Endemic paracoccidioidomycosis: relationship between clinical ...

Medical Mycology April 2013, 51, 313–318

Endemic paracoccidioidomycosis: relationship between clinical presentation and patients’ demographic features FERNANDO BELLISSIMO-RODRIGUES∗, VALDES ROBERTO BOLLELA†, BENEDITO ANTÔNIO LOPES DA FONSECA† & ROBERTO MARTINEZ† *Social Medicine Department, and †Infectious Diseases Division of Internal Medicine Department, Faculdade de Medicina de Ribeirão Preto, São Paulo University, Ribeirão Preto, São Paulo State, Brazil

Paracoccidioidomycosis (PCM) is a systemic fungal disease endemic to Latin America and characterized by two clinical presentations, i.e., patients develop either acute/ subacute or chronic clinical manifestations. The differences in clinical presentations are mainly dependent on the host immune response, but may also be related to demographic characteristics of some patients. In this retrospective study, 1,219 PCM cases treated between 1970 and 2009 in a university medical center, located in southeastern Brazil, were analyzed according to their clinical and demographic features. The most affected anatomical sites were lungs (63.8%) and oral mucosa (50.0%), with increasing involvement of these sites in accord with the age of the patients. Generalized lymphadenopathy (28.1%) and skin lesions (29.6%) were more frequent on the first decades of life. Involvement of the larynx (16.1%), gut (7.5%), spleen (4.7%), central nervous system (3.4%), bones and joints (2.2%), and adrenal (2.1%) were also variable according to the age of the host. The acute/subacute form of the disease accounted for 26.4% of PCM cases and, on a multivariate analysis, was inversely associated with aging (OR ⫽ 0.8 per year, P ⬍ 0.001), and directly associated with female sex (OR ⫽ 7.2, P ⬍ 0.001), mixed black and white racial background (OR ⫽ 2.3, P ⬍ 0.001) or black skin color (OR ⫽ 4.6, P ⬍ 0.001). Based on these findings, we have shown that host immune response, as well as age, gender and ethnicity may influence the clinical presentation of PCM. Keywords paracoccidioidomycosis, clinical presentation, age, sex, ethnicity

Introduction Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), a granulomatous endemic disease prevalent in most of Latin America. PCM is a pleomorphic disease, exhibiting many clinical presentations, which may be roughly classified into two forms, the acute/ subacute and the chronic forms. Diversity of clinical presentation has been attributed to the enhanced pathogenicity of some P. brasiliensis strains [1] and particularly to host factors that modulate the immune response against the fungus [2]. Received 29 March 2012; Received in final revised form 25 June 2012; Accepted 17 July 2012 Correspondence: Fernando Bellissimo-Rodrigues, Avenida dos Bandeirantes, 3900, Campus Universitá rio - Monte Alegre, CEP: 14048-900, Ribeirão Preto, São Paulo, Brazil. Tel: (55 16) 3602 2714; fax: (55 16) 3633 1386; E-mail: [email protected]

© 2013 ISHAM

Some patients’ demographic characteristics may influence the clinical course of the infection and the disease after exposure to P. brasiliensis. For instance, it is well established that the chronic presentation of PCM is more prevalent among men, which may be related to the fact that agricultural work is most often done by men, resulting in their higher exposure to the fungus in the soil [3]. It is also assumed that women in their childbearing years are protected by estrogens, whose high levels in post-puberal period may inhibit the transformation of fungal conidia into yeasts, which is essential for disease development [4]. Age range is also a relevant factor influencing the clinical presentation of PCM. Children and young adults most frequently present with an acute/subacute form of disease (juvenile type), which is a more widespread disease, involving the lymphohematopoietic system, as well as many other tissues. Older patients generally have a chronic form of disease (adult type), which affects primarily the lungs DOI: 10.3109/13693786.2012.714529

