Overview of Fungal Infections☆

Glorijoy Shi En Tan, Tan Tock Seng Hospital, Communicable Diseases Centre, Singapore, Singapore
Li Yang Hsu, National University of Singapore, Singapore, Singapore; Tan Tock Seng Hospital, Communicable Diseases Centre,
Singapore, Singapore
ã 2018 Elsevier Inc. All rights reserved.

Introduction 1
Definition and Classification 1
Superficial and Cutaneous Mycoses 2
Piedra 2
Pityriasis Versicolor 2
Dermatophytosis 2
Subcutaneous Mycoses 2
Chromoblastomycosis 3
Mycetoma 3
Sporotrichosis 3
Systemic Mycoses 3
Candidiasis 3
Cryptococcosis 4
Aspergillosis 4
Mucormycosis 5
Pneumocystis jirovecii 5
Dimorphic Fungi 6
Histoplasmosis 6
Blastomycosis 6
Coccidioidomycosis 6
Antifungal Agents and Therapeutic Considerations 6
Conclusion 7
References 7

Introduction

Fungi are ubiquitous on earth, thriving even in extreme environments (Le Calvez et al., 2009; Cox et al., 2016). Over 1.5 million
species of fungi have been identified, but only a small fraction (approximately 300) are known to cause disease in humans (CDC,
2017). Although even healthy individuals can be infected, true invasive fungal disease (IFD)—where fungi invade and damage the
internal organs of the body—occurs primarily in people with impaired immune systems; the latter are also termed opportunistic
infections. IFDs are increasing in prevalence and importance worldwide, largely because of an increase in the population at risk.
They are a significant cause of mortality and morbidity in people with many types of impaired immunity, including but not limited
to those with human immunodeficiency virus (HIV) infections, recipients of solid organ transplants (SOT) and hematopoietic stem
cell transplants (HSCT), and hospital in-patients who have undergone major surgery and/or are critically ill (Enoch et al., 2006).
The increasing use of novel immunosuppressive agents and more intense chemotherapeutic regimens not only has resulted in
improved survival of individuals with otherwise life-threatening conditions such as cancer or autoimmune diseases but also puts
them at risk for invasive fungal infections. Patients who develop IFDs have up to 14-fold increased risk in mortality as those who do
not (Mattner et al., 2005).

Definition and Classification

Fungi are a group of saprophytic and parasitic spore-producing eukaryotic organisms that lack chlorophyll. They may reproduce
asexually or sexually. Asexual reproduction occurs by budding, fragmentation, or the production of spores. Most but not all fungi
can also reproduce sexually through meiosis and fusion to give rise to diploid nuclei, also producing spores. This introduces genetic
variation into the general fungi population, distinct from asexual reproductive methods where the spores are genetically identical to
the parent cell.

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Change History: April 2017. Glorijoy Shi En Tan and Li Yang Hsu hasn’t made changes to this chapter.

Reference Module in Biomedical Sciences https://doi.org/10.1016/B978-0-12-801238-3.98320-X 1

2 Overview of Fungal Infections

Fungi exist in two main forms, yeasts and molds. Yeasts are solitary cells that reproduce by budding. Examples of yeasts include
Candida spp. and Cryptococcus spp. Molds, such as aspergillus, form multicellular hyphae and can grow by apical extension
(McGinnis and Tyring, 1996). A number of fungi may exist phenotypically in both morphologies depending on the temperature
and environment. These fungi are called dimorphic fungi, of which Histoplasma spp., Coccidioides spp., Blastomyces dermatitidis,
Paracoccidioides spp., and Sporothrix spp. are some examples.
Fungal infections may be broadly divided into superficial and systemic mycoses, which are caused by different species of fungi.
Superficial and subcutaneous mycoses affect the skin, keratinous tissues, and mucosal surfaces, whereas systemic mycoses manifest
in the form of bloodstream infections and major organ involvement. The term “endemic fungi” refers to fungi that occupy a specific
ecological niche in the environment. In the United States, the three main endemic fungi are histoplasmosis, coccidioidomycosis,
and blastomycosis, while histoplasmosis, penicilliosis, and sporotrichosis are the most common in the Asia-Pacific region
(Chakrabarti and Slavin, 2011).

