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 early recognition, choice of therapy, and medication compliance. 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.

Objectives:

• 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.

Introduction

Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by a dimorphic fungus endemic to the Americas, found from Mexico to Argentina, with the highest incidence in Brazil, Venezuela, and Colombia.[1] PCM is the most frequent systemic, endemic mycosis in this region and 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. This disease is caused by a thermally dimorphic fungus from the genus Paracoccidioides. PCM can also be caused by other species of this genus, including P. americana, P. restrepiensis, P. venezuelensis, and P. lutzii.[2] Paracoccidioides brasiliensis and Paracoccidioides lutzii are considered the primary pathogens given the high rate of isolation of these strains.[1]

Etiology

The genus Paracoccidioides belongs to the phylum Ascomycota, order Onygenales, and includes species from different phylogenetic lineages: PS1 (more frequent in South America), PS2 (found in Brazil and Venezuela), PS3 (found in Colombia), and PS4 (limited to Venezuela).[3][4] In "Diagnosis and Treatment of Human Mycoses," Hospenthal describes Paracoccidioides as a dimorphic fungus with mycelial growth at 22° to 24° C, displaying thin septated hyphae, occasional chlamydospores, and conidia. It also describes their growth as a yeast, growing at 36° to 37° C, identified by multiple-budding yeast cells (“pilot’s wheel”). The two main species lack a sexual stage (teleomorph). Paracoccidioides grow in the soil form in humid regions with a medium to a high rainy season, mild temperatures, and the presence of forests and rivers.[3] 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.[4]

Epidemiology

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.[5][6] The infection has been reported as far north as Mexico and as far south as Argentina.[7][8] 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.[9] The prevalence of positive intradermal tests with Paracoccidioides 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.[10] Incidence rates range from 1 to 4 cases per 100,000 inhabitants per year in geographic areas with stable endemicity of 9 to 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.[4]

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.[11] 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.[4] 

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.[4] The chronic form of the infection has a strong association with smoking. The risk of developing diseases is 14 times higher in smokers than nonsmokers. Alcohol intake in quantities exceeding 50 g per day also favors the onset of PCM.[4]

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.[12]

Pathophysiology

Paracoccidioides infection is acquired mainly via inhalation of conidia, and more rarely, by direct inoculation of the skin or oral mucosa (due 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.[13][14]

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, can cause granulomas in multiple organs and tissues.[10]

The chronic form usually results from the 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.[15][16] 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.[16]

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.[16] 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.[16] 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 (greater than 95%) will be asymptomatic and develop an asymptomatic pulmonary infection that can only be detected by the intradermal paracoccidioidin test.[17] In those patients that do manifest the disease, two clinical forms have been described: the juvenile (acute/subacute) form and the chronic adult form.

Juveline Form (Acute/Subacute Paracoccydiomycosis)

The juvenile form is seen in approximately 10% of the cases.[5] It usually appears within 45 days after exposure and is seen generally in children, adolescents, and adults less than 30 years old.[18] 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. This is a progressive and more severe form of the disease. Physical exam findings include enlarged lymph nodes, abscesses, or draining fistulae.[17]

Chronic Form (Reactivation Paracoccydiomycosis)

The adult or chronic form is seen in 80 to 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 such as pulmonary fibrosis, bullae, and pulmonary hypertension. As mentioned before, this is considered a reactivation and can occur months to years after the primary infection. Pulmonary involvement is the most frequent manifestation. Enlarged lymph nodes are not common, except in children. In over 50% of the cases, there is a hematogenous spread with mucous membrane involvement. 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.[19] Cervical chronic lymphadenopathies may be seen, along with axillary and inguinal adenopathy. 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.[20]

Evaluation

The diagnosis includes visualization of fungal elements suggestive of Paracoccidioides species 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).[21][22] It is often described as multipolar budding yeast with daughter cells resembling a “Mickey mouse head” or a “steering wheel.”[17] This remains the cornerstone diagnostic tool due to its specificity and rapid yield.[17] 

Culture: Sabouraud dextrose agar is the ideal fungal media to recover Paracoccidiodes. However, due to the slow yield, the fungi will grow in 20 to 30 days, its utility in diagnosis remains low.[17] 

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.[5] 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.[23] 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 as there are no validated serological techniques for the diagnosis of infection with P. lutzii.[17]  Counterimmunoelectrophoresis shows a sensitivity between 77% to 100% and a specificity of greater than 95%.[24][20] Other available techniques, such as complement fixation and ELISA, have limited utility due to antigenic cross-reactivity, especially with Histoplasma capsulatum and Aspergillus.[25]

