare in the absence

of impaired immunity. Individuals at high risk for disease due to C.

neoformans include patients with hematologic malignancies, recipients

of solid-organ transplants who require ongoing immunosuppressive

therapy, persons whose medical conditions necessitate glucocorticoid

therapy, and patients with advanced HIV infection and CD4+ T lymphocyte counts of <200/μL. In contrast, C. gattii–related disease is not

215 Cryptococcosis

Arturo Casadevall

associated with specific immune deficits and often occurs in immunocompetent individuals.

Cryptococcal infection is acquired from the environment.

C. neoformans and C. gattii species complexes inhabit different ecologic niches. C. neoformans is frequently found in soils contaminated

with avian excreta and can easily be recovered from shaded and humid

soils contaminated with pigeon droppings. In contrast, C. gattii is not

found in bird feces. Instead, it inhabits a variety of arboreal species,

including several types of eucalyptus tree. C. neoformans strains are

found throughout the world; however, var. grubii (serotype A) strains

are far more common than var. neoformans (serotype D) strains among

both clinical and environmental isolates. The geographic distribution

of C. gattii was thought to be largely limited to tropical regions until an

outbreak of cryptococcosis caused by a new serotype B strain began in

Vancouver in 1999. This outbreak has extended into the United States,

and C. gattii infections are being encountered increasingly in several

states in the Pacific Northwest.

The global burden of cryptococcosis was estimated in 2012 at

~1 million cases, with >600,000 deaths annually, although the prevalence

of this disease has declined since then with the greater availability of

antiretroviral therapy (ART) for HIV. Thus cryptococci are important human pathogens. Since the onset of the HIV pandemic in the

early 1980s, the overwhelming majority of cryptococcosis cases have

occurred in patients with AIDS (Chap. 202). To comprehend the

impact of HIV infection on the epidemiology of cryptococcosis, it

is instructive to note that in the early 1990s there were >1000 cases

of cryptococcal meningitis each year in New York City—a figure far

exceeding that for all cases of bacterial meningitis. With the advent of

effective ART, the incidence of AIDS-related cryptococcosis has been

sharply reduced among treated individuals. Therefore, most cases of

cryptococcosis now occur in resource-limited regions of the world.

The disease remains distressingly common in regions where ART is

not readily available (e.g., parts of Africa and Asia); in these regions,

up to one-third of patients with AIDS have cryptococcosis. Among

HIV-infected persons, those with a decreased percentage of memory B

cells expressing IgM may be at greater risk for cryptococcosis.

■ PATHOGENESIS

Cryptococcal infection is acquired by inhalation of aerosolized infectious particles. The exact nature of these particles is not known; the

two leading candidate forms are small desiccated yeast cells and basidiospores. Little is known about the pathogenesis of initial infection.

Serologic studies have shown that cryptococcal infection is acquired

in childhood, but it is not known whether the initial infection is

symptomatic. Given that cryptococcal infection is common while

disease is rare, the consensus is that pulmonary defense mechanisms

in immunologically intact individuals are highly effective at containing

this fungus. It is not clear whether initial infection leads to a state of

immunity or whether most individuals are subject throughout life to

frequent and recurrent infections that resolve without clinical disease.

However, evidence indicates that some human cryptococcal infections

lead to a state of latency in which viable organisms are harbored for

prolonged periods, possibly in granulomas. Thus, the inhalation of

cryptococcal cells and/or spores can be followed by either clearance

or establishment of the latent state. The consequences of prolonged

harboring of cryptococcal cells in the lung are not known, but evidence

from animal studies indicates that the organisms’ prolonged presence

could alter the immunologic milieu in the lung and predispose to

allergic airway disease.

Cryptococcosis usually presents clinically as chronic meningoencephalitis. The mechanisms by which the fungus undergoes extrapulmonary dissemination and enters the central nervous system (CNS)

remain poorly understood. The mechanism by which cryptococcal

cells cross the blood-brain barrier is a subject of intensive study. Current evidence suggests that both direct fungal-cell migration across the

endothelium and fungal-cell carriage inside macrophages as “Trojan

horse” invaders can occur. Cryptococcus species have well-defined

virulence factors that include the expression of the polysaccharide capsule, the ability to make melanin, and the elaboration of enzymes (e.g.,

1669CHAPTER 215 Cryptococcosis

discovered incidentally during the workup of an abnormal chest radiograph obtained for other diagnostic purposes. Pulmonary cryptococcosis can be associated with antecedent diseases such as malignancy,

diabetes, and tuberculosis.

