Oral paracoccidioidomycosis: a retrospective study of 95 cases from a single center and literature review.

BACKGROUND: The ecoepidemiological panorama of paracoccidioidomycosis (PCM) is dynamic and still ongoing in Brazil. In particular, data about the oral lesions of PCM are barely explored. The aim of this study was to report the clinicopathological features of individuals diagnosed with oral PCM lesions at an oral and maxillofacial pathology service in Rio de Janeiro, Brazil, in the light of a literature review. MATERIAL AND METHODS: A retrospective study was conducted on oral biopsies obtained from 1958 to 2021. Additionally, electronic searches were conducted in PubMed, Embase, Scopus, Web of Science, Latin American and Caribbean Center on Health Sciences Information, and Brazilian Library of Dentistry to gather information from large case series of oral PCM. RESULTS: Ninety-five cases of oral PCM were surveyed. The manifestations were more frequent among males (n=86/90.5%), middle-aged/older adults (n=54/58.7%), and white individuals (n=40/51.9%). The most commonly affected sites were the gingiva/alveolar ridge (n=40/23.4%) and lip/labial commissure (n=33/19.3%); however, one (n=40/42.1%) or multiple sites (n=55/57.9%) could also be affected. In 90 (94.7%) patients, "mulberry-like" ulcerations/moriform appearance were observed. Data from 21 studies (1,333 cases), mostly Brazilian (90.5%), revealed that men (92.4%; male/female: 11.8:1) and individuals in the fifth and sixth decades of life were the most affected (range: 7-89 years), with the gingiva/alveolar ridge, palate, and lips/labial commissure being the sites most frequently affected. CONCLUSIONS: The features of oral PCM lesions are similar to those reported in previous studies from Latin America. Clinicians should be aware of the oral manifestations of PCM, with emphasis on the clinicodemographic aspects and differential diagnoses, especially considering the phenomenon of the emergence of reported cases in rural and/or urban areas of Brazil.

A surprising finding: The curious case of a tongue lesion misdiagnosed as paracoccidioidomycosis.

BACKGROUND: Paracoccidioidomycosis is an endemic mycosis caused by members of the Paracoccidioides genus. Brazil remains the focus area and, to a lesser extent, the disease has been reported from Argentina, Colombia and Venezuela. AIMS: A Venezuelan Paracoccidioides brasiliensis strain, isolated from a patient diagnosed with chronic multifocal paracoccidioidomycosis, was subjected to whole genome sequencing to provide more insight about Paracoccidioides outside the endemic focus area. METHODS: P. brasiliensis strain CBS 118890 was whole genome sequenced using nanopore; library preparation with the 'native barcoding genomic DNA kit' was followed by sequencing on Flongle and MinION flowcells. Batches of strain CBS 118890 were re-identified by sequencing the internal transcribed spacer (ITS) region, and final identification was made based on phylogenetic analysis. RESULTS: Surprisingly, the Venezuelan P. brasiliensis strain CBS 118890 turned out to be a Nannizziopsis species. The batches of this strain were ITS sequenced followed by phylogenetic analysis and resulted in the final identification of Nannizziopsis arthrosporioides. CONCLUSIONS: Nannizziopsis infections are commonly seen in a wide variety of reptiles, but are particularly rare in human infections. This case underlines the need for molecular characterization of cases that clinically mimic paracoccidioidomycosis but that are serologically negative for Paracoccidioides.

Systematic review of neuroparacoccidioidomycosis: The contribution of neuroimaging.

BACKGROUND: Advanced neuroimaging demonstrated that neurological involvement occurs in up to 30% of paracoccidioidomycosis (PCM) cases. Current knowledge of neuroparacoccidioidomycosis (NPCM) is based on a 2009 systematic review. However, in the last decade, several new cases have been published, with modern neuroimaging techniques. OBJECTIVES: We believe a new systematic review is needed to summarise these advances. METHODS: We searched PubMed/MEDLINE, Embase and LILACS for studies from January 2010 to May 2022. Case series and case reports of NPCM were included. We performed a metaproportion to estimate a summary proportion with 95% confidence intervals (CI). RESULTS: Thirty-four studies including 104 patients were evaluated. We combined our data with the results from the previous review that included 257 cases, totalling 361 patients. We found no new important demographic, clinical or laboratory characteristics. On magnetic resonance imaging (MRI), we found that 72% (95%CI: 38-91) had hyperintensity on T1-weighted image; 84% (95%CI: 71%-92%) had hypointensity on T2-weighted image; 80% (95%CI: 66-89) had contrast enhancement with the classical ring-enhancing pattern. All 8 patients undergoing spectroscopy presented lipid peaks. We found a 16% mortality, lower than in the previous review (44%). CONCLUSION: NPCM presents a characteristic pattern on MRI that may help to differentiate it from other causes of single or multiple brain lesions. Albeit there is a frequent pattern, it is not specific, as other granulomatous diseases may show similar findings. Advances in neuroimaging with early diagnosis and appropriate management of the disease may have contributed to reducing its mortality.

