Paracoccidioidomycosis

Etiology

The genus Paracoccidioides belongs to the phylum Ascomycota, order Onygenales. It 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 yeast, growing at 36° to 37° C, identified by multiple-budding yeast cells (“pilot’s wheel”). The 2 main species lack a sexual stage (teleomorph). Paracoccidioides grow in the soil in humid regions with a medium to high rainy season, mild temperatures, and forests and rivers.[3] Characteristically, Paracoccidioides infection is reported in areas of coffee and tobacco crops. The main accidental hosts are humans and 9-banded armadillos (Dasypus novemcinctus). 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 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% 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 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 inhibiting the transformation from conidia to yeasts and modulating 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 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 in 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 using twigs to clean teeth). A non-specific inflammatory response is initiated once the fungus invades the lungs in the yeast form. Neutrophils and alveolar macrophages 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 generally 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 forms granulomas. In children, adolescents, and immunocompromised patients, the infection could progress rapidly to systemic disease (acute/subacute infection). On the other hand, in adults, the agent may disseminate through the lymphatic vessels and veins, usually after 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. Most patients seek medical consultation only after dissemination to extra-pulmonary sites or multifocal diseases.[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 patients (greater than 95%) are asymptomatic and develop an asymptomatic pulmonary infection that can only be detected by the intradermal paracoccidioidin test.[17] In those patients who do manifest the disease, 2 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 generally seen 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 present with pulmonary sequelae such as pulmonary fibrosis, bullae, and pulmonary hypertension. As mentioned, this is 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, stridor, and 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. Malabsorption syndrome may occur in cases with mesenteric lymph node fibrosis.

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, and 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 reveals 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, the fungi grow in 20 to 30 days due to the slow yield, and their 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 and 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 are useful for diagnosis and 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 diagnosing infection with P lutzii.[17]  Counterimmunoelectrophoresis shows a sensitivity between 77% to 100% and a specificity greater than 95%.[24][20] Other 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 diagnosing 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, and disease prevalence among special populations, 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.(A1)

Itraconazole

Itraconazole is the treatment of choice in mild to moderate cases due to its high response rate.[27] The 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](A1)

Voriconazole

Voriconazole 400 mg twice daily on the first day and 200 mg twice daily after that was 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.(B3)

Ketoconazole

In small observational studies, Ketoconazole has a cure rate of 85% to 90% and a relapse rate of less than 10%. The dose was 5 mg/kg/day in children or 200 to 400 mg/day in adults for 6 to 18 months.[27](A1)

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] (B2)

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, compared to 12 months for itraconazole.[24](B2)

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 for 3 to 5 years. Cure rates of 70% are expected, but relapse rates may be as high as 30%.[27](A1)

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 3 months of treatment and every 3 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 but does not decrease the risk of pulmonary fibrosis.[30] Long-term radiologic follow-up of patients with PCM treated with itraconazole did not reveal any improvement in pulmonary fibrosis over a mean follow-up duration of 5.6 years.[30]