Skin testing: Can be positive in a healthy individual from endemic areas. This is not a useful test for the diagnosis of active disease, and the sensitivity is limited in severely ill patients.[17] 

General laboratory abnormalities noted in children with acute PCM include anemia (90%), hypergammaglobulinemia (89%), eosinophilia (76%), hypoalbuminemia (73%), hyperbilirubinemia (44%), and mildly elevated transaminases (20%).[26]

Treatment / Management

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 outlined below.[23] 

Paracoccidioidomycosis infections have a high incidence in Central and South America, however robust evidence regarding treatment efficacy is still lacking. PCM has been treated with antifungal agents including ketoconazole, itraconazole, voriconazole, posaconazole, terbinafine, and amphotericin B.[27] Fluconazole is not commonly used because of its lower response rate and more frequent relapses. Trimethoprim-sulfamethoxazole has been studied for the treatment of PCM however, it has been shown to require a longer duration of therapy (at least 24 months), with lower cure rates, and higher relapse rates when compared to itraconazole.[28][24] It is therefore not the primary choice of therapy for PCM. In general, the treatment should be continued until there is the resolution of symptoms and radiologic signs of infection along with a substantial decrease in serum serologic titers. In severe diseases, the duration of treatment should be longer than the drug-specific recommended duration.

Itraconazole

Itraconazole is the treatment of choice in mild to moderate cases due to its high response rate.[27] Recommended dose range is between 100 mg to 400 mg once daily. The pediatric dose of itraconazole is 5 to 10 mg/kg once daily (maximum dose 200 mg). The duration of therapy is 6 months. Efficacy has been reported as high as 91%.[29] It is important to remember that capsule formulations of the drug require gastric acidity to enhance absorption. Patients taking acid-suppressive therapy should not take itraconazole capsule formulation. The relapse rate with itraconazole is less than 5% if the treatment course is completed.[30]

Voriconazole

Voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter was shown to be as effective as itraconazole for chronic PCM in a small open-label comparative study of 53 patients.[31] Duration of therapy is recommended between 6 to 12 months.

Ketoconazole

Ketoconazole has a cure rate of 85% to 90% and a relapse rate of less than 10% in small observational studies. The dose used was 5 mg/kg/day in children or 200 to 400 mg/day in adults for a course of 6 to 18 months.[27]

Amphotericin B

Amphotericin B deoxycholate is reserved for severe PCM. It is the treatment of choice in patients with PCM sepsis. Lipid formulation of amphotericin B has demonstrated efficacy with lower adverse side-effects when used to treat severe cases of PCM. Observational studies with a small number of cases show high efficacy (greater than 95%) in patients with severe PCM.[32][33] Amphotericin B was shown to have a relapse rate of 20 to 30%.[5] A step-down approach with a transition to itraconazole in patients initially treated with amphotericin B has been shown to decrease relapse rates.[5] 

Trimethoprim-sulfamethoxazole

A second-line medication is trimethoprim-sulfamethoxazole (TMP/SMX) 160/800mg twice daily, which has 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.[24]

Sulfadiazine

Sulfadiazine is another alternative, the maximum dose is 4 g/day in adults and should be given until clinical and mycologic response is noted. Then the dose can 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%.[27]

Differential Diagnosis

Differential diagnosis includes other granulomatous diseases and endemic infections:

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

Prognosis

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.[30] Relapses are common and thought to be due to medication noncompliance. 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).

Complications

The most common complication is pulmonary fibrosis. Other common complications include malnourishment, anemia, Addison syndrome, and superinfection with bacteria or other fungal pathogens. Itraconazole has been shown to treat acute infection however it does not decrease the risk of pulmonary fibrosis.[30] Longterm radiologic follow-up of patients with PCM who were treated with itraconazole did not reveal any improvement in pulmonary fibrosis over a mean follow-up duration of 5.6 years.[30]

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.

In immunocompromised patients, most paracoccidioidomycosis infections have been reported in patients with HIV. Lymphomas are the most common hematologic malignancy associated with PCM, and some cases have been reported with kidney transplantation. Clinicians should counsel immunocompromised patients before traveling to endemic areas to avoid high-risk exposures.[34] A high level of suspicion is needed for providing the best care for 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 and assist the medical team in avoiding drug-drug interactions. Clinical pharmacists play a crucial role in monitoring the patient for adverse reactions to therapy as all antifungals are associated with multiple hepatic and hematologic toxicities. The clinical nurse is essential in educating the patient about the expected long duration of therapy and the risk of complicated disease if treatment is prematurely discontinued. A collaborative interprofessional team can help provide a multifaceted treatment approach for the patient and help improve patient outcomes.[Level 5]