Clinical manifestations and diagnosis of chronic paracoccidioidomycosis

INTRODUCTION — Paracoccidioidomycosis is a systemic endemic mycotic disease caused by the thermally dimorphic fungi of the genus Paracoccidioides, encompassing Paracoccidioides brasiliensis complex and Paracoccidioides lutzii. The fungus has a geographic distribution limited to Mexico and Central and South America, where paracoccidioidomycosis is mostly diagnosed in male rural workers. However, an increasing number of cases have been documented in patients from non-endemic areas who acquired the disease during visits to Latin American countries [1].

The clinical manifestations and diagnosis of chronic paracoccidioidomycosis will be reviewed here. The clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis as well as the mycology, epidemiology, and treatment of paracoccidioidomycosis are discussed separately. (See "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis" and "Mycology and epidemiology of paracoccidioidomycosis" and "Treatment of paracoccidioidomycosis".)

CLINICAL MANIFESTATIONS — Following inhalation, Paracoccidioides spp typically cause asymptomatic pulmonary infection. If the infection is not contained by the host, the disease may evolve into one of two patterns: (1) the chronic form, which represents reactivation of the primary infection, has an insidious evolution, and is the most common clinical form, or (2) the acute/subacute form, with limited host response and fast dissemination to the reticuloendothelial system [2]. (See "Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis".)

Over 80 to 90 percent of cases of paracoccidioidomycosis are the chronic form, which may present months or years following the primary infection [3]. It most commonly affects men who work in agriculture, and are between 30 and 60 years of age [4]. In one study that described the clinical manifestations of 34 cases of paracoccidioidomycosis caused by P. lutzii, all patients presented with the chronic form and had clinical characteristics similar to those described in cases caused by P. brasiliensis [5] (See "Mycology and epidemiology of paracoccidioidomycosis", section on 'Epidemiology'.)

Paracoccidioides spp can disseminate to any part of the body by the hematogenous or lymphatic routes. Thus, as with other systemic endemic fungal infections, any organ can be affected. Signs and symptoms usually progress slowly, and may be related to a single organ or to several organs. (See "Mycology and epidemiology of paracoccidioidomycosis", section on 'Pathogenesis'.)

Signs and symptoms — The chronic form of the disease usually presents as pulmonary infiltrates and upper respiratory mucosal lesions [6]. Unifocal disease occurs in only 25 percent of cases and is most commonly described in the lungs [3]. Disease can be severe, and in one study that evaluated 6732 hospitalizations due to paracoccidioidomycosis, the overall in-hospital mortality was 5 percent [7].

Lungs — The lungs are frequently involved in chronic paracoccidioidomycosis, either alone or with other organs. In a review of 352 patients with paracoccidioidomycosis, 77 percent had lung involvement [3]. Dry cough and dyspnea are the most frequent presenting symptoms, but sputum production may be observed [8]. Hemoptysis may occur in some patients [9]. However, it is common for patients to present with extensive lung involvement (including fibrosis) with few or no symptoms of pulmonary disease [10,11]. This is important because there is an increased risk of progressive pulmonary fibrosis among patients with more extensive radiologic findings at the initial presentation [11]. (See 'Sequelae' below and 'Radiographic findings' below.)

Mucosa — Mucosal involvement occurs in over 50 percent of cases. The mouth (oropharynx, lips, tongue, gingiva, palate) is most frequently affected, followed by the larynx [12-15]. The typical lesion is a painful ulcer with ragged borders and small spots of hemorrhage (picture 1 and picture 2). Patients complain of soreness, sialorrhea, hoarseness, odynophagia, and/or dysphagia.

Other sites — Other sites that can be involved in patients with chronic paracoccidioidomycosis include the skin [16], lymph nodes [17], adrenal glands [18], and central nervous system (CNS) (picture 2) [19]. Adrenal lesions are very common in patients with disseminated disease; this involvement is manifested by asymptomatic limited adrenal reserve in 15 to 40 percent and, less commonly, by Addison's disease in approximately 3 percent [18,20]. CNS involvement has been reported in 10 to 15 percent of patients and presents with clinical manifestations associated with space-occupying lesions such as seizures and focal neurologic signs [21,22]. Less frequently involved organs include bones [23,24], joints [23], genital organs [25] and eyes [26,27].

Radiographic findings — Lung imaging (chest radiograph or computed tomography [CT]) typically reveals mixed interstitial and alveolar infiltrates, which are usually perihilar, bilateral, and symmetrical with predominantly lower lung field involvement (image 1) [3,9,11,28]. The most frequent images on chest CT are ground-glass attenuations, consolidations, nodules, masses, cavities, and septal or interlobular thickening; the reversed halo sign may be present [2,29]. Long-standing pulmonary involvement may lead to serious sequelae such as fibrosis, bullae, and emphysema (image 2) [6,11].