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and upper airways [3]. Regarding ethnicity, until now there has not been any substantial evidence that any race is particularly susceptibility to the disease [5]. A prevalence rate of 3–25% for the acute/subacute cases has been reported from a number of cases series [2,5]. A hypothesis to explain such results is that the diverse social and demographic characteristics common to the populations exposed to the fungus eventually play a role in the disease presentation, a factor that has not been fully investigated. The aim of this study was to analyze the relationship between PCM clinical presentations and demographic characteristics of more than 1,000 patients followed in the last four decades and living on a hyper-endemic area in the Brazilian southeast. The data presented here represent one of the largest case series ever reported and expands the analysis of the epidemiological features of this disease as reported previously with a fraction of these patients [6].

Material and methods Study setting The Hospital of Clinics of the School of Medicine of Ribeirão Preto of the University of São Paulo is a public, large tertiary-care hospital located at Ribeirão Preto, a city located in the northeastern region of São Paulo State (21°14′42″ S, 47°48′24″ W). The Infectious Diseases Division of the Internal Medicine Department is involved in ambulatory services for a population of about 5 million people living in Ribeirão Preto and neighboring cities. In this geographic area, a mean annual incidence of 2.7 new cases of PCM per 100,000 inhabitants has been detected on the last decades [6]. Data collection This study evaluated 1,219 patients with confirmed PCM based on the clinical features, as well as on the results of mycological, histopathological and/or serologic tests (counterimmunoelectrophoresis). Because their underlying disease may modify the PCM clinical presentation, HIV/AIDS-infected and other immunosuppressed patients were excluded. Data were retrospectively collected from the medical records of patients followed from 1970–2009 and included age at diagnosis, sex, ethnicity (skin color), tissue/organ involvement and clinical manifestation of PCM. The pulmonary involvement was evaluated by routine radiographic examination, where as involvement of the gut, adrenal, larynx, central nervous system and bones were detected by means of ultrasonography, endoscopy, computed tomography, magnetic nuclear resonance, and laboratory tests applied only to patients with symptoms

suggestive of involvement of these organs. According to clinical presentation, patients were classified as having either acute/subacute or chronic forms of PCM [7]. Statistics A data set was created using the Epi-Info software (CDC, version 3.5.1) and most of the data was analyzed with the same software. Possible associations between demographic characteristics and the clinical forms of the disease were evaluated by a χ2 test, Pearson’s corrected, Wilcoxon test and a logistic regression model, constructed on the Stata® software (version 9.0).

Results The age of the 1,219 patients studied ranged from 3–85 years old, including 154 patients (12.6%) younger than 21 years-old, and 42 (3.4%) 3–10 years of age. Considering all age groups, we observed a male:female ratio of 6.1:1 (1,048:171). We found that 942 (77.3%) patients were classified as white, 168 (13.8%) as having mixed racial backgrounds and 109 (8.9%) as black. Table 1 shows the frequency of each organ or tissue involvement in the PCM patients. Lungs, upper respiratory tract mucosa (including mouth, tongue, pharynx, nose and larynx), lymph nodes and skin were the most frequent sites where P. brasiliensis lesions were detected. The central nervous system, adrenal, gut, bones, joints, testis and epididymis were less frequently involved. Figures 1 and 2 present the frequency of the association of each organ or tissue according to age of the patients at Table 1 Frequency of organ and tissue involvement among 1,219 patients with paracoccidioidomycosis in Ribeirão Preto, Brazil, from 1971–2009. Organs or tissues∗

No. of cases (%)

Lungs (X-ray evaluated) Oral mucosa Skin (one or multiple lesions) Generalized Lymphadenomegaly§ Localized Lymphadenomegaly⫹ Larynx Gut Splenomegaly Nervous Central System Osteoarticular Adrenal (Addison’s Disease) Nasal mucosa Testis or epididymis or prostate Bronchus or trachea

778 (63.8) 610 (50.0) 361 (29.6) 342 (28.1) 276 (22.6) 196 (16.1) 92 (7.5) 57 (4.7) 42 (3.4) 27 (2.2) 26 (2.1) 19 (1.6) 9 (0.7) 5 (0.4)

*In addition of these organs/tissues, esophagus, stomach, eye and psoas were also involved in one case each; §Enlarged lymph nodes were detected on the neck bilaterally and in one or more different sites of the body; ⫹Enlarged lymph nodes were detected only on the neck.