Superficial and Cutaneous Mycoses

Superficial mycoses are limited to the outermost layer of the skin (stratum corneum) and do not elicit any inflammation because
the fungi essentially subsist and grow on the dead keratin that form this layer of skin (Walsh et al., 1996). The most common
etiologies of superficial mycoses are Piedraia hortae, Trichosporon spp., and Malassezia furfur. These give rise to black piedra, white
piedra, and pityriasis versicolor, respectively (Walsh et al., 1996).

Piedra
Piedra, which means stone in Spanish, refers to a superficial infection of the hair shaft, which was first described in 1969 (Beigel,
1869). Two types of piedra are clinically recognized—white and black piedra, both of which have distinct characteristics. White
piedra is more common in temperate and semitropical climates. It commonly results in soft white nodules along the shafts of pubic
hair, axillary hair, mustaches, eyebrows, and eyelashes. This is in contrast to black piedra that preferentially affects scalp hair. Black
piedra results in the formation of firm nodules along the shaft of the hair. The diagnosis of piedra may be made easily by
observation of hyphae on affected hair. Clipping of the affected hair is usually the most effective treatment modality, followed by
application of topical antifungals or keratolytics.

Pityriasis Versicolor
Pityriasis versicolor presents as a rash affecting the trunk, neck, and shoulders. Versicolor comes from the Latin term varsare, which
means to turn color, and the condition is thus named because the affected skin appears discolored, with scaly copper brown, pink,
brown, hyperpigmented or hypopigmented macules. It may be diagnosed clinically, but the use of Wood’s (ultraviolet) lamp
examination to illustrate yellow-green fluorescence on affected skin is useful. The diagnosis can be confirmed via direct microscopy
of skin scrapes treated with 10% potassium dihydroxide (KOH), which typically shows hyphae and budding yeasts arranged in
what is classically described as a “spaghetti and meatballs” appearance.

Dermatophytosis
Fungi that cause infections (with inflammation, as opposed to the fungi that cause superficial mycoses earlier) of the skin, nails,
hairs, and other body surfaces are known as dermatophytes, and these infections are collectively known as dermatophytoses or
tinea (or more colloquially—ringworm). Dermatophytoses are classified according to sites of infection and are very common,
affecting 20%–25% of the world’s population (Havlickova et al., 2008). Tinea pedis and tinea manuum refer to dermatophytosis of
the feet and hands and tinea cruris to lesions of inguinal, pubic, perineal, and perianal areas, whereas tinea corporis affects the
glabrous skin excluding the aforementioned areas, tinea unguium (onychomycosis) the nails, tinea barbae the facial area of
bearded men, and tinea capitis the scalp (Zhan and Liu, 2016). The fungi in the genera Trichophyton, Microsporum, and Epidermo-
phyton are the most common causes of dermatophytoses (Havlickova et al., 2008).
Most superficial and cutaneous mycoses may be diagnosed clinically based on the constellation of history, physical
examination, and confirmation with microscopy and culture of skin or nail specimens. Although usually amenable to treatment,
these infections may have a significant effect on an individual’s quality of life. Topical drugs are usually effective in the treatment of
cutaneous or superficial mycoses. Systemic antifungals are reserved for patients who fail topical treatment.

