Introduction
In systemic fungal infections (SFI), the gateway is a deep organ or site, such as the lung, gastrointestinal tract or paranasal sinuses(Carrasco-Zuber et al., 2016). The mycosis develops through hematogenous spread, causing a generalized infection, usually with secondary mucosal involvement. The most common global mycoses are caused by Candida spp. (superficial/cutaneous fungal infections), Cryptococcus neoformans and Aspergillus spp. (Sabol & Gumbo, 2008). Some dimorphic fungi are also associated, such as Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides spp, and Paracoccidioides brasiliensis, (Colombo, Tobón, Restrepo, Queiroz-Telles, & Nucci, 2011; Berto, Wirth, Barth, & Hermes, 2018) as well as the subphylum Mucoromycotina, which causes Mucormycosis (Neville, Damm, Allen, & Chi, 2016).
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.
Considering the role of epidemiological studies in the prevention and treatment of diseases, the aim of this study was to report the prevalence and characteristics of oral lesions in patients diagnosed with SFI in an oral diagnostic referral service in southern Brazil over a 25-year period.
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.
Table 1. Collected data from patients.
F: female; M: male; N.I: not informed; PCM: paracoccidioidomycosis.
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).
Figure 1. 48 years-old man, driver, melanoderma with asymptomatic diffuse mulberry lesions (moriform stomatitis) on the jugal mucosa (A), lips and upper alveolar ridge; incisional biopsy (B) confirmed the diagnosis of PCM. 59 years-old man, rural worker, melanoderma with symptomatic diffuse moriform lesions on the alveolar ridge (C, D)
Figure 2. 56 years-old man, bricklayer, melanoderma with swelling and diffuse lesions on the jugal mucosa (A), and palate (B). Incisional biopsy (B) confirmed the diagnosis of histoplasmosis.
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 hyper-endemic 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 mainly affects adult men, especially farm/rural workers or people who, at some point, were involved with the rural environment (Sposto et al., 1993; Bicalho et al., 2001; Godoy & Reichart, 2003; Paniago et al., 2003; Verli, Marinho, Souza, Figueiredo, & Yurgel, 2005; Brazão-Silva et al., 2011; Azenha, Caliento, Brentegani, & Lacerda, 2012; Barbosa de Paulo, Faria, & Durighetto Jr., 2014; López-Martínez et al., 2014; Souza, Jorge, & Xavier, 2014; Martinez, 2017; Trindade et al., 2017; Dutra et al., 2018), corroborating the present findings, with 90.32% of cases in men, almost half of rural workers (48.38%). In general, PCM reaches a wide age group, from children to the elderly, but the prevalence is higher between the third and sixth decades of life (Martinez, 2017). The age range of patients found in our analysis was 28-69 years, with an average of 46.9 years. Some studies have found similar results, with greater involvement in the fourth decade of life (Sposto et al., 1993; Bicalho et al., 2001; Paniago et al., 2003; Verli et al., 2005; Brazão-Silva et al., 2011; Trindade et al., 2017). The ethnic predisposition for the development of PCM is still not well established (Martinez, 2017), although some studies (Bicalho et al., 2001; Trindade et al., 2017) corroborate our results where the majority of patients were Caucasian.
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.
Corroborating our findings, most studies show that histoplasmosis mainly affects men (Economopoulou et al., 1998; Couppié et al., 2002; Ferreira, Cardoso, Borges, Ferreira, & Loyola, 2002; Singh et al., 2019; Lv, Jiang, He, Li, & Meng, 2020). However, regarding ethnicity there are some discrepancies among studies. Economopoulou et al. (1998) observed a higher occurrence in Caucasian (33.3%), whereas Ferreira et al. (2002) reported that 90% patients were melanoderma. In our analysis, 66.66% patients were melanoderma. Although oral lesions occur more commonly in immunosuppressed patients (Iqbal et al., 2014), in the present study, all cases were immunocompetent individuals, with the palate being the most affected site. According to the literature, tongue, palate, jugal mucosal and gingiva are commonly affected (Scully & Almeida, 1992; Economopoulou et al., 1998; Couppié et al., 2002; Ferreira et al., 2002; Valle et al., 2006).
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 (Vidya et 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.
Camila Camarini cahhcamarini@gmail.com