© 2013 ISHAM, Medical Mycology, 51, 313–318

PCM clinical and demographic features

Fig. 1 Percentage of selected organs or tissues involvement among 1,219 patients with paracoccidioidomycosis, according to age at the time of diagnosis in Ribeirão Preto, Brazil, from 1971–2009. Mu, oropharyngeae mucosa; Lu, lungs; Sk, skin; Ly, generalized lymphadenomegaly.

the time of PCM diagnosis. The involvement of lungs, oropharyngeal mucosa and larynx increased with aging, while generalized lymphadenomegaly, splenomegaly, osteoarticular, intestinal and skin involvement decreased in older hosts. Involvement of the central nervous system and adrenal was detected most often among patients older than 30 years of age (data not shown on figures). Most of the patients (73.6%) had the chronic form of PCM, exhibiting predominantly a chronic lung disease, oropharyngeal and/or upper respiratory tract ulcers, with or without regional lymph node enlargement. The remaining 26.4% of patients presented with an acute/subacute form of disease, characterized mainly by a generalized lymphadenomegaly associated or not to hepatosplenomegaly, skin, gut or bone lesions. Table 2 presents the proportion of acute/subacute/ chronic cases according to sex, skin color and age. The acute/subacute form of the disease was associated with

Fig. 2 Percentage of selected organs or tissues involvement among 1,219 patients with paracoccidioidomycosis, according to age at the time of diagnosis in Ribeirão Preto, Brazil, from 1971 to 2009. La, larynx; Gu, gut; Os, osteoarticular; Sp, splenomegaly.

females (OR ⫽ 7.2, P ⬍ 0.001), those of mixed racial background (OR ⫽ 2.3, P ⬍ 0.001) and blacks (OR ⫽ 4.6, P ⬍ 0.001), while the aging of the patient population (OR ⫽ 0.8 per year, P ⬍ 0.001) was associated with the chronic form of PCM. Since almost all patients in the first two decades of life presented the acute/subacute form of PCM, we performed a separate analysis of the data for patients older than 20 years old, which yielded similar results to those described above. The acute/subacute form of the disease was noted in females (OR ⫽ 7.0, P ⬍ 0.001), mixed racial background (OR ⫽ 2.5, P ⬍ 0.001) and blacks (OR ⫽ 4.9, P ⬍ 0.001), while aging of these individuals (OR ⫽ 0.8 per year, P ⬍ 0.001) was still associated with the chronic form of the PCM. Figure 3 shows the association of PCM and race background, for both men and women, and it is clear that, in the first two decades of life, almost all patients presented with the acute/subacute form of the disease, independent

Table 2 Demographic characteristics of 1,219 patients with paracoccidioidomycosis, and their relationship with the acute/subacute form of the disease in Ribeirão Preto, Brazil, from 1971–2009. Parameters Sex Male Female Ethnicity (skin color) White Mixed racial background Black Age (in years) Mean ⫾ SD* Median (p25–p75)

Chronic form n (%)

Acute/subacute form n (%)

Univariate analysis⫹

Multivariate analysis§

842 (93.9) 55 (6.1)

206 (64.0) 116 (36.0)

⫺ OR ⫽ 8.6, P ⬍ 0.001

⫺ OR ⫽ 7.2, P ⬍ 0.001

757 (84.4) 94 (10.5) 46 (5.1)

185 (57.4) 74 (23.0) 63 (19.6)

⫺ OR ⫽ 3.2, P ⬍ 0.001 OR ⫽ 5.6, P ⬍ 0.001

⫺ OR ⫽ 2.3, P ⬍ 0.001 OR ⫽ 4.6, P ⬍ 0.001

47.1 ⫾ 11.5 46 (39–55)

22.6 ⫾ 11.5 21 (15–29)

⫺ P ⬍ 0.001

⫺ OR ⫽ 0.8 per year P ⬍ 0.001

⫹ χ2 Pearson’s corrected for sex and ethnicity, Wilcoxon for age; §Logistic regression, each variable was adjusted for the other two; ∗Standard deviation.