Skin lesions are common in patients with disseminated cryptococcosis and can be highly variable, including papules, plaques, purpura,

vesicles, tumor-like lesions, and rashes. The spectrum of cryptococcosis in HIV-infected patients is so varied and has changed so much

since the advent of ART that a distinction between HIV-related and

HIV-unrelated cryptococcosis is no longer pertinent. In patients with

AIDS and solid-organ transplant recipients, the lesions of cutaneous

cryptococcosis often resemble those of molluscum contagiosum

(Fig. 215-2; Chap. 196).

■ DIAGNOSIS

A diagnosis of cryptococcosis requires the demonstration of yeast cells

or cryptococcal antigen in normally sterile tissues. Visualization of the

capsule of fungal cells in cerebrospinal fluid (CSF) mixed with India

ink remains a useful rapid diagnostic technique. Cryptococcal cells in

India ink have a distinctive appearance because their capsules exclude

ink particles. However, the CSF India ink examination may yield negative results in patients with a low fungal burden. Cultures of CSF and

blood that are positive for cryptococcal cells are diagnostic for cryptococcosis. In cryptococcal meningitis, CSF examination usually reveals

evidence of chronic meningitis with mononuclear cell pleocytosis and

increased protein levels. A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood. The assay is based on serologic detection of cryptococcal polysaccharide and is both sensitive and

specific. A major advance in recent years has been the introduction of

rapid point-of-care CRAgs that provides results in minutes. A positive

CRAg test provides strong presumptive evidence for cryptococcosis;

however, because the result is often negative in pulmonary cryptococcosis, the test is less useful in the diagnosis of pulmonary disease and is

of only limited usefulness in monitoring the response to therapy.

In areas of Africa where there is a high prevalence of HIV infection,

routine screening of blood for CRAg in HIV-infected patients with low

CD4+ T lymphocyte counts may identify individuals at high risk of

cryptococcal disease who are candidates for antifungal therapy. CRAg

screening has shown that a significant proportion of HIV-infected

patients hospitalized with pneumonia in Thailand harbor cryptococcal

infection. Inexpensive point-of-care CRAg tests are under development

and could be of great diagnostic benefit in resource-limited regions.

FIGURE 215-1 Cryptococcal antigen in human brain tissue, as revealed by

immunohistochemical staining. Brown areas show polysaccharide deposits

in the midbrain of a patient who died of cryptococcal meningitis. (Reproduced

with permission from SC Lee, A Casadevall, DW Dickson. Immunohistochemical

localization of capsular polysaccharide antigen in the central nervous system cells

in cryptococcal meningoencephalitis. Am J Pathol 148:1267, 1996.)

FIGURE 215-2 Disseminated fungal infection. A liver transplant recipient developed

six cutaneous lesions similar to the one shown. Biopsy and serum antigen

testing demonstrated Cryptococcus. Important features of the lesion include a

benign-appearing fleshy papule with central umbilication resembling molluscum

contagiosum. (Photo courtesy of Dr. Lindsey Baden; with permission.)

phospholipase and urease) that enhance the survival of fungal cells in

tissue. Among these virulence factors, the capsule and melanin production have been most extensively studied. The cryptococcal capsule

is antiphagocytic, and the capsular polysaccharide has been associated

with numerous deleterious effects on host immune function. Cryptococcal infections can elicit little or no tissue inflammatory response.

The immune dysfunction seen in cryptococcosis has been attributed to

the release of copious amounts of capsular polysaccharide into tissues,

where it probably interferes with local immune responses (Fig. 215-1).

In clinical practice, the capsular polysaccharide is the antigen that is

measured as a diagnostic marker of cryptococcal infection.

