Oral manifestations of systemic fungal infections: 25-year experience in an endemic region

. Some mycoses are endemic. They develop through hematogenous spread, causing a generalized infection, usually with secondary mucosal involvement. The aim of this observational and retrospective study was to report the prevalence and characteristics of oral lesions in patients diagnosed with systemic fungal infections (SFI) over a 25-year period in southern Brazil. Demographic (age, sex, ethnicity, occupation) and clinical (anatomical location, symptoms, histopathological diagnosis and management) data from the medical records of patients with SFI were collected from 1995 to 2019. 34 cases of SFI were found, of which 31 (91.18%) were diagnosed as paracoccidioidomycosis (PCM) and 3 (8.82%) as histoplasmosis. Men were much more affected (n = 31; 91.18%), with an average age of 46.9 years. Most patients (n = 18; 58.06%) were Caucasian; 48% (n = 15) were farm/rural workers and the most affected region was the jugal mucosa (n = 13; 25.49%) followed by the alveolar ridge (n = 12; 23.52%). All patients with histoplasmosis were immunocompetent men (mean age: 52.67 years), and the palate was the most affected. All patients underwent incisional biopsy and were referred to an infectologist. The dentist has an essential role in the recognition of SFI, whose oral manifestations may be the first sign. SFI should be included in differential diagnosis in patients from endemic areas. In addition, the inevitable human mobility and globalization make knowledge of these mycoses necessary worldwide, especially since advanced cases in immunocompromised patients can be fatal.

Some of these mycoses are endemic. Humid geographical areas, with high rainfall and acidic soil conditions favor infection (Bicalho, Espírito Santo, Ferreira de Aguiar, & Santos, 2001). Paracoccidioidomycosis (PCM), for example, is a rare disease in the world, but is endemic to Latin America, with the highest prevalence in South America (Trindade et al., 2017;Tracogna et al., 2019). Histoplasmosis is most common in North America (Folk & Nelson, 2017). However, globalization and considerable human mobility in recent years highlight the importance of knowledge of these diseases worldwide, since they can have an aggressive course, especially in immunocompromised patients. Early recognition and management of histoplasmosis, e.g., are of paramount importance in maintaining health and prolonging life of HIV + patients (Economopoulou, Laskaris, & Kittas, 1998). As oral manifestations are usually the first signs of the disease, knowledge about its epidemiology, clinical and demographic characteristics is essential to avoid misdiagnosis and delays in treatment.
The age range of patients found in our analysis was 28-69 years, with an average of 46.9 years.

Histoplasmosis
Of the three male patients (50-55 years; mean: 52.67 years) diagnosed with histoplasmosis, two (66.66%) were melanoderma and in one case (33.33%), the information was missing. Regarding the profession, one (33.33%) was a rural worker, one (33.33%) was a bricklayer and one (33.33%) was a mechanic. Again, multifocal involvement was frequent, and the palate, jugal mucosa and alveolar ridge were affected ( Figure 2). All patients were immunocompetent.