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Fig. 3 Percentage of acute/subacute cases of paracoccidioidomycosis according to the age and ethnicity in males and females, separately, in Ribeirão Preto, Brazil, from 1971–2009.

of their sex and skin color. In the subsequent decades of life, this form was more frequent among white women and among non-white men and women.

Discussion The present study included virtually all adults and children with PCM in the Ribeirão Preto region during the period of the study who had access to full medical care and medicines required for the treatment of the disease. The inclusion of such a large number of patients and the

diversity of the studied population made it possible to highlight the influence of age, sex and ethnic background on the clinical expression of endemic PCM. The predominance of the chronic form, typically with lung and oral mucosa involvement, has been described by others who have analyzed case series from different areas of Brazil [8,9]. However, the proportion of acute/subacute cases observed in our study (26.4%) was higher than any other reported previously, either from the Midwest or Southeast regions of Brazil (15.4–20%) [10,11]. This might be explained by the higher proportion of children, women and Afro-descendants in our investigation as they are more likely to develop this form of PCM. The tradition of intense agricultural activity in the Ribeirão Preto region has involved the recruitment of large number of workers which may have contributed to, beyond men, the occupational exposure of women to P. brasiliensis. Even children were also recruited until 1990 to work on the fields but, more recently, fungal infections among children seem to occur more frequently in those living on suburban areas, which may be associated with a behavior change in the population living in this area. The high percentage of Afro-descendants (22.7%) among the 1,219 patients reflects the ethnic composition of the studied population (21% in Ribeirão Preto city according to the 2000 census) and they are part of the Brazilian population most involved with agriculture. Furthermore, when Japanese immigrants first arrived in Brazil decades ago, they were mostly employed in the agriculture sector of the Brazilian economy, and so, they were exposed to the same environmental factors, what may explain why they represented approximately 20% of PCM cases in São Paulo State [12]. Thus, it seems that for both Japanese and Afro-descendants, there is no inherent race-related predisposition to PCM, but rather their increased exposure to the fungus in hyperendemic areas. Patients’ demographic characteristics have a strong relationship with the degree of dissemination in the body as observed by the distinct clinical presentations of PCM. Probably, they modulate, either directly or indirectly, the host immune response against the etiologic agent. Age was the first of these characteristics to be recognized [2,13] due to the striking predominance of acute/subacute form in the first decades of life [14,15] and the chronic form in older patients [7]. The same distribution is also observed among patients with Histoplasma capsulatum infection, in which a disseminated disease is typically identified among children, while chronic lung infection, oral mucosa and adrenal involvement are mostly observed among adults [16]. The immaturity of the immune system is considered responsible for the hematogenic dissemination of this fungus, which is also supposed to occur on the acute/subacute form of PCM. © 2013 ISHAM, Medical Mycology, 51, 313–318

