INTRODUCTION — Paracoccidioidomycosis is a systemic endemic mycotic disease caused by thermally dimorphic fungi of the genus Paracoccidioides. Two species are recognized to cause paracoccidioidomycosis: Paracoccidioides brasiliensis and Paracoccidioides lutzii. The fungus has a geographic distribution limited to Mexico and Central and South America, with the largest number of cases reported in Brazil, Argentina, and Colombia.

Basic aspects of the fungal pathogen and the epidemiology of paracoccidioidomycosis will be reviewed here. Clinical manifestations, diagnosis, and treatment of paracoccidioidomycosis are discussed separately. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis" and "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis" and "Treatment of paracoccidioidomycosis".)

MYCOLOGY — P. brasiliensis and P. lutzii are thermally dimorphic fungi that are found as a mycelium at 22 to 26ºC and as a yeast at 37ºC. This species lack a sexual stage (teleomorph).

In its mycelial form, Paracoccidioides species appear as thin septated hyphae with occasional chlamydospores and conidia [1]. In the yeast form, Paracoccidioides species are characterized by oval or round budding yeast cells of varying sizes (4 to 40 microns). The typical appearance is that of a large mother cell surrounded by multiple budding daughter cells (blastoconidia), often called a "pilot's wheel" (picture 1). When the mother cell has only two budding cells, it may resemble a "Mickey mouse head." (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Microscopy'.).

The use of multilocus sequence typing has differentiated P. brasiliensis from P. lutzii, and has identified three cryptic species of P. brasiliensis: species 1 (S1), the most widely distributed species, which is present in Brazil, Argentina, Uruguay, Paraguay, Peru, and Venezuela; phylogenetic species 2 (PS2), which is present in Brazil and Venezuela; and PS3, which is restricted to Colombia [2]. P. lutzii occurs predominantly in the western-central region of Brazil, as well as in southern and northern Brazil, and Ecuador [3]. Although the clinical impact of this genotypic diversity is not completely understood, data suggest that patients infected with P. lutzii may be negative for the immunodiffusion test that detects antibodies against the gp43 antigen [4]. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Serologic tests'.)

EPIDEMIOLOGY — Based on epidemiological surveys that employed intradermal tests for paracoccidioidin, the prevalence of Paracoccidioides infection in endemic areas may be as high as 50 to 75 percent among the adult population, and almost 10 million people may have been infected by this pathogen [5].

Active paracoccidioidomycosis is estimated to develop in 2 percent of infected individuals [5]. An epidemiologic study in a city in Brazil in which paracoccidioidomycosis is hyperendemic reported a mean incidence of 2.7 cases per 100,000 inhabitants per year, with a stable incidence between 1960 and 1999 [6]. However, a subsequent study reported an incidence ranging from 9.4 to 40 cases per 100,000 inhabitants per year in a hyperendemic area in the state of Rondonia, West Amazon [7]. In Colombia, simulations of the incidence of paracoccidioidomycosis based on published series suggest that the six cities with the highest endemicity may have rates of 0.8 to 3.1 cases per 100,000 inhabitants per year [8].

Paracoccidioidomycosis is observed as a natural infection mostly in humans, but sporadic infections have been reported in wild and domestic animals, particularly in nine-banded armadillos (Dasypus novemcinctus) [9,10].

Geography — Paracoccidioides species have a geographic distribution primarily limited to certain regions of Mexico and Central and South America (figure 1). Approximately 80 percent of cases have been reported in Brazil, with Colombia, Venezuela, and Argentina having the next highest numbers of cases [11-13]. Infections with Paracoccidioides species have also been observed as far north as Mexico and as far south as Argentina [14,15]. However, paracoccidioidomycosis has not been observed in certain countries within these latitudes, such as Chile, Surinam, Guyana, Nicaragua, Belize, and most of the Caribbean islands [1].

About 60 cases of paracoccidioidomycosis were reported in European countries, the United States, Canada, Japan, Africa, and the Middle East, all of them affecting patients who had visited or lived in South America [13].

In Brazil, the largest endemic area comprises the southeast, midwest, and south. However, in the 1990s, the disease spread to the eastern border of the Amazon River, and subsequently to the western Amazon region, with a incidence 9.4 cases per 100,000 inhabitants [7,14]. In a study that analyzed records from 6732 hospitalizations due to paracoccidioidomycosis in Brazilian public hospitals from 1998 to 2006, paracoccidioidomycosis represented 4.3 hospitalizations per 1.0 million inhabitants [16]. Hospitalizations occurred in all 26 states, illustrating that the disease remains endemic in a broad area of Brazil.