Head and neck manifestations of paracoccidioidomycosis: A retrospective study of histopathologically diagnosed cases in two medical centers in southern Brazil.

BACKGROUND: Paracoccidoidomycosis (PCM) is a granulomatous systemic mycosis endemic in southern Brazil. OBJECTIVES: Analyze the clinical and epidemiological characteristics of cases of PCM with head and neck manifestations in southern Brazil. MATERIAL AND METHODS: Retrospective study of histopathologically diagnosed cases of PCM with head and neck manifestations referred to two medical centers in the municipality of Santa Cruz do Sul, state of Rio Grande do Sul, Brazil, during a 10-year period (2011-2020). RESULTS: Twenty-eight patients were selected. The number of cases usually ranged from one to four per year, although 11 cases were diagnosed in 2019. Most patients were between 40 and 59 years old. In total, 21 patients were men and seven were women (male:female ratio 3:1). Most (92%) were Caucasian and 46% were smokers. Patients were from 12 municipalities in the central-eastern region of the state. The most frequent site of the lesions was the larynx. Associated HIV and squamous cell carcinoma were both present in three cases. CONCLUSIONS: This is the first study to analyze PCM cases from central-eastern Rio Grande do Sul. PCM is endemic in southern Brazil, and more epidemiological data are needed, considering that its incidence may be higher than currently estimated, as demonstrated by our results.

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 mycosesnecessary worldwide, especially since advanced cases in immunocompromised patients can be fatal.

Diagnosis at different stages of paracoccidioidomycosis with oral manifestation: Report of two cases.

Paracocciodiomycosis (PCDM) is a chronic systemic fungal infection, mainly affecting residents and rural workers, being characterized by a long incubation period, which it can take months or years without clinical manifestations, making diagnosis late and difficult. Depending on the stage of the disease, it can cause sequelae and low quality of life, so its correct diagnosis is of great importance for the accurate treatment. Therefore, the aim of this report is to present two cases of diagnosis of patients with PCDM at different stages, who developed chronic manifestations, pain, clinical involvement of the oral cavity and in one case also presented lung injury with fibrosis, as well as to weight loss, dysphagia and cachexia. Both of patients were treated with antifungal therapy and it was observed total remission of the lesions and no recurrences were detected.

Comparison of clinico-epidemiological and radiological features in paracoccidioidomycosis patients regarding serological classification using antigens from Paracoccidioides brasiliensis complex and Paracoccidioides lutzii.

Genotyping of the genus Paracoccidioides showed its diversity and geographical distribution. Four species constituting the Paracoccidioides brasiliensis complex and Paracoccidioides lutzii are etiological agents of paracoccidioidomycosis (PCM). However, there are no studies comparing the clinical and epidemiological aspects between PCM caused by the P. brasiliensis complex and by P. lutzii. Demographic and clinical data from 81 patients with PCM-confirmed by mycological and/or histopathological examination-from Mato Grosso do Sul state (Brazil) were studied. All patients underwent serology by immunodiffusion with antigens obtained from the P. brasiliensis complex (ExoPb and gp43) and Cell Free Antigens obtained from P.lutzii (CFAPl).The cases were classified regarding their serological profile into three groups: G1: PCM patients seropositive to ExoPb and/or gp43 and seronegative to CFAPl (n = 51), assumed to have PCM caused by P. brasiliensis complex; G2: PCM patients seronegative to gp43 and seropositive to CFAPl (n = 16), with PCM caused by P. lutzii; and G3: PCM patients seropositive to ExoPb or gp43 and seropositive to CFAPl (n = 14), with undetermined serological profile, was excluded from the analyses. The Fisher's exact test or the Mann-Whitney U test, and cluster analysis according to Ward's method and Euclidean distance were used to analyze the results. Patients with serological profile suggestive of P. lutzii lived predominantly in municipalities in the Central and Southern regions of the state, while those with serological profile indicative of the P. brasiliensis complex were distributed throughout the state. No differences were found between the two groups regarding gender, age, schooling, rural work, clinical form, severity, organs involved, intensity of pulmonary involvement, degree of anemia, erythrocyte sedimentation rate values, and therapeutic response. PCM patients with serological profile suggestive of P. lutzii and PCM patients with serological profile indicative of P. brasiliensis complex showed the same clinical and radiological presentations.