Subcutaneous Mycoses

Subcutaneous mycoses most commonly occur as a result of direct inoculation of fungi into the subcutaneous tissue following
minor trauma to the skin. The three main types of subcutaneous mycoses are chromoblastomycosis, mycetoma, and sporotrichosis.
 Overview of Fungal Infections 3

Chromoblastomycosis
Chromoblastomycosis is a chronic cutaneous and subcutaneous fungal infection caused by one of several pigmented (de-
matiaceous) fungi, most commonly Fonsecaea pedrosoi, Phialophora verrucosa, and Cladophialophora carrionii. Rhinocladiella aqua-
spersa and Exophiala dermatitidis have also been reported as etiologic agents (Naka et al., 1986; Kinkead et al., 1996; Hoffmann Cde
et al., 2011). It usually presents as cauliflower-like nodules that appear on the limb, subsequently coalescing to form a plaque.
Histopathologic diagnosis of the condition is made when characteristic dark-colored, thick-walled, muriform bodies (medlar
bodies) are observed when skin scrapings from infected tissue are examined with direct microscopy in 10% KOH (Krzyściak et al.,
2014). The disease is present worldwide, with highest prevalence reported in the humid tropical and subtropical climate areas of
America, Asia, and Africa (Najafzadeh et al., 2011).

Mycetoma
Eumycetoma is a suppurative and granulomatous subcutaneous fungal infection, most often affecting the lower extremity. It is
usually confined to the subcutaneous tissues but may extend to involve underlying fascia, bone, and, rarely, regional lymph nodes
via contiguous dissemination (el Hassan and Mahgoub, 1972). Although cases have been reported worldwide, it is primarily
endemic in Mexico, Sudan, and India (van de Sande, 2013) typically affecting healthy males who work as field laborers and farmers
and who thus have frequent exposure to soil. A large number of molds are capable of causing eumycetoma, the most common
being Madurella mycetomatis, Madurella grisea, Leptosphaeria senegalensis, and Pseudallescheria boydii/Scedosporium apiospermum, which
collectively account for 90% of cases (van de Sande, 2013). Infection usually presents as painless nodules that progress to form
sinuses that drain out pus and aggregated fungi that are seen macroscopically as grains.

Sporotrichosis
Sporothrix schenckii is the etiologic agent for sporotrichosis, which most often causes lymphocutaneous infections but can
occasionally occur at other sites in immunocompromised hosts. It is a common saprophyte of soil and decayed wood. The disease
is endemic in developing areas, and persons with greatest risk are those who handle plants and are involved in landscaping or
gardening, where direct inoculation occurs with exposure to soil (Mahajan, 2014). A nontender noduloulcerative lesion, also
known as a sporotrichotic chancre, first appears at the site of inoculation. The infection commonly remains localized, appearing as
asymptomatic, erythematous, papules, papulopustules, nodules, or verrucous plaques and occasionally nonhealing ulcers or small
abscesses (Mahajan, 2014). Ascension of infection along the lymphatic chain to cause satellite nodules followed by lymphade-
nopathy is uncommon, while extracutaneous sporotrichosis occurs primarily in the setting of advanced immunosuppression and
can cause pulmonary, ocular, central nervous system and osteoarticular disease. Tissue culture is the gold standard for diagnosis of
sporotrichosis (Barros et al., 2011), although other methods such as direct microscopy and polymerase chain reaction may be of
diagnostic value but are of poorer sensitivity (Hsu et al., 2012).

Systemic Mycoses

Candida spp. and Aspergillus spp. are the leading causes of IFDs worldwide (Kontoyiannis et al., 2010). The rising incidence of IFDs
over the course of the past couple of decade is a cause of concern. The three main populations at risk are patients with hematologic
malignancies, recipients of organ transplants and HSCTs, and heterogeneous group of otherwise immunosuppressed patients
(Ruping et al., 2008). The overall incidence reported among patients who have undergone HSCT in the United States ranges
between 0.9% and 13.2% (Kontoyiannis et al., 2010). Other systemic mycoses include cryptococcosis, Pneumocystis jirovecii
pneumonia (PCP), mucormycosis, and infections caused by dimorphic fungi.

