Most of the patients (> 95%) will be asymptomatic, and the infection will be detected only by the intradermal paracoccidioidin test. In those patients that do manifest the disease, two clinical forms have been described: The juvenile (acute/subacute) and the chronic adult form.

The juvenile form is seen in 10% of the cases, approximately.[4] It usually appears within 45 days after exposure and is seen generally in children, adolescents, and adults less than 30 years old.[16] The clinical manifestations are constitutional symptoms, such as fever, weight loss, malaise associated with multiple skin lesions, lymphadenopathies, draining fistulae, hepatic and splenic enlargement due to reticuloendothelial involvement, and/or bone marrow dysfunctions. Of note, in this form, mucosal and respiratory manifestations are unusual.

The adult chronic form is seen in 80%-90% of the cases and is more frequent in adult men. Clinical manifestations are primarily related to lung infection, including fever, malaise, cough, and dyspnea. One-third of the patients will present with pulmonary sequelae as pulmonary fibrosis, bullae, and pulmonary hypertension.  

In over 50% of the cases, mucous membrane involvement is noted. It usually includes laryngeal and pharyngeal lesions resulting in dysphonia, dysphagia, and stridor, as well as perioral granulomatous plaques. Gingival involvement is frequent and may lead to tooth loss. Characteristic oral mulberry-like erosions (Aguiar-Pupo stomatitis) may be associated with nasal and pharyngeal ulcers.[17] Cervical chronic lymphadenopathies are common, followed by axillary and inguinal. In the case of intra-abdominal lymph node involvement, patients may present with diffuse abdominal pain and jaundice due to biliary tract compression. Partial intestinal obstruction can also be observed. In cases with fibrosis of the mesenteric lymph nodes, malabsorption syndrome may occur.

Cutaneous lesions are seen in 25% of the cases. Ulcers, crusted papules, nodules, plaques, and verrucous lesions are typical. Generally, they are caused by hematologic dissemination from the lungs. In rare cases, these lesions result from direct inoculation.[18]

The diagnosis includes visualization of fungal elements suggestive of Paracoccidioides spp by direct microscopy and/or culture specimens, biopsy and histopathology, as well as serologic testing.

Microscopic visualization: Direct examination with potassium hydroxide (KOH) is positive in about 90% of the cases with a suppurative skin lesion, and in sputum samples or biopsy material from affected sites. It will reveal spherical thick-walled yeast cells of variable size, with peripheral buds protruding from a central cell (pilot's wheel).[19][20]

Culture: Sabouraud dextrose agar is the ideal fungal media to recover Paracoccidiodes, which will grow in 20 – 30 days.

Histologic findings: Methenamine silver stain or periodic acid Schiff stain are used to identify fungal elements in tissue samples. Histopathologic findings reveal epithelioid and giant cells, along with cellular infiltrates of polymorphonuclear leukocytes, monocytes, and macrophages surrounding the multiple budding yeasts.[4] In skin and mucous membrane lesions, pseudo-epitheliomatous hyperplasia with intra-epidermal abscesses may be seen. Lymph nodes may exhibit caseous necrosis. In the juvenile form, a diffuse tissue reaction is characteristic. 

Blood tests: These are useful for diagnosis and for monitoring response to therapy.[21] Quantitative immunodiffusion testing is the most widely available assay in endemic regions and represents a reliable method with 84.3% sensitivity and 98.9% specificity. In patients with P. lutzii, this technique may give negative results. Counterimmunoelectrophoresis shows a sensitivity between 77% to 100% and specificity > 95%.[22][18] Other available techniques, such as complement fixation and ELISA, have limited utility due to antigenic cross-reactivity, especially with Histoplasma capsulatum and Aspergillus.[23]

Skin testing: Can be positive in a healthy individual from endemic areas, is not useful for diagnosis of active disease, and the sensitivity is limited in severely ill patients.

For mild to moderate disease, the first treatment option is itraconazole at the dose of 100 to 400mg orally daily, with a length of therapy of 6 months. Effectiveness close to 95% has been reported. This drug is considered superior to ketoconazole because of shorter treatment courses, fewer relapse rates (3% to 5%), and lower toxicity.