Thinking in paracoccidioidomycosis: a delayed diagnosis of a neglected tropical disease, case report and review of clinical reports and eco-epidemiologic data from Colombia since the 2000.

BACKGROUND: Paracoccidioidomycosis is a neglected tropical disease, endemic in several countries of South America including Colombia. We report a case of a patient with Chronic Multifocal Paracoccidioidomycosis with long-standing symptoms and a delayed diagnosis caused by several barriers to achieve it. We did a review of the papers published in Colombia about this disease, focusing in clinical data and eco-epidemiology with the finding of a lack of new information on this topic since the 2000 in our region. CASE PRESENTATION: We present a 54-year-old man, farmer in his youth, with a chronic ulcerated lesion in the lower lip similar to a lip carcinoma, a deforming lesion in the nose, and respiratory symptoms with emphysematous lung. Lip biopsy with silver methenamine stain revealed small and large budding yeasts that resembles a "mariner's wheel" confirming Chronic Multifocal Paracoccidioidomycosis. He was treated successfully but subsequently lost to follow up. CONCLUSIONS: It is very important to focus attention, reinforce the search and create networks for the study of neglected tropical diseases. The presented case illustrates a usual clinical presentation, but with a delayed diagnosis due to the difficulties that still occur in some regions like ours for the early recognition of a case of chronic multifocal paracoccidioidomycosis.

Virulence factors of Paracoccidioides brasiliensis as therapeutic targets: a review.

Paracoccidiodomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii. The disease requires long and complicated treatment. The aim of this review is to address the fungal virulence factors that could be the target of the development of new drugs for PCM treatment. Virulence factors favoring the process of fungal infection and pathogenicity are considered as a microbial attribute associated with host susceptibility. P. brasiliensis has some known virulence factors which are 43 kDa glycoprotein (gp 43) which is an important fungal antigen, 70 kDa glycoprotein (gp 70), the carbohydrates constituting the fungal cell wall α-1,3, glucan and ß-1,3-glucan, cell adhesion molecules and the presence of melanin pigments. The discovery and development of drugs that interact with these factors, such as inhibitors of ß-1,3-glucan, reduced synthesis of gp 43, inhibitors of melanin production, is of great importance for the treatment of PCM. The study of virulence factors favors the understanding of pathogen-host relationships, aiming to evaluate the possibility of developing new therapeutic targets and mechanisms that these molecules play in the infectious process, favoring the design of a more specific treatment for this disease.

Evaluation of antifibrotic and antifungal combined therapies in experimental pulmonary paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the Paracoccidioides genus. Most of the patients with chronic form present sequelae, like pulmonary fibrosis, with no effective treatment, leading to impaired lung functions. In the present study, we aimed to investigate the antifibrotic activity of three compounds: pentoxifylline (PTX), azithromycin (AZT), and thalidomide (Thal) in a murine model of pulmonary PCM treated with itraconazole (ITC) or cotrimoxazole (CMX). BALB/c mice were inoculated with P. brasiliensis (Pb) by the intratracheal route and after 8 weeks, they were submitted to one of the following six treatments: PTX/ITC, PTX/CMX, AZT/ITC, AZT/CMX, Thal/ITC, and Thal/CMX. After 8 weeks of treatment, the lungs were collected for determination of fungal burden, production of OH-proline, deposition of reticulin fibers, and pulmonary concentrations of cytokines and growth factors. Pb-infected mice treated with PTX/ITC presented a reduction in the pulmonary concentrations of OH-proline, associated with lower concentrations of interleukin (IL)-6, IL-17, and transforming growth factor (TGF)-ß1 and higher concentrations of IL-10 compared to the controls. The Pb-infected mice treated with AZT/CMX exhibited decreased pulmonary concentrations of OH-proline associated with lower levels of TGF-ß1, and higher levels of IL-10 compared controls. The mice treated with ITC/Thal and CMX/Thal showed intense weight loss, increased deposition of reticulin fibers, high pulmonary concentrations of CCL3, IFN-γ and VEGF, and decreased concentrations of IL-6, IL-1ß, IL-17, and TGF-ß1. In conclusion, our findings reinforce the antifibrotic role of PTX only when associated with ITC, and AZT only when associated with CMX, but Thal did not show any action upon addition.