Candidiasis
Candida spp. are ubiquitous. They are found primarily on human mucosal surfaces such as the gastrointestinal and urogenital tracts
as a commensal and most commonly cause invasive disease as a result of alterations in the normal microbiological flora, breaches
in the mucocutaneous barrier, or defects in the host cellular response. In additional to the traditional risk factors for developing
IFDs, the presence of central venous catheters, use of total and parenteral nutrition, use of indwelling urinary catheters, and the use
of broad-spectrum antibiotics increase one’s risk of developing invasive candidiasis (Antinori et al., 2016).
The term invasive candidiasis refers to invasion of the deep tissues of the body by Candida spp. A special subset of invasive
candidiasis is candidemia, which is the presence of Candida spp. in the blood. It may or may not be associated with other deep
tissue invasion. Invasive candidiasis remains responsible for majority of all systemic mycoses. It is estimated that there are
approximately 46,000 cases of healthcare-associated invasive candidiasis that occur annually in the United States (CDC, 2017).
While there are over 350 subspecies of Candida, 90% of all such infections are accounted for by five species, namely, Candida
albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei (Antinori et al., 2016). C. albicans is the most
4 Overview of Fungal Infections

common isolate causing 62% of all invasive candidiasis, while C. glabrata has become an important emerging pathogen in the
United States with reported incidence rates of 20%–25% of all candidemia episodes (Pfaller and Diekema, 2007).
Invasive candidiasis may present with a wide spectrum of clinical conditions, including isolated candidemia or deep tissue
infections such as intraabdominal infections with abscesses, urinary tract infections, and peritonitis. Less common manifestations
include Candida endocarditis (Antinori et al., 2014), meningitis, and ocular involvement. More often than not, invasive candidiasis
presents with nonspecific symptoms with early clinical manifestations as that of sepsis resulting in a delayed diagnosis.
The diagnosis of invasive candidiasis is usually made via traditional cultures from blood or other tissue samples, which has a
sensitivity of up to 93% in endocarditis but performs poorly in deep-seated tissue infections with <50% sensitivity. Other
molecular and antigen-based detection methods are becoming increasingly available in the clinical setting.

Cryptococcosis
Cryptococcosis is a mycotic infection caused by the encapsulated yeast Cryptococcus spp. Two main pathogenic subspecies have been
identified: C. neoformans and C. gattii. Both C. neoformans and C. gattii are found abundantly in decaying material within hollows of
various tree species, while C. neoformans is also strongly associated with the dessicated excreta of birds (such as pigeons),
environmental scavengers such as sow bugs and ameba (Chowdhary et al., 2012; Maziarz and Perfect, 2016). Ninety-five percent
of all cryptococcal infections are caused by C. neoformans (serotype A). The remaining 5% of infections are caused of C. neoformans
(serotype D) or C. gattii (Maziarz and Perfect, 2016). Positive antibodies to C. neoformans have been found in as high as 56% of
children below the age of five, consistent with the ubiquitous nature of the fungus in the environment (Goldman et al., 2001).
Cryptococcus spp. were first discovered in the 19th century as human pathogens when it was found to be the cause chronic
periostitis of the tibia (Freij and Freij, 2015). They only became recognized as a significant cause of morbidity during the AIDS
pandemic in the following century (May et al., 2016), although since then, outbreaks of C. gattii in less immunocompromised
patients have been described in new geographic locations, likely as a consequence of heavy environmental exposure (Chen et al.,
2014). In addition to the usual risk factors for developing IFIs, patients with liver disease (Spec et al., 2016) and sarcoidosis
(Bernard et al., 2013) have been found to also be at increased risk.
Human hosts acquire infection through the inhalation of fungal cells from the environment. In immunocompetent hosts,
C. neoformans fungal spores are mostly cleared by the immune system although some may establish an asymptomatic latent
infection (Maziarz and Perfect, 2016). In the presence of subsequent immunosuppression, the yeast may then reactivate to cause
invasive disease. Both C. neoformans and C. gattii primarily cause disease in the lung and central nervous system. Other rarer sites of
disease include the skin—appearing as cutaneous nodules or cellulitis—and the prostate in men (Park et al., 2009).
In 2009, the burden of cryptococcal meningitis in the HIV population was estimated to be 957,900 cases each year, resulting in
624,700 deaths within 3 months from infection (Park et al., 2009). Clinical manifestations of CNS cryptococcosis include fever,
headache, focal neurological deficits, change in mental state, and signs of meningism. The symptom complex is often subacute in
onset, progressing over the course of weeks. Cryptococcosis of the lung may manifest as asymptomatic colonization of the airways,
a solitary pulmonary nodule, or severe pneumonia with acute respiratory distress syndrome (Brizendine et al., 2011). Cutaneous
infections are the third most common clinical manifestation of cryptococcosis. The skin lesions are usually indistinguishable from
other infections, and thus, a skin biopsy is usually required to make the diagnosis. Primary cutaneous cryptococcosis is very rare
and usually suggests disseminated disease.
Definitive diagnosis of cryptococcosis is made by culture of the organism from a clinical specimen or direct detection of the
yeast using special stains on sterile specimens. An India ink stain is the most rapid method, which visualizes globular, encapsulated
yeast cells measuring between 5 and 20 mm in diameter each. Although highly specific, it has a low sensitivity of approximately 30%
(Maziarz and Perfect, 2016), which increases to 80% in the HIV/AIDS population (Kaplan et al., 2009). The use of a serological test
for the detection of the cryptococcal polysaccharide capsular antigen is an additional tool to aid in the diagnosis of cryptococcosis,
with overall sensitivities and specificities of 93%–100% and 93%–98%, respectively (Tanner et al., 1994).