APPROACH TO THE PATIENT

Cryptococcosis

Cryptococcosis should be included in the differential diagnosis

when any patient presents with findings suggestive of chronic meningitis. Concern about cryptococcosis is heightened by a history of

headache and neurologic symptoms in a patient with an underlying

immunosuppressive disorder or state that is associated with an

increased incidence of cryptococcosis, such as advanced HIV infection or solid-organ transplantation.

■ CLINICAL MANIFESTATIONS

The clinical manifestations of cryptococcosis reflect the site of fungal

infection. The spectrum of disease caused by Cryptococcus species consists predominantly of meningoencephalitis and pneumonia, but skin

and soft tissue infections also occur; in fact, cryptococcosis can affect

any tissue or organ. CNS involvement usually presents as signs and

symptoms of chronic meningitis, such as headache, fever, lethargy, sensory deficits, memory deficits, cranial nerve paresis, vision deficits, and

meningismus. Cryptococcal meningitis differs from bacterial meningitis

in that many Cryptococcus-infected patients present with symptoms of

several weeks’ duration. In addition, classic characteristics of meningeal

irritation, such as meningismus, may be absent in cryptococcal meningitis. Indolent cases can present as subacute dementia. Meningeal cryptococcosis can lead to sudden catastrophic vision loss.

Pulmonary cryptococcosis usually presents as cough, increased

sputum production, and chest pain. Patients infected with C. gattii can

present with granulomatous pulmonary masses known as cryptococcomas.

Fever develops in a minority of cases. Like CNS disease, pulmonary

cryptococcosis can follow an indolent course, and the majority of cases

probably do not come to clinical attention. In fact, many cases are

1670 PART 5 Infectious Diseases

TREATMENT

Cryptococcosis

Cryptococcal disease has two general patterns of manifestation: (1)

pulmonary cryptococcosis, with no evidence of extrapulmonary

dissemination; and (2) extrapulmonary (systemic) cryptococcosis,

with or without meningoencephalitis. Pulmonary cryptococcosis

in an immunocompetent host sometimes resolves without therapy.

However, given the propensity of Cryptococcus species to disseminate from the lung, the inability to gauge the host’s immune status

precisely, and the availability of low-toxicity therapy in the form

of fluconazole, the current recommendation is for pulmonary

cryptococcosis in an immunocompetent individual to be treated

with fluconazole (200–400 mg/d for 3–6 months). Extrapulmonary

cryptococcosis without CNS involvement in an immunocompetent

host can be treated with the same regimen, although amphotericin

B (AmB; 0.5–1 mg/kg daily for 4–6 weeks) may be required

for more severe cases. In general, extrapulmonary cryptococcosis

without CNS involvement requires less intensive therapy, with the

caveat that morbidity and death in cryptococcosis are associated

with meningeal involvement. Thus, the decision to categorize cryptococcosis as “extrapulmonary without CNS involvement” should

be made only after careful evaluation of the CSF reveals no evidence of cryptococcal infection. For CNS involvement in a host

without AIDS or obvious immune impairment, most authorities

recommend initial therapy with AmB (0.5–1 mg/kg daily) during

an induction phase, which is followed by prolonged therapy with

fluconazole (400 mg/d) during a consolidation phase. For cryptococcal meningoencephalitis without a concomitant immunosuppressive condition, the recommended regimen is AmB (0.5–1 mg/kg)

plus flucytosine (100 mg/kg) daily for 6–10 weeks. Alternatively,

patients can be treated with AmB (0.5–1 mg/kg) plus flucytosine

(100 mg/kg) daily for 2 weeks and then with fluconazole (400 mg/d)

for at least 10 weeks. Patients with immunosuppression are treated

with the same initial regimens except that consolidation therapy

with fluconazole is given for a prolonged period to prevent relapse.

Cryptococcosis in patients with HIV infection always requires

aggressive therapy and is considered incurable unless immune

function improves. Consequently, therapy for cryptococcosis in

the setting of AIDS has two phases: induction therapy (intended

to reduce the fungal burden and alleviate symptoms) and lifelong

maintenance therapy (to prevent a symptomatic clinical relapse).

