Dermatology

paracoccidioidomycosis(South American Blastomycosis, Brazilian Blastomycosis, Lutz-Splendore-Almeida disease, Mucocutaneous-lymphangitic paracoccidioidomycosis)

Paracoccidioidomycosis, South American Blastomycosis, Brazilian Blastomycosis, Lutz-Splendore-Almeida disease, Mucocutaneous-lymphangitic paracoccidioidomycosis

Are You Confident of the Diagnosis?

Paracoccidioidomycosis is a tropical infectious disease that can have an acute, subacute, or a chronic evolution. The diagnosis of paracoccidioidomycosis it not easily made. The large variety of clinical manifestations is a consequence of complex interactions between the host, the fungal agent, and the environment.

What you should be alert for in the history

Paracoccidioidomycosis is an autochthonous disease, restricted to South and Central Americas; 90% of the patients are male, between 30-50 years old. It is important to ask about travel to countries like Brazil, Colombia, Venezuela and Argentina. The onset of illness may be noted years later; indeed, in one reported case a man was diagnosed in the USA, 60 years after he left Brazil.

Characteristic features on physical examination

Paracoccidioidomycosis infection refers to those patients who had contact with the agent, were infected, developed the pulmonary primary complex, but in whom the disease did not evolve. This primary complex can be oligo-symptomatic or even asymptomatic, and there are rare radiological or histological findings. Hilar lymphadenopathy can be found. In endemic countries; about 50% of the individuals have positive antibodies to paracoccidioidomycosis.

Paracoccidioidomycosis disease results from the progression of primary complex, endogenous, or exogenous reinfections. In the acute / subacute form, patients will complain about superficial lymphadenopathy, fever, anorexia, weight loss and adynamia. The physician will encounter a child or a teenager, male, or female with hepatomegaly, splenomegaly and / or jaundice, characteristic cervical superficial lymphadenopathy. or less often axillary, inguinal or deep lymphadenopathy that may drain purulent material, with abscess and fistula formation. Due to hematogenous spread, patients will have papules and acneiform eruptions, located anywhere on the skin. Those lesions can ulcerate or vegetate (Figure 1, Figure 2). Mucosal lesions are seen in only about 5% of cases (Figure 3).

Figure 1.

Keratotic lesion of the calcaneus. (Courtesy of Sílvio Alencar Marques, MD)

Figure 2.

Vegetating lesion of the arms. (Courtesy of Sílvio Alencar Marques, MD)

Figure 3.

Moriforme stomatitis (Courtesy of Sílvio Alencar Marques, MD)

Patients may present with lytic lesions and spontaneous fractures in any bone, such as the clavicles, ribs, legs and arms. Blood exams often demonstrate anemia, leucocytosis, eosinophilia, and an elevated erythrocyte sedimentation rate.

In the chronic form—the classical and most common form of the disease—the physician will encounter a typical farmer, adult and male, presenting with an association of mucosal, cutaneous and pulmonary lesions. The oral cavity is most commonly affected, especially the lower lips and the gums, with painful ulcerated lesions containing micro-granules and hemorrhagic dots classically called “moriform stomatitis” (of Aguiar-Pupo). Less frequently involved sites are the nasal pyramid and septum (Figure 4), the upper lips, bulbar conjunctiva and genital mucosae. Cutaneous lesions can appear contiguous to mucosal, lymphonodal or bony lesions, or after hematogenous spread.

Figure 4.

Necrotic ulcer from nasal vestibulum. (Courtesy of Sílvio Alencar Marques, MD)

The site most commonly affected is the face, in the form of an ulcerated, ulcero-vegetating, verrucous or acneiform lesion that can have the characteristic hemorrhagic dots (Figure 5). In this form, patients must have pulmonary disease that can range from discrete, symmetric and bilateral interstitial para-hilar infiltrates, to an infiltrate affecting all the lung parenchyma, with nodules in a pneumonic configuration. Respiratory symptoms are not proportional to pulmonary involvement.

Figure 5.

"Black-dots" simulating chromoblastomycosis. (Courtesy of Sílvio Alencar Marques, MD)

Neuroparacoccidioidomycosis usually occurs in middle-aged men working as farm laborers. The characteristic symptoms are motor deficits and intracranial hypertension. Most of the cases are associated with pulmonary forms of the disease. The mortality rate is high and survivors have sequela in half of the cases. The main sequelae is motor impairment.

Expected results of diagnostic studies

The laboratory diagnosis of paracoccidioidomycosis can only be made with confidence if the fungus is viewed and correctly recognized. Samples for analysis can be obtained by shaving a lesion, bronchial secretions, pus, other fluids and biopsies of skin or mucosa. In direct examination, an ovoid, hyaline, double-layered cell, surrounded by one or more narrow-based buds, can be seen. That structure generally resembles a “mariner´s wheel” (Figure 6)

Figure 6.