Aspergillosis
Aspergillosis is caused by the fungus Aspergillus spp., and the most common human pathogens are A. fumigatus, A. flavus, and
A. terreus (Balajee et al., 2007). Aspergillus spp. is ubiquitous in the environment, and conidia (spores) are inhaled all the time,
although infection occurs in only a very small susceptible subset of the population, as the mold needs to overcome several
components of the host defense system in order to cause disease. The risk of clinically evident infection and the spectrum of
diseases caused by Aspergillus spp. are primarily dependent on the underlying host immunity, although other factors including the
use of broad-spectrum antibiotics, corticosteroids, and environmental factors (building works are usually associated with a higher
load of airborne conidia, as an example) may affect infection risk (Miceli et al., 2017; Haiduven, 2009).
In immunocompetent persons, allergic bronchopulmonary aspergillosis can develop in the rare subset, particular those with
asthma or cystic fibrosis, that mount a severe Th2-mediated reaction (Stevens et al., 2003; Segal, 2009). In persons with underlying
structural lung disease but otherwise normal immune systems, fungal balls, also known as aspergillomas, may develop within
preexisting cavities (Moodley et al., 2014). These fungal lesions may slowly invade into the underlying tissue in patients with
milder forms of immune impairment, manifesting as subacute or chronic invasive fibrocavitary pulmonary disease, usually termed
 Overview of Fungal Infections 5