CNS radiographic findings typically include ring-enhancing lesions located in the cerebrum, thalamus, cerebellum, brainstem, and/or spinal cord (image 1) [19], frequently with perilesional edema. Meningeal involvement and hydrocephalus may also be present [30].

Joint involvement is characterized by effusion, periarticular bony erosions, and/or narrowing of the joint space, whereas the typical radiographic finding of bone involvement is bone lysis with or without a rim of sclerosis [23].

Other radiographic findings depend upon which organs are affected [31] (See 'Signs and symptoms' above.)

Sequelae — An important aspect of chronic paracoccidioidomycosis is the development of sequelae, mostly represented by chronic respiratory failure that results from fibrosis (image 2), and limited adrenal reserve or Addison's disease [6,11]. Other sequelae include emphysema, formation of bullae, and pulmonary arterial hypertension [6,11]. Microstomia and stenosis of the glottis and/or trachea with associated dysphonia can also occur (picture 3) [3]. Residual neurologic deficits may also occur, manifested as recurrent seizures or motor deficits [32]. (See 'Lungs' above and 'Other sites' above.)

Early diagnosis is important to help prevent progression to fibrosis. As an example, in a retrospective study of 47 patients with chronic paracoccidioidomycosis who were treated with itraconazole and then followed for a median of 5.6 years, fibrosis correlated with the severity of the infiltrates at the time of diagnosis. Fibrosis was detected during the study in 83 percent of those with very severe infiltrates at diagnosis compared with 13 percent of patients with mild infiltrates [11].

However, lung scarring can occur even in the setting of adequate antifungal therapy. In a study that evaluated 50 patients with inactive disease (≥6 months of treatment, negative mycology, resolution of skin and mucous lesions, low antibody titers), radiologic abnormalities were present on high resolution chest CT scans in 98 percent of cases [33]. Findings included architectural distortion (90 percent), reticulate and septal thickening (88 percent), and centrilobular and paraseptal emphysema (84 percent). Pulmonary function and aerobic capacity were impaired in the majority of patients.

DIFFERENTIAL DIAGNOSIS — In patients with chronic paracoccidioidomycosis with lung involvement, there is a broad differential diagnosis, which includes infectious causes such as tuberculosis, fungal infections (especially histoplasmosis), and noninfectious causes such as carcinoma, sarcoidosis, and idiopathic pulmonary fibrosis [6,34]. Upper respiratory tract involvement may be suggestive of carcinoma. Mucosal and skin findings may be similar to those of leishmaniasis.

DIAGNOSIS — The diagnosis of paracoccidioidomycosis is based upon the microscopic visualization of fungal elements suggestive of Paracoccidioides spp and/or by culturing this fungus from clinical specimens. Serologic testing can be useful both for diagnosis and for monitoring the response to therapy [35].

Microscopy — The yeast form of Paracoccidioides spp can be visualized in sputum, abscess fluid, lymph node aspirates, scrapings of skin lesions, and/or biopsy samples of affected organs [4]. Routine methods for wet mount preparation include potassium hydroxide (KOH) and calcofluor. Direct microscopy using KOH yields a diagnosis in over 90 percent of cases [4]. A positive direct exam in the proper host is highly suggestive of the diagnosis, even if culture is negative. (See "Mycology and epidemiology of paracoccidioidomycosis", section on 'Mycology'.)

When demonstrated in clinical samples, Paracoccidioides spp are characterized as large (4 to 40 microns) round or oval "mother" yeast cell surrounded by multiple, attached, narrow-necked budding daughter yeast cells (resembling a "pilot's wheel") or mother yeast cell possessing only two attached daughter buds (resembling a "Mickey mouse head") (picture 4). If the typical multiple budding cells are not found, differentiation from other fungi, such as Blastomyces dermatitidis, can be difficult.

Culture — Paracoccidioides spp can be cultured from sputum, biopsy samples, and/or abscess fluid using Sabouraud dextrose agar or yeast extract agar containing chloramphenicol and cycloheximide incubated at room temperature. The mold form of Paracoccidioides spp usually takes as long as 20 to 30 days to grow [3]. Some authors have suggested that cultures for Paracoccidioides are positive in up to 80 percent of samples [4]. However, in our experience, cultures are frequently negative for Paracoccidioides because most specimens are obtained from sites that are colonized by bacteria, which inhibit fungal growth in culture. Consequently, the final diagnosis for most patients relies on the identification of typical yeast cells in direct exam of body fluids or tissue biopsy.

