Demographic data have consistently shown that the clinical manifestations of PCM predominate in adults (over 85 % of cases). In healthy Colombian populations, skin testing with paracoccidioidin proved reactive in 10 %, indicating a previous contact (infection) with the fungus [20]. When the same test was applied in Brazil where PCM is of greater importance, the incidence rates were higher especially in the southern, southeastern, and mid-western regions [1, 12]. Additionally, when the gp43 antigen was used for this purpose, higher (43 %) prevalence rates of infection were recorded [21, 22]. Overall, the disease prevalence rates in Latin America are low, 0.33–3 cases per 100,000 inhabitants [23, 24]. In Brazil, mortality rates attributable to the mycosis represent 3 % of all reported cases [12, 25, 26].

As a disease process, PCM is more often diagnosed in males than in females (ratio of 13:1), even though paracoccidioidin skin testing has shown similar infection rates in both sexes [1, 6, 20–22]. This mycosis is relatively uncommon in children, with approximately 5 % of all patients being less than 10 years of age. When children and adolescents (< 14 years old) are set together, approximately 15 % of all cases correspond to this age bracket, with 8 % more being less than 20 years of age [6, 12, 13, 23, 27, 28]. PCM occurs most commonly in middle-aged men (40–60 years), with the exception of immunosuppressed patients who tend to be younger [6, 11–13, 29, 30]. Most patients (73 %) have current or past agriculture-related occupations [1, 6, 11–13, 27, 28].

Risk factors include living and working in these areas, malnutrition, as well as alcoholism and smoking [1, 6, 12, 13]. A direct relation to underlying immunosuppressive conditions, including HIV disease, has not been clearly demonstrated. Sarti et al. found that in a cohort of over 1000 HIV-infected patients, PCM accounted for only 3.3 % of the deaths (in contrast with histoplasmosis which caused 38 % of fatalities) [29]. Morejon et al. estimated that in HIV patients the prevalence of P. brasiliensis coinfection was low, 1.4 % [30]. Isolated case reports of the mycosis in immunocompromised individuals are rarely found [31, 32].

One of the most relevant characteristics of PCM is its restricted geographic limitation to Central and South America from Mexico (23° North) to Argentina (34° South), sparing certain countries within these latitudes (Chile, Surinam, the Guyana, Nicaragua, Belize, most of the Caribbean Islands) [6, 11–13, 27, 28]. Also of note is the fact that within endemic countries the mycosis is not diagnosed everywhere, but in areas with relatively well-defined ecologic characteristics. These characteristics include the presence of tropical and subtropical forests, abundant watercourses, mild temperatures (< 27ºC), high rainfall (2000–2999 mm), all of which favor crops, such as coffee and tobacco [33].

According to geospatial technologies, association between climatic factors and clinical diagnosis of this mycosis, tend to indicate that Paracoccidioides spp. complex would occur preferentially at sites where the environment has a high rainfall index and the soils show optimal permeability, a combination associated with high relative humidity and abundance of vegetation and watercourses [33]. Estimates indicated that during the rainy season the water volume is high, and temperatures oscillate between 18 and 28 °C, conditions that appear favorable for spore formation and aerial dispersion of the fungus [9, 12, 33, 34]. In a southern region of Brazil, the influences of soil water storage, absolute air humidity higher than normal and presence of the climatic anomaly caused by the 1982/1983 El Niño Southern Oscillation, were shown to be associated with a cluster of acute/subacute cases appearing within a lapse of 1–2 years [35].

Approximately 80 PCM cases have been reported outside the endemic areas, namely, in North America, Europe, and Asia. Of note, every patient had a record of previous residence in recognized endemic countries [36, 37]. These cases demonstrate that P. brasiliensis primary infections can remain dormant for long periods (mean of 13 years) from the time of infection to the moment of disease manifestations [17]. No data on imported P. lutzii cases have been presented. Latency/dormancy may explain why the habitat(s) corresponding to members of the Paracoccidioides complex had not been precisely demonstrated, as with the usual delays in diagnosis, and the mycosis slow progression, one tends to forget the site and type of activities that had led to primary infection [14]. No outbreaks have been reported and the isolation of the fungus from nature (e.g., soil) has seldom been successful [38]. By means of molecular studies (nested polymerase chain reaction, PCR), sampling by aerobiological procedures detected ITS sequences in air samples that were highly similar with the homologous P. lutzii sequences kept at the GenBank database, even if the fungus could not be isolated from the environment by regular culture isolation strategies [39].