as chronic necrotizing aspergillosis (Denning et al., 2003). Finally, in severely immunocompromised hosts, invasive aspergillosis
may occur as a rapidly progressive and fatal disease.
Invasive aspergillosis is the most common mold infection in humans, accounting for >85% of invasive mold disease (Alastruey-
Izquierdo et al., 2013). Prolonged severe neutropenia (>10 days; < 500 cells/mm3) as a result of chemotherapy is the single most
important risk factor (Schmiedel and Zimmerli, 2016). If left untreated, the mortality associated with invasive aspergillosis
approaches 100% in the HSCT population (Ruping et al., 2008). The primary sites of invasive disease are naturally the lungs
and sinuses, although other organ systems such as the brain and kidneys may be involved in disseminated disease (Ruhnke et al.,
2007; Guermazi et al., 2003; Vodovnik, 2009). Diagnosing invasive aspergillosis in susceptible hosts requires a high index of
clinical suspicion, as clinical and X-ray findings may be subtle. A computer tomography scan of the chest has a high sensitivity in
detection of early aspergillosis compared with a chest X-ray (Caillot et al., 1997). The earliest sign of invasive aspergillosis is a
pulmonary nodule, which may then progress to a macronodule surrounded by a rim of ground glass changes caused by alveolar
hemorrhage. This is classically known as the “halo sign,” first described in 1985 (Kuhlman et al., 1985).
The use of antigen-based assays that rely on the detection of galactomannan or beta-D-glucan, both components of the fungal
cell wall, can facilitate the diagnosis of invasive aspergillosis. However, definitive diagnosis requires demonstration of hyphae
accompanied by evidence of tissue damage on histological examination of a tissue specimen, consistent with the consensus
definitions developed by the Invasive Fungal Infections Cooperative Group of the European Organization for Research and
Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) (De Pauw et al., 2008). In the absence of histological
confirmation, the diagnosis may be termed “probable” or “possible” IA (Schmiedel and Zimmerli, 2016).

Mucormycosis
The angioinvasive disease mucormycosis is caused by several members of different families of filamentous fungi under the
Mucorales order of the class of Zygomycetes, including genera such as Rhizophus, Cunninghamella, Mucor, and Rhizomucor
(Spellberg et al., 2005). In addition to the traditional risk factors for developing IFIs, the disease may also rarely affect patients
with uncontrolled diabetes mellitus, trauma, and prolonged used of Aspergillus active agents such as voriconazole (Petrikkos et al.,
2012; Kontoyiannis et al., 2005). In particular, an iron-overloaded state has been found to be a risk factor for developing
mucormycosis (Maertens et al., 1999).
It can cause a broad array of clinical syndromes depending on the site of infection, although involvement of the sinuses and
adjoining organs (i.e., rhino-orbital or rhino-cerebral mucormycosis) and the lungs occurs most commonly (Kuhlman et al.,
1985). Other less common sites of involvement include the gastrointestinal tract, kidneys (especially in India (Chakrabarti and
Singh, 2014), isolated central nervous system, the skin, heart valves, bone, and disseminated disease (Kuhlman et al., 1985).
Diagnosis requires a high index of clinical suspicion, and microscopic tissue examination is critical as there are no definitive
serological tests and cultures are often unyielding. Histopathologic diagnosis is characterized by tissue necrosis resulting from
angioinvasion by fungal hyphae and vascular thrombosis. Fungal elements are characterized by broad, irregularly shaped, non
septate hyphae that branch at right angles seen when tissue specimens are stained with potassium hydroxide (Binder et al., 2014).
The prognosis of mucormycosis is poor—worse than most other invasive fungal infections because of its rapidly progressive nature
and the relative lack of efficacy of many antifungal agents.