Pathology — Methenamine silver stain or periodic acid Schiff stain are used to identify fungal elements in tissue samples due to their higher sensitivity compared with the hematoxylin-eosin stain. The presence of the characteristic large round yeast cells with multiple narrow-necked budding yeasts establishes the diagnosis (picture 4). (See 'Microscopy' above.)

Histopathologic findings include chronic granulomatous or mixed granulomatous and suppurative infiltrates with the presence of epithelioid histiocytes, macrophages, and multinucleated giant cells surrounding the yeast cells [3,9]. Granulomas surrounding the yeast cells are typical in patients with paracoccidioidomycosis [9] but may also occur in patients with other endemic fungal infections.

Serologic tests

●P. brasiliensis – Detection of specific antibodies is used for the initial evaluation of patients suspected to be infected by P. brasiliensis complex. Serologic tests can also be used to monitor the response to therapy; a good clinical response is often associated with a reduction in the titer of serum antibodies. (See "Treatment of paracoccidioidomycosis", section on 'Serologic testing'.)

Various serologic tests are available, including quantitative immunodiffusion, complement fixation, enzyme-linked immunosorbent assay (ELISA), and counterimmunoelectrophoresis [36]. However, the utility of some of these serologic tests, such as complement fixation and ELISA, is limited by antigenic cross-reactivity between P. brasiliensis and other fungi, especially Histoplasma capsulatum [4,36]. (See "Diagnosis and treatment of pulmonary histoplasmosis".)

Quantitative immunodiffusion testing is the most widely available assay in endemic regions. When testing for P. brasiliensis infection, any positive result should be considered suggestive of disease [37]. Immunodiffusion testing represents the most reliable method for serologic diagnosis due to its high sensitivity and specificity, and because it is simple to perform [4]. As an example, in a study that used a seven-day exoantigen in the immunodiffusion assay, the sensitivity was 97 percent and the specificity was 100 percent [38]. Another study, which evaluated the performance of a double immunodiffusion assay in 401 cases, reported the sensitivity and specificity as 90 percent and 100 percent, respectively [39]. However, unpublished experience with a larger number of samples suggests lower sensitivity (70 to 90 percent) and specificity (>90 percent). In addition, serologic testing has a lower sensitivity in immunocompromised patients, such as those with human immunodeficiency virus (HIV) infection, compared with immunocompetent individuals. (See 'Immunocompromised hosts' below.) [40]

●P. lutzii – Patients infected with P. lutzii may be negative for the immunodiffusion test that detects antibodies against the gp43 antigen [41]. However, a test for P. lutzii infection using a cell-free antigen preparation has been developed. In a study evaluating sera from 17 patients who had a clinical diagnosis of paracoccidioidomycosis, but a negative serologic test using a traditional immunodiffusion assay, all patients were reactive for P. lutzii by immunodiffusion using cell free antigen enzyme-linked immunosorbent assay, and Western blot [42].

1,3-beta-D-glucan test — 1,3-beta-D-glucan, a cell wall component of many fungi, is detected by the beta-D-glucan (BDG) assay. Although we do not routinely order this test as part of the initial workup in a patient with suspected paracoccidioidomycosis, a positive test could be consistent with infection. In one report, the BDG test was evaluated in 29 patients with paracoccidioidomycosis and was positive in all 17 patients with acute and 11 of 12 patients with chronic paracoccidioidomycosis, with high BDG serum levels (mean value of 3860 pg/mL and 1208 pg/mL in the acute and chronic forms, respectively) [40]. However, a clinical response to treatment was not associated with decrease in BDG serum levels. It must be remembered that the BDG test is not specific for any fungal species, and the specificity of the assay can be decreased by multiple other clinical variables. More detailed information on this test is presented elsewhere. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

Skin testing — Skin testing for the paracoccidioidin antigen is not useful for diagnosis of active disease. The sensitivity of this test is limited in severely ill patients. By contrast, it may be positive in healthy individuals from endemic areas previously exposed to the fungus.

Experimental methods — Other diagnostic modalities are being developed, but are not yet commercially available.

Tests that detect antigen have been developed. These tests detect specific glycoprotein antigens (gp43 and gp70) in serum, cerebrospinal fluid, and bronchoalveolar lavage fluid using immunoenzymatic assays, and appear to have higher sensitivity and specificity compared with traditional antibody detection methods [36,43,44]. In addition, antigen detection may be particularly useful in immunocompromised patients as serologic testing may be falsely negative [4]. (See 'Serologic tests' above.)