Histopatological image (Courtesy of Sílvio Alencar Marques, MD)

Material should be cultured in agar-Sabouraud or agar-Sabouraud-dextrosis with actidion and chloramphenicol and incubated in ambient temperature. The culture has a shape that resembles a little popcorn.

Diagnosis confirmation

In most cases, it is impossible to clinically differentiate paracoccidioidomycosis from other diseases. In chromoblastomycosis, for example, the black dots could be confused with the micro-granules and hemorrhagic dots, and periodic acid Schiff (PAS) staining would help differentiate the characteristic fumagoid bodies from the “mariner´s wheel”–shaped cellules in paracoccidioidomycosis.

In the cases of sporotrichosis and leishmaniasis, it is important to notice the characteristic lymphatic cord next to the original lesion. When ganglia infarction is not present, direct exam based on swabs and staining biopsy specimens could be helpful in both cases. Note that in all three cases, patients will not have respiratory symptoms. The differential diagnosis also includes tuberculosis and tuberculoid leprosy, where Koch bacilus and Hansen bacilus can be found, respectively, in B.A.A.R staining. Cultures will help distinguish from histoplasmosis and cryptococcosis. Serology will diagnose a case of syphilis. Other diseases, such as Hodgkin lymphoma, NK cell lymphoma, Wegener´s granulomatosis and squamous cell carcinoma should be differentiated by histopathological exams.

Who is at Risk for Developing this Disease?

Paracoccidioidomicosis is an autochthonous disease, restricted to South and Central Americas. It is more frequent in Brazil, Colombia, Venezuela and Argentina, but even in those countries it is more prevalent in cities with higher pluviometric rates and fertile soils. Men are affected more than women and most patients are between 30-50 years old. Some studies show that estrogen could be a protective factor. The disease has a higher prevalence among alcoholics and smokers. Cottagers and farmers are the most exposed.

What is the Cause of the Disease?

Etiology

Paracoccidioides brasiliensis is a dimorphic fungus that has a micelian phase in 25oC and a yeast phase in 37°C. This fungus has an antigenic fraction called GP-43 that shows proteolytic activity, being capable of destroying collagen and elastic fibers, thus influencing their virulence. On the other hand, GP-43 helps the fungus to adhere to the host’s extracellular matrix.

Pathophysiology

Transmission occurs through inhalation of fungus spores. In the lungs the host immune system responds to create the primary pulmonary complex. During this phase, a transitory hematogeneous spread occurs, disseminating the fungus to different organs. The infection is asymptomatic until this time, and it can have a spontaneous resolution with complete healing of the primary complex, although viable quiescent fungi can remain inside other organs. Another possibility is that the disease progresses just after the infection, or later, related to any imbalance between the host and fungus.

Systemic Implications and Complications

Paracoccidioidomycosis can behave as an opportunistic fungus and can be very severe. Immunocompromised patients such as those with hematogenous cancers, diabetes, AIDS, transplantations, or patients on dialysis or receiving high doses of corticosteroids, paracoccidioidomycosis may behave in the acute manner. The disease is very severe and the mortality rate is up to 35%.

The most incapacitating sequelae from paracoccidioidomycosis are chronic obstructive pulmonary disease or restrictive pulmonary disease, both related to healing and fibrosis. Other complications due to fibrosis include: microstomia, laryngeal, pharyngeal, anal and vaginal stenosis, suprarenal insufficiency and testicular destruction. Continuous use of amphotericin-B can result in renal failure and ketoconazole may worsen testicular destruction, with consequent gynecomastia.

Treatment Options

Treatment options are summed up in Table I.

Table I.

Treatment options for paracoccidiodomycosis
Medical Treatment Surgical Procedures Physical Modalities
Removal of the fibrotic scars
Sulfonamides
Amphotericin-B Tracheotomy Physiotherapy
Azole derivates
Gastrostomy

Optimal Therapeutic Approach for this Disease

Explain the natural history of the disease to the patient and their family so that they understand that the cure of the disease is not directly proportional to symptomatic improvement. Explain to patients that healing fibrosis and the side effects of medications can also bring discomfort; encouraging them not to give up on the treatment. If risk factors such as smoking and alcoholism are present, every effort should be made to help the patient cease.

In mild to moderate forms, the drug of choice is sulfametoxazole-trimetoprim (400/80mg). The daily dose ranges: for adults sulfametoxazole 800-1200mg and trimetoprim 160-240mg, orally. For children: sulfametoxazole 8-10mg/kg and trimetoprim 40-50mg/kg, orally every 12 hours. Treatment duration is 12 months in mild cases, and 18 to 24 months in moderate cases.