Discussion
We report the experience of 25 years in a reference service in the diagnosis and treatment of oral lesions in southern Brazil. Epidemiological studies represent an important tool for the design of risk factors for a disease in a population. It is known that habits, ethnicity, geographical position and socioeconomic situation are some of the factors that influence the incidence of various diseases. In particular, SFI are endemic, emphasizing the importance of knowing their risk groups and clinical characteristics. Moreover, the socioeconomic impact caused by these diseases can be remarkable, adding to the serious and potentially fatal course of some cases. Acta Scientiarum. Health Sciences, v. 44, e58157, 2022 There are two varieties of SFI: opportunistic (systemic candidiasis, aspergillosis and mucormycosis) and respiratory endemic mycoses (histoplasmosis, blastomycosis, coccidioidomycosis, PCM and cryptococcosis) (Carrasco-Zuber et al., 2016). Of these, only PCM and histoplasmosis were found in this study. All cases of candidiasis were superficial (pseudomembranous and erythematous).
PCM or South American Blastomycosis, caused by the dimorphic fungus P. brasiliensis, mainly affects the lungs and can involve other organs by hematogenous route, such as lymph nodes, skin and oral mucosa (Godoy & Reichart, 2003;Trindade et al., 2017;Dutra et al., 2018). Transmission occurs through inhalation of the fungus, which reaches the pulmonary alveoli (primary site of infection), where the conditions are adequate for it to begin its transition to the yeast phase (Godoy & Reichart, 2003;Marques, 2010;Dutra et al., 2018;). Frequently, the oral mucosa is affected, being the primary clinical manifestation in many patients (Trindade et al., 2017).  PCM is a rare disease in the world; it is endemic and acquired exclusively in Latin America, with the highest prevalence in South America (Trindade et al., 2017). P. brasiliensis has a geographic distribution limited to tropical and subtropical rural areas, from southern Mexico to parallel32-34ºS in Argentina and Uruguay (Tracogna et al., 2019). In Brazil, the most affected regions are the Southeast, Midwest and South. A second endemic area is located along the eastern border of the Amazon region (Martinez, 2015) and a third hyperendemic area most recently installed in the western Amazon region (Martinez, 2017). The region where the present study was carried out is in southern Brazil, where agriculture is an important activity, being within the known endemic area of the country.
PCM most often affects the soft palate, gingiva, lower lip, jugal mucosa and tongue (Marques, 2010). In our study, single and multiple lesions were found, in which the jugal mucosa (25.49%) and the alveolar ridge (23.52%) were the most affected sites. Godoy and Reichart (2003) found the most affected sites were gingiva (76%) and tongue (71%). Trindade et al. (2017) found that jugal mucosa (31.82%) was the most affected site for single lesions and the lip (19.23%) for multiple lesions. For Bicalho et al. (2001) and Verli et al. (2005), the alveolar ridge and the gingiva were the most affected sites, with 51 and 63.9% cases, respectively.
Histoplasmosis, caused by the fungus H. capsulatum, affects the lungs and rarely affects the oral mucosa (O'Sullivan, Whitby, Chahoud, & Miller, 2004). Transmission and infection occur through aerosolization and inhalation of spores, and the soil contaminated with bird and bat droppings is the main environmental reservoir of this fungus (Telles, Karki, & Marshall, 2017;Bauddha, Jadon, Mondal, Vikarm, & Sood, 2018). It most often manifests as an acute lung infection that can progress to chronic pulmonary histoplasmosis or the disseminated form of the disease (Ferreira & Borges, 2009). Oral lesions are present in 30% to 50% patients with disseminated histoplasmosis (Akin, Herford, & Cicciù, 2011), which generally occurs in severely immunocompromised patients (Iqbal, Schifter, & Coleman, 2014). This serious opportunistic infection in association with HIV has assumed considerable importance and disseminated histoplasmosis is inserted in the spectrum of AIDS-defining diseases (Economopoulou et al., 1998). In these cases, this respiratory condition may be fatal.
Histoplasmosis is more commonly found in the United States (Neville et al., 2016;Folk & Nelson, 2017); however, it also affects some regions of Central and South America, Africa, Asia and Australia (O'Sullivan et al., 2004;Folk & Nelson, 2017;Singh et al., 2019). In Brazil, although cases of histoplasmosis have been underestimated, it is believed that this mycosis is an important health problem (Valle et al., 2006), and that it is endemic to the country (Fava & Fava Netto, 1998). A recent systematic review (Almeida, Almeida-Silva, Guimarães, Almeida-Paes, & Zancopé-Oliveira, 2019) showed that the Northeast, Midwest, Southeast and South regions are the most affected, which again includes the region where the present study was developed.
For both mycoses, the treatment depends on the severity of the disease and is carried out by the infectologist. The dentist has an essential role in the recognition of the disease, whose oral manifestations may be the first sign. In this context, the performance of the biopsy is essential, since the microscopic examination confirms the diagnosis. It is also important to emphasize that, especially in patients with histoplasmosis, immunosuppressive conditions should be investigated, such as the HIV virus. For mild and moderate cases of PCM, itraconazole is the drug of choice (Marques, 2010). Other alternatives include trimethoprim-sulfamethoxazole and voriconazole (Marques, 2010).For severe cases, amphotericin B deoxycholate is used (Marques, 2010). For chronic pulmonary histoplasmosis and mild to moderate disease, itraconazole is the most indicated medication (Marques, 2010). In progressive disseminated or severe disease, amphotericin B is adopted, followed by the use of itraconazole (Marques, 2010). Posaconazole has been used as a rescue treatment for severe forms of histoplasmosis, when patients are intolerant to standard therapy or have refractory disease (Marques, 2010). In patients with AIDS, even with advances in antifungal therapy, mortality and morbidity from SFI have not changed significantly in the last years. Furthermore, long-term exposure to antifungal drugs (e.g. fluconazole) has led to the development of resistance in 6% to 36% cases (Vidya, Rao, Nittayananta, Liu, & Owotade, 2016). The development of new antifungal therapeutic agents and the use of alternative therapies appears to be urgent, as well as new effective strategies to enhance the host immune status (Vidyaet al., 2016). In all cases of the present study, after clinical and microscopic diagnosis, patients were referred for systemic treatment, reinforcing the importance of the dentist in recognizing the disease through its oral manifestations.

Conclusion
In short, systemic fungal infections should be included in the differential diagnosis in patients from endemic areas. In addition, the inevitable human mobility and globalization make knowledge of these mycoses necessary worldwide, especially because advanced cases in immunocompromised patients can be fatal. This requires training for clinical suspicion and application of all available tools to obtain early diagnosis, reducing morbidity, socioeconomic impact and mortality.