Pneumocystis jirovecii
Pneumocystis spp. are unicellular eukaryotic organisms that are naturally occurring in the lungs of many mammals. P. jirovecii is a
human-specific yeast-like fungus that is the causative agent of PCP. It was once termed Pneumocystis carinii but was renamed in the
late 20th century in order to distinguish the human-specific organism from its close relative P. carinii that infected lower animal
species (Frenkel, 1999).
Similar to other mycoses, P. jirovecii may be found in the lungs of healthy individuals without causing overt disease (i.e.,
asymptomatic carriage). The risk of disease increases in persons with impaired cell-mediated immunity, especially those with CD4 +
T-cell counts below 200 or CD4 cell count percentage below 14% (Phair et al., 1990). To date, it is the most common acquired
immunodeficiency disease syndrome (AIDS) defining illness (Buchacz et al., 2010). In recent decades, the administration of highly
active antiretroviral therapy (HAART) and the use of prophylactic trimethoprim–sulfamethoxazole have dramatically reduced the
incidence of PCP (Mocroft et al., 2010).
In the HIV/AIDS population, PCP often presents insidiously with a gradual onset nonproductive cough, dyspnea, and low-grade
fever, leading to respiratory failure. Rarely, it may also present with acute pleuritic chest pain and tachypnea as a result of a
pneumothorax (Thomas and Limper Pneumocystis, 2004). The mortality rate of PCP in the HIV/AIDS population has been
reported to be as high as 20% and increases with the need for mechanical ventilation. Non-HIV-immunosuppressed patients with
PCP typically present more abruptly, the timing of which may correlate with an increased dosage of immunosuppressants. In this
population, the mortality rate may be as high as 60% (Sepkowitz, 2002).
Radiological features of PCP are that of interstitial or alveolar infiltrates on a chest radiograph or patchy and nodular ground
glass attenuation seen on a high-resolution computer tomography scan. Direct visualization of the cystic or trophic forms of the
fungus in respiratory secretions (induced sputum or bronchoalveolar lavage specimens) with the use of special staining techniques
such as Gomori methenamine silver, cresyl violet, Gram-Weigert, and toluidine blue O confirms the diagnosis, since P. jirovecii
cannot be cultured. PCR is increasingly being used to make the diagnosis, but cannot distinguish between colonization and disease
(Song et al., 2016).
6 Overview of Fungal Infections

Dimorphic Fungi
Histoplasmosis
Histoplasma capsulatum is a thermally dimorphic fungus, existing as a mold in the environment and a yeast at body temperature. It is
the most prevalent endemic mycosis in the United States (Chu et al., 2006), found best in soils with high nitrogen content enriched
with avian guano. Infections and outbreaks have been described as a consequence of various occupational activities (construction
and demolition feature prominently) and other recreational activities such as cave exploration (Benedict and Mody, 2016). In
North America, H. capsulatum is endemic in the Mississippi and Ohio River valleys. It has been described in almost all countries in
Central and South America, including the Caribbean. Other endemic areas include parts of Africa, Asia (India, China, Philippines,
and Thailand), and Australia (Adenis et al., 2014). Infection typically occurs from disruption of soil containing the organism and
inhalation of hyphal elements. Pulmonary diseases are most commonly described, although the fungus can disseminate—
especially in immunosuppressed patients—to involve the liver and spleen, adrenals, skin, and even the CNS (Kauffman, 2007).
Histoplasma duboisii is a close relative of H. capsulatum and is the etiologic agent of African histoplasmosis. It is a large-celled form
of H. capsulatum and is found predominantly on the African continent (Loulergue et al., 2007). Clinical manifestations of H. duboisii
are distinct from H. capsulatum, predominantly causing skin and bone infections (Loulergue et al., 2007), although disseminated
disease has been reported (Ndiaye et al., 2011; Minta et al., 2014).

Blastomycosis
Blastomycosis is an endemic mycosis caused by the fungus B. dermatitidis, which can also infect other animals such as dogs and cats
(Bromel and Sykes, 2005; Davies et al., 2013). Most cases originate in North America, although rare cases have been reported from
Canada (Kepron et al., 1972), Africa (Baily et al., 1991), and India (Kumar et al., 2014). Between 1990 and 2010, 1216 deaths in
the United States were found to be blastomycosis-related (Khuu et al., 2014). Middle aged men who work outdoors with soil
exposure are at greatest risk of developing disease, which may be acute or subacute in onset. Extrapulmonary disease can affect the
bones, skin, genitourinary tract, and, in rare instances, the CNS (Crampton et al., 2002).