Lack of data on two main issues, namely, the habitat of P. brasiliensis/P. lutzii and the manifestations of primary infection, have hindered the understanding of the initial steps in the pathogenesis of PCM. Experimental animal models have been produced by initiation of the paracoccidioidal infection via inhalation of conidia (elements small enough (< 5 m) to reach the alveoli) which transform into yeast cells [18, 19]. The fungus then multiplies in the lung parenchyma and proceeds to disseminate by the venous/lymphatic routes to extrapulmonary organs (Fig. 19.3). Infection gives rise to an intense host response with alveolitis and presence of abundant neutrophils leukocytes engulfing the fungus, cells that are later on replaced by migrating mononuclears which, in turn, convert into epithelial cells thus initiating the formation of granulomas and attracting various subtypes of T lymphocytes of which the relative proportions depend on the host immune status [1, 40–42]. In mice with pulmonary infection with P. brasiliensis, fungal load was controlled by CD8 ⁺ T cells, whereas antibody production and delayed type sensitivity reactions were regulated by CD4 ⁺ T cells [43]. It has been shown that lymphocytes from PCM patients are poorly activated, express low levels of interleukin 15 receptor alpha (IL-15R alpha) and produce only basal levels of cytotoxic granules [43–46]. These findings may account for the observed defect in vitro cytotoxic activity [40, 41, 44, 46].

The characteristics of the immune responses in patients with overt disease have been the subject of numerous studies. Immune reactivity to P. brasiliensis antigens is characterized by depressed Th1 cellular immune responses that revert to normal or almost normal ranges with treatment and patient improvement [46, 47]. Patients with the acute type disease not only have depressed Th1 but have also polarized Th2 responses, characterized by the increased release of the cytokines IL-4, IL–5, and IL-10, high levels of circulating anti-P. brasiliensis antibodies of the immunoglobulin G4 (IgG4) and immunoglobulin E (IgE) subclasses, and marked eosinophilia [41, 42]. This pattern is reflected by abundant fungal multiplication and extrapulmonary dissemination with progression of disease [43, 44, 46]. This Th-2 polarization is regularly reverted with treatment. A Th1 cellular immune response to P. brasiliensis is detected in those individuals who were once exposed to the fungus but did not develop the disease [43]. More recently, a role for T-regulatory cells in cell-mediated immune suppression has been found in patients with active disease, which was also reverted with treatment [41]. The participation of the newly described Th17, Th21, and Th9 subsets in the patients’ immune response has recently been documented revealing Th17 and Th21 responses in the case of the adult type disease while Th9 response was detected mostly in the juvenile type disease [46].

The factors that determine the different outcomes of the infection are not known. In most instances, the subclinical infection is resolved, possibly leaving viable yeast cells that eventually may enter into a dormant-like state for decades [14]. The chronic adult-type disease would then originate from reactivation of these dormant yeast cells and this would explain why these patients tend to develop a chronic, progressive disease, marked by pulmonary damage, and accompanied, in most cases, by dissemination to the lymphatic system, the mucosa, the adrenals, the skin, and other organs [1, 11–13, 16, 23]. Lung damage can progress to fibrosis leaving behind sequelae with variable impact on respiratory function, reinforcing the importance of early diagnosis and treatment [1, 16, 47, 48]. In the rare instances, when the primary infection is not checked by the host’s immune responses, P. brasiliensis disseminates through the lymphohematogenous route resulting in the acute- or juvenile-type disease [1, 42, 49, 50]. Overall, the prevalence of the disease is low even in endemic areas, while that of infected-only individuals is high, reaching up to 46 % of the population in certain highly endemic settings according to skin testing studies [1, 20–22, 51].

In PCM, polymorphonuclear neutrophils (PMNs) have been implicated not only in phagocytosis and pathogen destruction but also in granuloma formation. In cases presenting only loose granulomas, a greater quantity of fungi are to be found in comparison to those corresponding to well-organized granulomas. In either case, neutrophils are present in tissues and participate in granuloma formation largely contributing to the inflammatory response [52]. The major biological significance of granuloma is the limitation of the infection to a local area but if such formation is loose, dissemination would ensue [1, 53].

Antibodies are detected in most PCM patients although the isotypes differ according to clinical type. Thus, the reactivity of immunoglobulin G (IgG) and immunoglobulin M (IgM) to certain antigens was greater in patients with the acute form while immunoglobulin A (IgA) was more reactive in those with the chronic form [54–56]. Nonetheless, their role in the pathogenesis of human disease is still unclear.

PCM is a disorder characterized by protean manifestations that in most patients tend to run a chronic progressive course involving various organs and systems with mortality rates that average 0.9 per 1 million inhabitants in Brazil [46]. Most patients exhibit constitutional symptoms, such as general malaise, asthenia, adynamia, weight loss, and fever, as well as symptoms related to the infected organs. The primary infection occurs in the lungs, but often neither the patient nor the clinical examiner finds abnormalities at this site. On the basis of the clinical presentation and the host immune response to PCM, the disease is categorized as (1) subclinical infection, or (2) symptomatic infection, which is subdivided in two forms, the acute/subacute juvenile and the chronic adult type. A third residual form characterized by fibrotic sequelae is also recognized [1, 6, 11–13]. On the basis of gallium image studies, it is presently accepted that the various manifestations of PCM entail multiple organ involvement, thus negating the former division of the disease into a unifocal or a multifocal process [48]. With the increase in the number of immunocompromised individuals, particularly those with AIDS, the mycosis is being recognized more frequently [25, 26, 29, 30, 57]. In such patients, the corresponding clinical presentation does not allow to categorize the process as chronic or acute but rather as a mixed (opportunistic) form [58–62]. Table 19.1 summarizes the key factors leading to consider the diagnosis of paracoccidioidomycosis.