Continuing Education Activity
Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by a dimorphic fungus, endemic in Central and South America. The morbidity and mortality caused by this infection are strongly associated with a patient's socioeconomic background. This activity describes the etiology, pathophysiology, and evaluation of paracoccidioidomycosis and highlights the role of the interprofessional team in the care of patients with this condition.
- Review the pathophysiology of paracoccidioidomycosis.
- Describe the appropriate evaluation of paracoccidioidomycosis.
- Outline the management options for paracoccidioidomycosis.
- Summarize the importance of improving care coordination amongst the interprofessional team to improve outcomes for patients affected by paracoccidioidomycosis.
Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by a dimorphic fungus, endemic to the Americas where it is found from Mexico to Argentina, with the highest incidence in Brazil, Venezuela, and Colombia. The illness, which is the most frequent systemic endemic mycosis in this region, was first recognized by Adolfo Lutz in Brazil in 1908. Later, Splendore described the morphology of the fungus and described four clinical cases. In 1930 Floriano Paulo de Almeida named the causing agent Paracoccidiodes brasiliensis.
The genus Paracoccidioides belongs to the phylum Ascomycota, order Onygenales, and includes two species, P. brasiliensis and P. lutzii. P. brasiliensis presents four different phylogenetic lineages: PS1 (more frequent in South America), PS2 (found in Brazil and Venezuela), PS3 (found in Colombia), and PS4 (limited to Venezuela). Paracoccidioides is a dimorphic fungus with mycelial growth at 22 to 24 degrees C, displaying thin septated hyphae, occasional chlamydospores, and conidia, as well as a yeast growth, at 36 to 37 degrees C, identified by multiple-budding yeast cells (“pilot’s wheel”). The two species lack a sexual stage (teleomorph).
Paracoccidioides grows in the soil form in humid regions with a medium to the high rainy season, mild temperatures, and the presence of forests and rivers. Characteristically, Paracoccidioides infection is reported in areas of coffee and tobacco crops. Human beings and nine-banded armadillos (Dasypus novemcinctus) are the main accidental hosts. Inter-human transmission has not yet been reported.
Paracoccidioides has a geographic distribution primarily limited to certain regions of Central and South America. About 80% of cases have been reported in Brazil, followed by Colombia, Venezuela, and Ecuador. The infection has been reported as far north as Mexico and as far south as Argentina. However, PCM has not been observed in certain countries of the continent, such as Chile, Surinam, Guyana, Nicaragua, Belize, and most of the Caribbean islands.
The prevalence of positive intradermal tests with paracoccidioidin in endemic areas could be as high as 50 to 75 percent among the adult population. Nearly 10 million patients are infected in Latin America by this pathogen, although only 1% to 2% will eventually develop any clinical form of the disease.
Incidence rates range from 1 to 4 cases per 100,000 inhabitants per year in geographic areas with stable endemicity to 9-40 cases /100.000 inhabitants per year in hyperendemic areas, such as the west Amazon region and southeastern part of Rondônia state, in Brazil. Less than 5% of patients with PCM are expected to die from the disease.
Paracoccidioides infection is acquired mainly via inhalation of conidia, and more rarely, by direct inoculation of the skin or oral mucosa in relation to the use of twigs to clean teeth. Once the fungus invades the lungs in the yeast form, a non-specific inflammatory response is initiated. Neutrophils and alveolar macrophages will tend to form granulomas depending on the immunological state of the patient and the T helper (TH) lymphocytes response. TH1 responses have been associated with a localized process that, in general, limits the infection. On the other hand, TH2 responses are associated with the disseminated form and a worse clinical outcome.
After the primary infection, the host will form granulomas. In children, adolescents, and immunocompromised patients, the infection could progress rapidly to systemic disease (acute/subacute infection). On the other hand, in the adult, the agent may disseminate through the lymphatic vessels and veins, usually after a period of several years (chronic infection), and depending on the host’s immunological response, originate granulomas in multiple organs and tissues.
PCM has some particular predisposing and modulating factors that differ from other endemic mycoses. After puberty, the illness affects predominantly males (75% to 95% of cases), even though women are equally exposed to the fungus. The presence of circulating estrogens has been described as a factor that would inhibit the transformation from conidia to yeasts and modulate the cellular immune response. Indeed, when women develop symptomatic infections, the disease paradoxically is often more severe and disseminated. Moreover, cases of reactivation of the infection have been described during pregnancy.
PCM is an occupational disease mostly related to farmers who live in rural areas. Workers involved in coffee and tobacco crops have an increased risk of acquiring the infection. PCM has also been reported among professionals who are exposed to aerosols containing soil particles.
The chronic form of the infection has a strong association with smoking. Indeed, the risk of developing diseases is 14 times higher in smokers than nonsmokers. Alcohol intake in quantities exceeding 50g per day also favors the onset of PCM.
The disease has been rarely associated with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) but has been reported in association with tuberculosis in 15% to 20% of patients. Regarding cancer and solid organ transplantation, a few cases of concurrent infection have been reported.
The chronic form usually results from reactivation of latent pulmonary foci formed during the primary infection, but reinfections may also occur. PCM has an insidious course in which the lung is the most frequently affected organ, with lesser involvement of the reticuloendothelial and lymphatic systems. Pulmonary manifestations are observed in about 90% of the patients with chronic disease; however, respiratory complaints are seldom the main reason for medical consultation. Lung sequelae in pulmonary PCM are reported in more than 50% of patients in advanced stages of the disease, even after effective treatment, and may severely impair respiratory function.
Unifocal pulmonary involvement occurs in only 25% of the cases. In most patients, medical consultation is sought only after dissemination to extra-pulmonary sites or multifocal disease. After dissemination, secondary lesions can affect numerous tissues, including mucous membranes and skin. The frequent involvement of the oral mucosa prompts patients to seek dental or medical consultation when the diagnosis is made. Other sites of involvement include the adrenal glands, long bones, and the central nervous system (CNS). CNS involvement may result in meningoencephalitis (as part of a disseminated syndrome).
History and Physical
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. It usually appears within 45 days after exposure and is seen generally in children, adolescents, and adults less than 30 years old. 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. 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.
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).
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. 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. 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%. Other available techniques, such as complement fixation and ELISA, have limited utility due to antigenic cross-reactivity, especially with Histoplasma capsulatum and Aspergillus.
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.
Treatment / Management
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.
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. 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:
- 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.
Deterrence and Patient Education
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.
Pearls and Other Issues
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. A high level of suspicion is needed for providing the best care of these patients.
Enhancing Healthcare Team Outcomes
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.