Pulmonary and extrapulmonary cryptococcosis without evidence

of CNS involvement can be treated with fluconazole (200–400 mg/d).

In patients who have more extensive disease, flucytosine (100 mg/kg

per day) may be added to the fluconazole regimen for 10 weeks,

with lifelong fluconazole maintenance therapy thereafter. For

HIV-infected patients with evidence of CNS involvement, most

authorities recommend induction therapy with AmB. An acceptable regimen is AmB (0.7–1 mg/kg) plus flucytosine (100 mg/kg)

daily for 2 weeks followed by fluconazole (400 mg/d) for at least

10 weeks and then by lifelong maintenance therapy with fluconazole

(200 mg/d). Fluconazole (400–800 mg/d) plus flucytosine (100 mg/kg

per day) for 6–10 weeks followed by fluconazole (200 mg/d) as

maintenance therapy is an alternative. Newer triazoles like voriconazole and posaconazole are highly active against cryptococcal

strains and appear to be clinically effective, but clinical experience

with these agents in the treatment of cryptococcosis is limited. Lipid

formulations of AmB can be substituted for AmB deoxycholate in

patients with renal impairment. Neither caspofungin nor micafungin is effective against Cryptococcus species; consequently, neither

drug has a role in the treatment of cryptococcosis. Cryptococcal

meningoencephalitis is often associated with increased intracranial

pressure, which is believed to be responsible for damage to the brain

and cranial nerves. Appropriate management of CNS cryptococcosis requires careful attention to the management of intracranial

pressure, including the reduction of pressure by repeated therapeutic lumbar puncture and the placement of shunts. Studies suggest

that the addition of a short course of interferon γ to antifungal

therapy in patients with HIV infection increases clearance of cryptococci from the CSF. In contrast, administration of dexamethasone

was associated with reduced fungal clearance and increased mortality. Antifungal drug resistance has not been a major problem with

cryptococcal strains, but there are increasing reports of drug-resistant

strains, including some emerging during the prolonged therapy

needed for cryptococcosis. Hence, cryptococcosis that is refractory

to antifungal therapy should prompt an investigation into the susceptibility of the clinical isolates in question.

In HIV-infected patients with previously treated cryptococcosis who are receiving fluconazole maintenance therapy, it may be

possible to discontinue antifungal drug treatment if ART results in

immunologic improvement.

■ PROGNOSIS AND COMPLICATIONS

Even with antifungal therapy, cryptococcosis is associated with high

rates of morbidity and death. For the majority of patients with cryptococcosis, the most important prognostic factors are the extent and the

duration of the underlying immunologic deficits that predisposed them

to develop the disease. Cryptococcosis is often curable with antifungal

therapy in individuals with no apparent immunologic dysfunction, but

in patients with severe immunosuppression (e.g., those with AIDS),

the best that can be hoped for is that antifungal therapy will induce

remission, which can then be maintained with lifelong suppressive

therapy. Before the advent of ART, the median overall survival period

for AIDS patients with cryptococcosis was <1 year. Cryptococcosis

in patients with underlying neoplastic disease has a particularly poor

prognosis. For CNS cryptococcosis, poor prognostic markers are a CSF

assay positive for yeast cells on initial India ink examination (evidence

of a heavy fungal burden), high CSF pressure, low CSF glucose levels,

low CSF pleocytosis (<2/μL), recovery of yeast cells from extraneural

sites, absence of antibody to capsular polysaccharide, a CSF or serum

cryptococcal antigen level of ≥1:32, and concomitant glucocorticoid

therapy or hematologic malignancy. A response to treatment does not

guarantee cure since relapse of cryptococcosis is common even among

patients with relatively intact immune systems. Complications of CNS

cryptococcosis include cranial nerve deficits, vision loss, and cognitive

impairment.