A latex test that detects both antibodies and the gp43 antigen of P. brasiliensis in sera, cerebrospinal fluid, and bronchoalveolar lavage has also been developed. The sensitivity and specificity for detecting antibodies was 98 and 94 percent, and for detecting antigen was 97 and 89 percent, respectively [45]. As with the other antigen tests, this assay is not available for use in clinical settings.

Polymerase chain reaction (PCR)-based deoxyribonucleic acid (DNA) amplification methods have high sensitivity and specificity and may be used to identify the pathogen in biologic materials and cultures, but are not widely available [46-48]. PCR can differentiate between P. brasiliensis and P. lutzii by sequencing the isolates, or using matrix-assisted laser desorption ionization-time of flight mass spectrometry [49].

EVALUATION — The diagnosis of paracoccidioidomycosis is sought in patients who present with suggestive epidemiological and clinical findings. A typical example would be a man between 30 and 60 years of age who is an agricultural worker in an endemic region and who presents with any of the following findings:

●Chronic lung infiltrates (fibrosis, alveolar and/or interstitial infiltrates, cavities) with or without symptoms (cough, dyspnea)

●Chronic mucosal ulcers in the upper airways

●Sialorrhea, odynophagia, hoarseness

●Chronic skin lesions (nodules, ulcers) around natural orifices or on the lower limbs

●Asymmetric lymph node enlargement (especially in the cervical region) with or without fistula formation

●Pseudotumoral brain lesions (see 'Clinical manifestations' above)

Approach to diagnosis — The initial evaluation of patients with suspected chronic paracoccidioidomycosis should include all of the following:

●Imaging of affected areas (eg, chest radiograph and computed tomography [CT], brain CT or magnetic resonance imaging [MRI]). Since most patients have chronic pulmonary involvement, multiple lesions, and fibrosis, CT scanning is required to optimally characterize the lung lesions. A baseline chest radiograph is also useful since this modality can be used to follow response to therapy. If signs or symptoms of CNS involvement are present, a brain CT or MRI should be performed.

●Direct examination and culture of sputum and/or biopsy specimens, depending upon sites of involvement

●Serologic testing (preferably by quantitative immunodiffusion or counterimmunoelectrophoresis)

Although the diagnosis is often established by direct examination and culture, serologic testing is important in order to have a baseline result for comparison during therapy since a reduction in antibody titers is expected during treatment (see "Treatment of paracoccidioidomycosis", section on 'Serologic testing'). A positive serologic test is also useful in cases in which direct microscopy and culture do not yield a positive result.

During the initial evaluation of patients with chronic paracoccidioidomycosis, special attention should be devoted to the lungs (radiographic studies, pulmonary function tests), larynx, oral cavity, adrenal glands, and central nervous system. Abdominal and central nervous system CT scans should be requested only for patients with signs and symptoms suggestive of specific organ involvement.

Considering the high frequency of adrenal dysfunction in patients with paracoccidioidomycosis, all patients (regardless of symptoms) should undergo adrenal evaluation at presentation. This includes an early morning serum cortisol level and evaluation of cortisol production in response to exogenous ACTH administration. Patients with clinical suspicion of Addison's disease require a complete investigation of adrenal function. (See "Determining the etiology of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults".)

Disseminated — The diagnosis of chronic paracoccidioidomycosis causing disseminated disease is usually made by the detection of characteristic budding yeasts in a tissue biopsy, respiratory specimens (eg, sputum, bronchoalveolar lavage), or scrapings of skin or mucosal lesions. Direct examination and cultures of sputum are also useful in detecting fungal elements suggestive of P. brasiliensis. In these patients, the sensitivity of serology is very high and antibody titers by immunodiffusion usually range between 1:8 and 1:64. (See 'Diagnosis' above.)

Unifocal — The diagnosis may be challenging in situations in which the disease is restricted to a single organ, especially if the infection is in the central nervous system. In such cases, sensitivity of serology is low, tissue is difficult to obtain, and cultures are frequently negative. The detection of specific antigens (gp48 and gp70) either in the blood or cerebrospinal fluid using an immunoenzymatic assay may be helpful [43]. (See 'Experimental methods' above.)

IMMUNOCOMPROMISED HOSTS — While paracoccidioidomycosis is typically a disease affecting nonimmunocompromised individuals from endemic regions, it has been reported in immunocompromised individuals such as people with HIV [50-52], patients with cancer [53], solid organ transplant recipients [54,55], and patients receiving tumor necrosis factor inhibitors [56].