A second-line medication is trimethoprim-sulfamethoxazole (TMP/SMX) 160/800mg twice daily, which has reported a lower cure rate than Itraconazole (51% versus 86%, respectively). The median treatment time is 23 months with TMP/SMX, as compared to 12 months for itraconazole.[22]

Sulfadiazine is another alternative, the maximum dose is 4 g/day in adults and should be given until clinical and mycologic response. Then the dose will be reduced by half and maintained over a period of 3 to 5 years. Cure rates of 70% are expected, but relapse rates may be as high as 30%. 

Ketoconazole has a cure rate of 85% to 90% and a relapse rate of less than 10%. The dose is 5 mg/kg/day in children or 200 to 400 mg/day in adults for a course of 6 to 18 months, depending on each case. Ketoconazole is associated with many drug-drug interactions, and significant toxicities, like hepatic dysfunction and sex hormone alterations.

Fluconazole is not commonly used because of its lower response rate and more frequent relapses.

Voriconazole has in vitro activity against the yeast cells of Paracoccidiodes brasiliensis and has been shown to be an effective agent.[24] Also, posaconazole has been used with reported success in this disease.

For severe cases, refractory to other forms of treatment, Amphotericin B is the drug of choice. Doses range from 1 to 2g (cumulative), based on clinical response. Its use is limited because of toxicity. Formulations as amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD) have shown less toxicity and better tolerance.

Differential diagnosis includes other granulomatous diseases and endemic infections:

• Blastomycosis
• Actinomycosis
• Histoplasmosis
• Coccidioidomycosis
• Leishmaniasis
• Leprosy
• Lobomycosis
• Lymphomas
• Tuberculosis
• Sporotrichosis
• Wegener granulomatosis

PCM is a disease with high morbidity but relatively low lethality except in immunosuppressed patients or cases with CNS involvement, in which the prognosis is poor. Recent studies indicate a case fatality rate of 7.6% for adults and 9.3% among children. As relapses are common, appropriate antifungal therapy and close follow-up are necessary for better outcomes. Re-evaluations must be performed monthly during the first three months of treatment and every three months thereafter, until the end of the first year. They must include general laboratory, serological, and radiologic tests (the latter to be repeated every 3 to 6 months during the first year).

In the severe forms of PCM, the exacerbated inflammatory response can be life-threatening. On the other hand, most of the complications are the result of fibrosis that occurs during the healing process, which produces chronic changes in the lungs, oral cavity, nasal cavity, and larynx. Other common complications include malnourishment and anemia, Addison syndrome, and superinfection with bacteria or other fungal pathogens.

Prevention of inhalation of the fungus in areas where it is widespread in the environment is not possible. Fortunately, only a small percentage of those infected get sick. The disease usually affects predominantly males exposed to outdoor environments in rural areas of Central and South America. PCM is considered an occupational disease in some of these areas. Education of the population is fundamental for early diagnosis of the disease and subsequent treatment.

The chronic form of the infection has a strong association with smoking and alcohol intake, so people in endemic areas should be encouraged to avoid these. Tobacco cessation counseling and medications may be of use.

In immunocompromised patients, most paracoccidioidomycosis infections have been reported in HIV patients. Lymphomas are the most common hematologic malignancy associated with PCM, and some cases have been reported in with kidney transplantation. Clinicians should counsel immunocompromised patients before traveling to endemic areas to avoid high-risk exposures.[25] A high level of suspicion is needed for providing the best care of these patients.

The management of PCM requires a closely coordinated, interprofessional team approach. The majority of patients present to a primary care provider or emergency clinician. Patients requiring hospitalization may need to be evaluated by pulmonologists and infectious disease specialists. Pharmacists can assist with the dosing of the medications. A history of exposure to endemic areas is fundamental. 

In 2017, the Brazilian guidelines for the clinical management of paracoccidioidomycosis were published, including a detailed discussion of outpatient treatments, severe disease forms, disease prevalence among special populations, and resource-poor settings, prevention, control measures, current challenges, and recommendations.