■ IMMUNE RECONSTITUTION INFLAMMATORY

SYNDROME

The immune reconstitution inflammatory syndrome (IRIS) occurs

when immunity rebounds in the setting of treated cryptococcosis (or

an undiagnosed asymptomatic infection) and the immune response to

cryptococcal antigens in tissue triggers an inflammatory response that

can be difficult to distinguish from a relapsing infection. IRIS can occur

when patients with AIDS and treated cryptococcosis are given ART

that results in improved immunity. A major consideration for clinicians

treating cryptococcosis in the setting of AIDS is when to begin ART,

which can trigger rebounding immunity. Current recommendations

are to start ART 4−6 weeks after initiation of antifungal therapy. Apart

from the difficulties in distinguishing IRIS from cryptococcal relapse,

the management of this syndrome is complex because it is caused by

the desirable outcome of improving immunity, which is important

in controlling cryptococcal infection and preventing relapses. The

approach to the patient with IRIS must attempt to balance resurgent

immunity against immune-mediated damage. Currently, management

of IRIS is individualized and can involve the use of glucocorticoids to

reduce inflammation.

■ PREVENTION

No vaccine is available for cryptococcosis. In patients at high risk (e.g.,

those with advanced HIV infection and CD4+ T lymphocyte counts of

<200/μL), primary prophylaxis with fluconazole (200 mg/d) is effective

in reducing the prevalence of disease. Since ART raises the CD4+

T lymphocyte count, it constitutes an immunologic form of prophylaxis.

1671CHAPTER 216 Candidiasis

The genus Candida encompasses >150 species, only a few of which

cause disease in humans. With rare exceptions (although the exceptions are increasing in number), the human pathogens are C. albicans,

C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, C. kefyr,

C. lusitaniae, C. dubliniensis, C. glabrata, and the emerging, multidrugresistant, C. auris, which has been responsible for several outbreaks in

health care facilities in recent years. Ubiquitous in nature, they inhabit

the gastrointestinal tract (including the mouth and oropharynx), the

female genital tract, and the skin in the majority of healthy persons.

Although cases of candidiasis have been described since antiquity in

debilitated patients, the advent of Candida species as common human

pathogens dates to the introduction of modern therapeutic approaches

that suppress normal host defense mechanisms. Of these relatively

recent advances, the most important is the use of antibacterial agents

that alter the normal human microbiota and allow nonbacterial species

to become more prevalent in the commensal flora. With the introduction of antifungal agents, the causes of Candida infections shifted from

an almost complete dominance of C. albicans to the common involvement of C. glabrata and the other species listed above. The non-albicans

species now account for approximately half of all cases of candidemia

and hematogenously disseminated candidiasis. Recognition of this

change is clinically important since the various species differ in susceptibility and are increasingly resistant to the newer antifungal agents.

Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm

in diameter and reproduces by budding. Organisms of this genus occur

in three forms in tissue: blastospores, pseudohyphae, and hyphae. Candida grows readily on simple media; lysis centrifugation enhances its

recovery from blood. Species are identified by biochemical testing (currently with automated devices) or on special agar (e.g., CHROMagar).

■ EPIDEMIOLOGY

Candida are present in humans as commensals, in animals, in foods,

and on inanimate objects. In developed countries, where contemporary medical therapeutics are commonly used, Candida species

are now among the most common nosocomial pathogens. In the

United States, these species are among the four most common pathogens isolated from the blood of hospitalized patients. In fact, in a recent

point-prevalence study in the United States, Candida species were the

most common organisms infecting the bloodstream of hospitalized

patients. In regions where advanced medical care is not readily available, mucocutaneous Candida infections, such as thrush, are more

common than deep-organ infections, which rarely occur. However, the

incidence of deep-organ candidiasis is increasing steadily as advances

216 Candidiasis

Michail S. Lionakis, Shakti Singh,

Ashraf S. Ibrahim, John E. Edwards, Jr.

■ FURTHER READING

Alanio A: Dormancy in Cryptococcus neoformans: 60 years of accumulating evidence. J Clin Invest 130:3353, 2020.

Boyer-Chammard T et al: Recent advances in managing HIV-associated

cryptococcal meningitis. F1000Res 8:F1000 Faculty Rev-743, 2019.

Kwon-Chung KJ et al: The case for adopting the “species complex”

nomenclature for the etiologic agents of cryptococcosis. mSphere

2:e00357, 2017.