Paracoccidioidomycosis in a child: exuberant presentation due to the inadvertent use of systemic corticosteroids.

Paracoccidioidomycosis is a fungal infection that occurs in immunocompetent patients and are classified into two forms: the acute-subacute form, predominantly in young patients, and the chronic adult form that may present classic ulcerated lesions to rare sarcoid ones. We present the case of a boy whose infection began with sarcoid lesions but, after being mistakenly diagnosed with cutaneous sarcoidosis and treated (for three years) with prednisone, developed painful ulcerations throughout the body. After the correct diagnosis, with evidence of the fungus in histopathological and mycological examinations, the patient was properly treated with itraconazole for eight months and evolved with total remission of the disease.

Paracoccidioidomycosis of the Central Nervous System: CT and MR Imaging Findings.

BACKGROUND AND PURPOSE: Paracoccidioidomycosis is a fungal infection mainly caused by the thermodimorphic fungus Paracoccidioides. The purpose of our study was to demonstrate the neuroimaging findings from 24 patients with CNS paracoccidioidomycosis. MATERIALS AND METHODS: We performed a retrospective analysis focusing on the radiologic characteristics of CNS paracoccidioidomycosis. The 24 selected patients underwent MR imaging and/or CT, and the diagnosis was made by the presence of typical neuroimaging features, combined with fungus isolation, a serologic test, or the presence of disseminated disease. RESULTS: Headache was the most common neurologic symptom, while the pseudotumoral form was the most common pattern. The number of lesions ranged from 1 to 11, with most localized on the frontal lobe with >2-cm lesions. CT showed mainly hypoattenuating lesions, whereas MR imaging demonstrated mainly hyposignal lesions on T1WI and T2WI. Furthermore, ring enhancement was present in most patients. The "dual rim sign" on SWI occurred in 100% of our patients with lesions of >2 cm. CONCLUSIONS: The diagnosis of CNS paracoccidioidomycosis is difficult. Nevertheless, imaging examinations can play an important role in the diagnosis and evaluation of the disease.

Paracoccidioidomycosis in a child: exuberant presentation due to the inadvertent use of systemic corticosteroids

Abstract: Paracoccidioidomycosis is a fungal infection that occurs in immunocompetent patients and are classified into two forms: the acute-subacute form, predominantly in young patients, and the chronic adult form that may present classic ulcerated lesions to rare sarcoid ones. We present the case of a boy whose infection began with sarcoid lesions but, after being mistakenly diagnosed with cutaneous sarcoidosis and treated (for three years) with prednisone, developed painful ulcerations throughout the body. After the correct diagnosis, with evidence of the fungus in histopathological and mycological examinations, the patient was properly treated with itraconazole for eight months and evolved with total remission of the disease.

Proteomic analysis of Paracoccidioides brasiliensis complex isolates: Correlation of the levels of differentially expressed proteins with in vivo virulence.

BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic mycosis commonly found in Latin America that is caused by distinct species of Paracoccidioides genus: Paracoccidioides brasiliensis complex (S1, PS2, PS3 and PS4) and Paracoccidioides lutzii. Its pathobiology has been recently explored by different approaches to clarify the mechanisms of host-pathogen interactions underpinning PCM. The diversity of clinical forms of this disease has been attributed to both host- and fungus-related factors. METHODOLOGY/PRINCIPAL FINDINGS: For better understanding of the molecular underpinnings of host-fungus interactions, we evaluated in vivo virulence of nine Paracoccidioides brasiliensis complex isolates and correlated it to protein expression profiles obtained by two-dimensional gel electrophoresis. Based on the recovery of viable fungi from mouse organs, the isolates were classified as those having low, moderate, or high virulence. Highly virulent isolates overexpressed proteins related to adhesion process and stress response, probably indicating important roles of those fungal proteins in regulating the colonization capacity, survival, and ability to escape host immune system reaction. Moreover, highly virulent isolates exhibited enhanced expression of glycolytic pathway enzymes concomitantly with repressed expression of succinyl-CoA ligase beta chain, a protein related to the tricarboxylic acid cycle. CONCLUSIONS/SIGNIFICANCE: Our findings may point to the mechanisms used by highly virulent P. brasiliensis isolates to withstand host immune reactions and to adapt to transient iron availability as strategies to survive and overcome stress conditions inside the host.