Coccidioidomycosis
Coccidioides immitis is principally endemic to the southwestern United States—Arizona, California, and Texas. The infectious spores
in the soil transform into spherules containing endospores at body temperature. Upsurges in number of cases periodically occur
during dust storms or soil disturbances (Stevens, 1995) and most commonly present as severe community-acquired pneumonia
with chest pain, cough, and fever (Valdivia et al., 2006). Acute infection usually developed between one to three weeks after
exposure and may resolve without specific therapy. It has protean manifestations, and a primary infection may often go
unrecognized. Occasionally, when the acute infection does not resolve, a progressive pneumonia or chronic lung infection results
(Stevens, 1995). A constellation of fever, arthralgia, erythema nodosum, or multiforme together with chest pain is commonly
referred to as “San Joaquin Valley fever” or “desert rheumatism,” deriving its name from the San Joaquin Valley of California where
it was discovered (Hirschmann, 2007). Coccidioidal meningitis is a granulomatous infection of the brain and is the most lethal
manifestation of coccidioidal infection (Blair, 2009). In the preazole era, the one-year mortality was reported to be a devastating
90% (Vincent et al., 1993). With the advent of antifungal therapy, mortality has been reduced but remains high at 40% (Mathisen
et al., 2010). The diagnosis may be confirmed through culture and serologic testing.

Antifungal Agents and Therapeutic Considerations

Current antifungal agents belong to a few main classes targeting either the fungal cell wall or metabolism and include the azoles,
echinocandins, polyenes, antimetabolites, and allylamines (Walsh et al., 1996; Nett and Andes, 2016).
Azoles are the most commonly used systemic antifungal agents in clinical practice and acts by inhibiting ergosterol biosynthesis,
which is a key component of the fungal cell membrane. First- and second-generation triazoles (fluconazole, itraconazole,
voriconazole, and posaconazole) have a broader antifungal spectrum and better safety profile than imidazoles (clotrimazole,
miconazole, and ketoconazole). Caspofungin, anidulafungin, and micafungin are echinocandins that inhibit the synthesis of
glucan in the fungal cell wall via noncompetitive inhibition of the 1,3-b-glucan synthase enzyme, which leads to disruption of the
fungal cell wall and thereafter cell death (Campoy and Adrio, 2016). As a drug class, they are generally well tolerated and safe to use,
with few known drug interactions and adverse reactions (Chang et al., 2017). Amphotericin B, a polyene, remains the most broad-
spectrum antifungal agent, with activity against most yeasts and molds, including the organisms that cause mucormycosis (Nett
and Andes, 2016). It was once the main antifungal agent for treating systemic mycoses, but its role had gradually been supplanted
by the other agents such as the azoles, although it continues to be broadly used for the treatment of life-threatening mycoses.
However, its clinical use is limited by intrinsic toxicities and need for intravenous administration. Another polyene, nystatin, is
more commonly used in the treatment of mucocutaneous candidiasis. Flucytosine is a pyrimidine analog with fungistatic activity
that interferes with pyrimidine metabolism, causing downstream effects with nucleic acid and protein synthesis. Finally, ally-
lamines inhibit squalene epoxidase, the enzyme required for ergosterol synthesis. Compounds of this class are used mainly for
superficial dermatophytic infections.
 Overview of Fungal Infections 7

The introduction of antifungal prophylaxis in patients who have planned immunosuppressive therapy has led to a large
reduction in the incidence of IFDs in these patients (Mariette et al., 2017). Azoles are the most commonly used prophylactic
agents because of the availability of oral formulations with relatively good oral bioavailability, safety profile, and broad-spectrum
activity. Fluconazole, itraconazole, and posaconazole have been studied in the hematologic and transplant patient populations and
have generally been shown to be effective and well tolerated (Keighley et al., 2017), conferring a survival advantage that persists for
years (Marr et al., 2000).

Conclusion

In the presence of an impaired immune system, either inherited or acquired, fungal infections can cause significant morbidity and
mortality. The incidence of such infections will continue to increase in light of development of more potent immunosuppressive
agents that are being used as therapeutic options, although the advent of HAART appears to mitigate the burden of disease. The
approach to all of these infections involves an in-depth review of host immunity and considerations of the natural history and
active antifungal agents available. A focus on understanding the epidemiology and improving diagnostics of fungal infections, as
well as developing new antifungal agents with improved biosafety profiles and efficacy, will enhance the way we deal with such
infections.

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