Within endemic countries, paracoccidioidomycosis has only been recognized in regions with certain ecologic characteristics, such as the presence of tropical and/or subtropical forests, abundant rivers, mild temperatures, high rainfall, and coffee and/or tobacco crops [1,8,11,12]. As an example, in 1985, a cluster of 10 cases of acute paracoccidioidomycosis in Brazil was associated with an increase in precipitation and air humidity caused by the 1982 to 1983 El Niño Southern Oscillation in the preceding years [17]. Similarly, a cluster of six cases of acute paracoccidioidomycosis was reported between 2009 and 2010 in the northeast part of Argentina and was associated with an El Niño Southern Oscillation that occurred in 2009 and 2010 [18]. An outbreak of acute paracoccidioidomycosis was also reported after deforestation and massive earth removal during the construction of a highway in the State of Rio de Janeiro, Brazil [19].

Habitat — The precise location of Paracoccidioides species in nature remains unclear, although it is suspected to be present in soil [8]. Reasons for this gap in knowledge are that Paracoccidioides species have been isolated rarely from the environment, the disease has a long latency period, and no outbreaks have been reported.

Most available data on the habitat of Paracoccidioides species suggest that the fungi are soil saprophytes. This evidence comes from high rates of positive paracoccidioidin skin tests among rural workers living in endemic areas, and also from sporadic isolation from soil samples and from internal organs of armadillos that are native to endemic areas [20,21].

Occupational exposure — Several investigators have indicated that paracoccidioidomycosis is more prevalent among rural workers engaged in intensive agriculture [1,22]. Human disease has been attributed to exposure to the fungus' habitat (soil) through agricultural work, primarily through coffee, cotton, and tobacco farming [8]. However, this epidemiologic scenario may change as a result of the evolution of agricultural practices, since the use pesticides and plant burning has become common practice [23]. The use of fire may significantly elevate the soil temperature making it inhospitable for Paracoccidioides species. Many agricultural fungicides are azole derivatives, which could lead to a reduction in Paracoccidioides species in the environment [23,24].

Gender distribution — One of the most peculiar aspects of paracoccidioidomycosis is its distribution by gender. In adults with the chronic form, paracoccidioidomycosis is most prevalent among men between the ages of 30 and 60 years. The average male to female ratio is 13:1 in Brazil but may it be as high as 70:1 in other South American countries [22]. Beta-estradiol seems to protect adult females from developing the disease but not from infection. Of note, the high male to female ratio is not observed in prepubescent individuals who may present with the acute/subacute (juvenile) form of disease [5]. (See "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis".)

PATHOGENESIS — The main portal of entry for Paracoccidioides species is via inhalation into the lungs. Following acquisition, neutrophils and activated macrophages will block fungal growth and prevent dissemination of infection in most individuals. A type 2 (Th2) T helper cell response has been linked to susceptibility to disease, whereas a Th1 response has been associated with control of infection [25-28].

Patients exposed to Paracoccidioides species will form granulomas at the sites of primary infection and sometimes at metastatic foci, which may contain viable but quiescent forms of the fungus. After a long period of time (years), following loss of immune balance due to conditions not clearly defined, the infection may progress and give rise to full-blown disease (chronic form of paracoccidioidomycosis). Less frequently, systemic disease may progress from the primary focus of infection without a latency period, with rapid clinical deterioration (acute or sub-acute paracoccidioidomycosis) [5].

Despite the fact that cell-mediated immunity plays a major role in the defenses against Paracoccidioides species, the disease has rarely been reported among patients with HIV or other diseases associated with T-cell mediated immunodeficiency, such as cancer or solid organ transplantation. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Immunocompromised hosts'.)

SUMMARY

●Paracoccidioidomycosis is a systemic endemic mycotic disease caused by the thermally dimorphic fungi of the genus Paracoccidioides, with two species: Paracoccidioides brasiliensis and Paracoccidioides lutzii. (See 'Introduction' above.)

●In its mycelial form, Paracoccidioides appears as thin septated hyphae with occasional chlamydospores and conidia. In its yeast form, Paracoccidioides is characterized by oval or round budding yeast cells of varying sizes. The typical appearance is that of a large mother cell surrounded by multiple budding daughter cells (blastoconidia), often called a "pilot's wheel." (See 'Mycology' above.).

●Paracoccidioidomycosis is observed as a natural infection mostly in humans, but sporadic infections have also been reported in wild and domestic animals, particularly in nine-banded armadillos. (See 'Epidemiology' above.)

●Paracoccidioides has a geographic distribution primarily limited to certain regions of Central and South America. Infection with Paracoccidioides has also been observed as far north as Mexico and as far south as Argentina. (See 'Geography' above.)

●The precise location of Paracoccidioides in nature remains unclear, although it is suspected to be present in soil. (See 'Habitat' above.)

●Human disease has been attributed to exposure to the fungus in soil through agricultural work, primarily coffee, cotton, and tobacco farming. (See 'Occupational exposure' above.)

●In adults with the chronic form, paracoccidioidomycosis is most prevalent among men between the ages of 30 and 60 years. (See 'Gender distribution' above.)

●The main portal of entry for Paracoccidioides is through inhalation into the lungs. (See 'Pathogenesis' above.)