Maziarz EK, Perfect JR: Cryptococcosis. Infect Dis Clin North Am

30:179, 2016.

Robertson EJ et al: Cryptococcus neoformans ex vivo capsule size is

associated with intracranial pressure and host immune response in

HIV-associated cryptococcal meningitis. J Infect Dis 209:74, 2014.

Srichatrapimuk S, Sungkanuparph S: Integrated therapy for HIV

and cryptococcosis. AIDS Res Ther 13:42, 2016.

in health care—such as therapy with broad-spectrum antibiotics, more

aggressive treatment of cancer, and the use of immunosuppression

for sustaining organ transplants—are implemented. In aggregate, the

global incidence of infections due to Candida species has risen steadily

over the past few decades.

C. auris is an emerging species of Candida that has spread rapidly in

recent years to >30 countries and is a major public health concern. This

concern stems from its occurrence in health care facilities, its ability

to adhere to and persist long term in inanimate objects (in hospitals)

and the human skin despite decolonization efforts, its association

with substantial mortality, its propensity for misidentification as other

Candida species, the incomplete understanding of its environmental

reservoirs, and its multidrug resistance to the current antifungal therapeutic armamentarium, with some C. auris strains being resistant to all

antifungal drug classes currently available for treatment. C. auris (auris

meaning ear in Latin) was first identified in 2009 from the ear drainage

of a patient with an ear infection in Japan. However, subsequent retrospective analysis of Candida strain collections identified the earliest

known C. auris strain to date back to 1996 in South Korea. Notably,

whole genome sequencing analysis of C. auris strains from South Asia,

East Asia, South America, and South Africa found that although strains

within each geographic region are closely related to each other, they

are distinct compared to strains from other geographic regions. These

findings indicate that C. auris emerged independently in multiple geographic locations around the same time; the epidemiologic reasons for

this emergence remain poorly understood.

 The presence of a central venous catheter and/or other invasive

medical devices and recent residence in nursing homes are major risk

factors for C. auris colonization and infection. Screening of selected

patients who are in a hospital or nursing home where C. auris has been

cultured and are at risk for dissemination from a colonization site may

help implementing effective infection control measures. Hand hygiene

with an alcohol-based hand sanitizer is recommended when hands are

not visibly soiled, in which case washing with soap and water is preferred. Identifying the source of contamination, if possible, and using

an Environmental Protection Agency (EPA)-registered hospital-grade

disinfectant effective against Clostridioides difficile spores are desirable.

If a patient develops an invasive or bloodstream infection, it is recommended that the health care facility informs the Centers for Disease

Control and Prevention (CDC), or a similar agency in other countries

and adheres to recommendations for infection control, including

isolation of patients (contact or enhanced barrier precautions), use of

proper personal protective coverings, enforcement of hospital environment hygiene, and communicating with other health care facilities if

the patient is being transferred.

■ PATHOGENESIS

In the most severe form of Candida infection, the organisms disseminate hematogenously and form microabscesses and small macroabscesses in major organs. Although the exact mechanism is not known,

Candida probably enters the bloodstream from mucosal surfaces after

growing to large numbers as a consequence of bacterial suppression

by antibacterial drugs and breaches in the integrity of the mucosal

barrier; alternatively, in some instances, the organism may enter the

bloodstream from the skin via central venous catheters. A change

from the blastospore stage to the pseudohyphal and hyphal stages

is generally considered integral to Candida’s penetration into tissue.

However, C. glabrata and C. auris can cause life-threatening infection,

even though they do not transform into pseudohyphae or hyphae.

Adherence to both epithelial and endothelial cells is thought to be the

first step in invasion and infection; several adhesins have been identified as well as a mucosal toxin, candidalysin. Biofilm formation also

is considered important in pathogenesis. Numerous reviews of cases

of hematogenously disseminated candidiasis have identified the predisposing factors or conditions associated with disseminated disease

(Table 216-1).

Several genes that are involved in the pathogenesis of other Candida

species—such as those responsible for biofilm formation, proteinases, lipases, phospholipases, hydrolases, adhesins, secreted aspartyl