In individuals with HIV, paracoccidioidomycosis usually presents as disseminated disease, characterized by more exuberant and widespread findings than those observed in immunocompetent patients with the chronic form [3,50,52,57,58]. In addition, mortality rates are usually higher in coinfected patients [57].

In a retrospective study that included 53 patients with HIV and 106 patients without HIV, HIV-infected patients had more rapid progression of disease and were significantly more likely to have fever (96 versus 51 percent), lymphadenopathy (80 versus 62 percent), hepatomegaly (64 versus 20 percent), and skin lesions (67 versus 46 percent) but were less likely to have ulceration of the oral or nasal mucosa (21 versus 51 percent) compared with non–HIV-infected patients [52].

Eighty-five percent of HIV-infected individuals had pulmonary involvement compared with 69 percent of non–HIV-infected individuals, a difference which did not reach statistical significance. HIV-infected patients were significantly less likely to have a positive serologic test (76 versus 96 percent). HIV-infected individuals were significantly more likely to have suffered relapse by 24 months (19 versus 3 percent). The majority of HIV-infected patients (84 percent) had a CD4 cell count ≤200 cells/microL.

This study suggests that paracoccidioidomycosis in HIV-infected patients has different clinical characteristics than the chronic form typically seen in immunocompetent adults. It is surprising that paracoccidioidomycosis does not occur more frequently in HIV-infected patients who live in endemic regions; in such patients, histoplasmosis and cryptococcosis occur more commonly than paracoccidioidomycosis despite a higher incidence of the latter disease in immunocompetent individuals [52].

SUMMARY AND RECOMMENDATIONS

●Introduction − Paracoccidioidomycosis is a systemic endemic mycotic disease caused by the thermally dimorphic fungi of the genus Paracoccidioides, with two species: Paracoccidioides brasiliensis and Paracoccidioides lutzii. The disease has a geographic distribution limited to Central and South America. (See 'Introduction' above.)

●Clinical manifestations

•Disease forms − Paracoccidioides spp typically causes asymptomatic pulmonary infection. However, if the infection is not contained by the host, the disease may evolve into one of two patterns: the chronic form, which represents reactivation of the primary infection, and the acute/subacute form. Over 80 to 90 percent of cases of paracoccidioidomycosis occur as the chronic form, which most commonly affects men who work in agriculture. (See 'Clinical manifestations' above.)

•Signs and symptoms − The lungs and oral mucosa are the most frequently involved sites in chronic paracoccidioidomycosis. (See 'Signs and symptoms' above.)

•Sequelae − An important aspect of chronic paracoccidioidomycosis is the development of sequelae, mostly represented by chronic respiratory failure, which results from fibrosis. Lung scarring occurs even in the setting of adequate antifungal therapy. Adrenal dysfunction is also frequently reported and mostly represented by asymptomatic limited reserve of adrenal function. (See 'Sequelae' above.)

●Differential diagnosis − In patients with chronic paracoccidioidomycosis with lung involvement, there is a broad differential diagnosis, which includes infectious causes such as tuberculosis, fungal infections (especially histoplasmosis), and noninfectious causes such as carcinoma, sarcoidosis, and idiopathic pulmonary fibrosis. (See 'Differential diagnosis' above.)

●Diagnosis − The diagnosis of paracoccidioidomycosis is based upon the microscopic visualization of fungal elements suggestive of Paracoccidioides spp and/or by culturing this fungus from clinical specimens. Serologic testing (preferably quantitative immunodiffusion) can be useful for both diagnosis and monitoring the response to therapy. (See 'Diagnosis' above.)

●Evaluation

•When to suspect chronic paracoccidioidomycosis − Chronic paracoccidioidomycosis should be suspected in patients with chronic lung infiltrates (fibrosis, alveolar and/or interstitial infiltrates, cavities) with or without symptoms (cough, dyspnea); chronic mucosal ulcers in the upper airways; sialorrhea, odynophagia, or hoarseness; chronic skin lesions (nodules, ulcers); and/or asymmetric lymph node enlargement (especially in the cervical region). (See 'Evaluation' above.)

•Approach to diagnosis − The initial evaluation of patients with suspected paracoccidioidomycosis should include imaging of affected areas (eg, chest computed tomography scan), direct examination and culture of sputum and/or biopsy specimens, and serologic testing. (See 'Approach to diagnosis' above.)

●Immunocompromised hosts − Paracoccidioidomycosis has been reported infrequently among patients with HIV or other causes of T cell–mediated immunodeficiency, such as cancer and solid organ transplantation. Patients with HIV usually present with disseminated disease and have high mortality rates. (See 'Immunocompromised hosts' above.)