PCM clinical and demographic features

Regarding sex distribution, in any endemic area, PCM exhibit a similar incidence among children of both sexes, but the disease is far more frequent in men than in women when they reach adulthood [3,17]. The male:female ratio identified (6.1:1) in the present investigation is one of the lowest ever reported, and quite similar to the ratio 5.4:1 observed in a neighboring endemic area, in the São Paulo State [11]. In spite of the fact that post-pubertal women are less likely to develop PCM, once they acquire the disease, they are more prone to develop the acute/subacute form, i.e., 67.8% of the 171 women analyzed presented with this form as compared to 19.7% of men. This represents a male:female ratio of 1.8:1 for the acute/subacute form and 15.3:1 for the chronic form. These results are similar to those from Midwest Brazil, where the male:female ratio was 3:1 for the acute/subacute form and 15:1 for the chronic form [10]. Comparable results were observed in the Rio de Janeiro area, where females accounted for 34.3% of the acute/subacute cases, but only 4.7% of the chronic cases [8]. These data provide an important piece of evidence that women generally develop the acute/ subacute form of PCM, especially after the age of 20. Pregnant women are recognized as being especially susceptible to some infectious diseases due to temporary immune suppression [18]. This appears to be the case for the coccidioidomycosis [19] and for PCM [20], since disseminated disease is often observed in such patients. This was also observed in this study but was not investigated further due to the small number of cases. Hormones and other factors inherent to female sex are probably involved on the development of PCM clinical presentations, an issue requiring further investigation. Previous studies demonstrated that ethnicity does not influence the risk of PCM but the relationship between ethnicity and the different clinical presentations has not been fully explored [5,12]. This association was evaluated in a study performed in Paraná State, a neighboring state to São Paulo State, where widespread disease and bone involvement in PCM were more frequently observed among young people with either black or mixed black and white race background [21]. To our knowledge, the present study is the first to demonstrate a clear association between the acute/subcute form of PCM and black or mixed black and white racial background. This result agrees with one showing a higher prevalence of disseminated coccidioidomycosis among Afro-Americans and Filipinos [19,22]. However, caution must be taken into consideration when analyzing the causality of this association, because income level was not taken into account, and it could represent a confounding factor. PCM is considered a neglected disease because it affects, most of the time, low-income persons and families © 2013 ISHAM, Medical Mycology, 51, 313–318

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[23]. Since Brazilian Afro-descendants are recognized as having a lower-income than whites, which significantly influences their living standards and working conditions, this could be the real reason for the higher proportion of acute/subacute cases observed among them. On the other hand, there are no differences in the skin color frequency when PCM patients are compared to the general population of the same area, making it unlikely that the higher prevalence of acute/subacute form of Afro-descendants found in this study is related to their social-economic status [6]. The increased severity of PCM identified in black or mixed black and white people may reflect a variation in their specific immune response against the P. brasiliensis, and it might be related to genetic background of these patients, as it has been demonstrated that with variants of the human major histocompatibility complex are more prone to develop a severe clinical manifestation [24,25]. The variable range of fungus dissemination observed in a murine model of PCM, according to the animal strain is in line with this hypothesis [26]. In Colombia, the progressive pulmonary form of PCM was associated with the HLA-A9 [25]. Another study from Brazil demonstrated the association of the allele DRB1*11 with the chronic form of PCM, and the authors suggested that HLA regulates the interaction of the host with P. brasiliensis [27]. Possibly, the relationship between ethnicity and the clinical presentation of PCM will be clarified through studies evaluating the genotypic background of Afro-descendants and Caucasian patients, in comparison to healthy people of the same background. For coccidioidomycosis, it has been demonstrated a clear association of one major histocompatibility complex haplotype with a disseminated disease, both in Caucasians, as in Afro-descendants [28]. In conclusion, our data confirm the clinical spectrum of endemic PCM and highlight the relationship between the clinical manifestations and some demographic characteristics of patients. Among white men older than 30, the chronic form predominates, involving particularly the lungs and the upper respiratory tract. The acute/ subacute form is more frequent among children and young adults of any sex or racial background, but after the age of 20, it is far more frequent among women and Afro-descendants.

Acknowledgements This work was partially supported by Fundação para o Apoio ao Ensino, Pesquisa e Assistência (FAEPA) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto of São Paulo University. The authors are grateful to Gleici da Silva Castro Perdoná, PhD, who assisted on the statistical analysis of data, and to Rosane Monteiro, who created and managed the data set.

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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.

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This paper was first published online on Early Online on 27 August 2012.