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment.

Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 µg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (≥2 log10) on the 5th and 7th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (≥1 log10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.

Clinical and epidemiological features of paracoccidioidomycosis due to Paracoccidioides lutzii.

BACKGROUND: The fungus Paracoccidioides lutzii was recently included as a new causative species of paracoccidioidomycosis (PCM) and most cases have been reported from Brazil. According to available epidemiological information, P. lutzii is concentrated in the Middle-West region in Brazil, mainly in the state of Mato Grosso. However, clinical and laboratorial data available on patients infected with P. lutzii remain extremely limited. METHODOLOGY/MAIN FINDINGS: This work describes the clinical manifestations of 34 patients suffering from PCM caused by P. lutzii, treated along 5 years (2011-2017) at a reference service center for systemic mycoses in Mato Grosso, Brazil. Adult rural workers (men), aged between 28 and 67 predominated. All patients had the chronic form of the disease, and the oral mucosa (n = 19; 55.9%), lymph nodes (n = 23; 67.7%), skin (n = 16; 47.1%) and lung (n = 28; 82.4%) were the most affected sites. Alcohol intake (n = 19; 55.9%) and smoking (n = 29; 85.3%) were frequent habits among the patients. No patient suffered from any other life-threatening disease, such as tuberculosis, cancer or other inflammatory or infectious parasitic diseases. The positivity in culture examination (97.1%) was higher than that found for the direct mycological examination (88.2%). Particularly, one patient presented fungemia at diagnosis, which lead to his death. The time elapsed between the initial symptoms and the initiation of treatment of PCM caused by P. lutzii was 19.7 (31.5) months, with most patients diagnosed 7 months after the symptoms' onset. CONCLUSIONS/SIGNIFICANCE: Compared with the classical clinical-epidemiological profile of PCM caused by P. brasiliensis, the results of this descriptive study did not show significant clinical or epidemiological differences that could be attributed to the species P. lutzii. Future studies may confirm or refute the existence of clinical differences between the two fungal species.

Impact of Paracoccidioides brasiliensis Coinfection on the Evolution of Schistosoma mansoni-Induced Granulomatous Liver Injury in Mice.

The pathogens Schistosoma mansoni and Paracoccidioides brasiliensis share common geographic areas, determining infectious diseases with high mortality rates worldwide. Histopathological and immunological changes induced by each pathogen are well understood; however, the host responses to S. mansoni and P. brasiliensis coinfection are still unknown. Thus, we investigated liver damage and cytokines production in a murine model acutely and chronically coinfected with these pathogens. Fourty male Swiss mice were infected with S. mansoni and P. brasiliensis alone or coinfected. The animals were euthanized with 50 (acute infection) and 120 (chronic infection) days of infection. All infected animals exhibited liver inflammation. Intense granulomatous inflammation was detected in animals infected with S. mansoni alone and those coinfected. Productive and involutive granulomas were clearly observed in acute and chronic infections, respectively. Granuloma size was reduced in the acute phase and increased in the chronic phase of S. mansoni and P. brasiliensis coinfection, compared with animals infected only with S. mansoni. In the chronic phase of infection, the granulomatous inflammation in coinfected animals was characterized by intense neutrophils accumulation and reduced eosinophils number. IFN-γ, IL-2, IL-4, and IL-5 circulating levels were increased in all infected groups. Coinfected animals presented attenuated IFN-γ and IL-4 production in the acute and chronic infections. Taken together, our findings indicate that coinfected animals exhibited a differential modulation of granulomatous inflammation during the acute and chronic phases of infection, which was potentially associated with a divergent profile of cytokines production and migration of neutrophils and eosinophils in response to S. mansoni and P. brasiliensis antigenic stimulation.