In cases of neuroparacoccidioidomycosis the drugs used are intravenous sulfametoxazole-trimetoprima or fluconazole 400-800mg/day.

Another option is Itraconazole, 200mg/day for adults, and 10mg/kg for children under 30kg and older than 5 years. Treatment duration is 6-9 months in mild forms of the disease, and 12-18 months in moderate cases.

In severe forms, defined as weight loss more than 10% associated with swallowing difficulty, a bad general condition, respiratory insufficiency, neurological signs or adrenal gland compromise, treatment should be administered in the hospital. The drugs of choice are intravenous amphotericin-B 1mg/kg/day or sulfametoxazole - trimetoprim 400/80mg every 8 hours, until the patient is well enough to take medication orally.

Patient Management

Explain the natural history of paracoccidioidomycosis to the patient before beginning treatment. This is a tropical infectious disease, which may result in severe pulmonary and physical problems if left untreated. Accordingly, if therapy is administered early in the course of illness, late complications may be abrogated. Inform patients that the treatment can last from 12 to 24 months and that the complications related to fibrosis may not be completely avoided. Encourage patients to persist with treatment; the complications can be treated later with specific physiotherapy, surgery, and medicine.

During the first appointment perfom a general assessment, including complete blood count (BC), erythrocyte sedimentation rate (ESR), alanine aminotransferase (ALT) , aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, sodium, potassium, K, paracoccidioldin serology and chest x-ray.

At 30 days: CBC, ESR, ALT, AST, GGT, alkaline phosphatase, Na, K.

Throughout the course of treatment, the patient should be reevaluated every 3 months. After the end of treatment, patient should return every 6 months for 1 year. Patients are considered cured in the absence of clinical signs, a normal chest x-ray, and negative serology for up to 2 years.

There are no measures to prevent the disease. Patients should be treated early to avoid evolution of the disease and its complications.

Unusual Clinical Scenarios to Consider in Patient Management

Neuroparacoccidioidomycosis involves infection of the central nervous system, a rare site for this infection. Patients are usually middle-age male farm laborers. The characteristic symptoms are motor deficits and intracranial hypertension. Most cases are related to pulmonary forms of the disease. The mortality rate is high and survivors have sequela in half of the cases. The main sequelae is motor impairment.

When there are co-infections with tuberculosis and HIV, paracoccidioidomycosis may become more severe. Often, adrenal gland and respiratory insufficiency are a result of fibrosis from the infection.

What is the Evidence?

Azevedo, RS, Gouvêa, AF, Lopes, MA, Corrêa, MB, Jorge, J. "Synchronous oral paracoccidioidomycosis and oral squamous cell carcinoma with submandibular enlargement". Med Mycol. . vol. 49. 2011. pp. 84-9.

(Describes similarities and differences between the oral lesions of paracoccidioidomycosis and oral squamous cell carcinomas. Emphasizes and discusses the significance of risk factors in the association of these two entities.)

de Freitas, RM, Prado, R, do Prado, FL, de Paula, IB, Figueiredo, MT, Ferreira, CS, Goulart, EM, Pedroso, ER. "Pulmonary paracoddidioidomycosis: radiology and clinical-epidemiological evaluation". Rev Soc Bras Med Trop . vol. 43. 2010. pp. 651-656.

(Compares respiratory signs and symptoms between patients with and without chest X-ray abnormalities in order to establish the meaning of radiographic findings in pulmonary paracoccidioidomycosis.)

Goldani, LZ. "Gastrointestinal paracoccidioidomycosis: an overview". J Clin Gastroenterol. vol. 45. 2010. pp. 87-91.

(Review summarizing the salient features of gastrointestinal paracoccidioidomycosis. Shows that gastrointestinal paracoccidioidomycosis can be part of progressive dissemination of the infection or a result of local complications from a silent healing process.)

Odashiro, AN, Odashiro, PR, Fernandes, PI, Leite, LV, Odashiro, M, Maloney, S, Fernandes, BF, Di Cesare, S, Burnier, MN. "Eyelid and conjunctival paracoccicioidomycosis simulating carcinoma". Int Ophthalmol.. vol. 31. 2011 Feb. pp. 63-7.

(Shows that despite being rare the most common ocular sites of paracoccidioidomycosis are the eyelids and conjunctiva and its clincal similarities with squamous cell carcinoma.)

de Freitas, RS, Dantas, KC, Garcia, RS, Magri, MM, de Andrade, HF. "Paracoccidioides brasiliensis causing a rib lesion in an adult AIDS patient". Hum Pathol . vol. 41. 2010. pp. 1350-4.

(Shows how paracoddidiodomycosis can be severe in patients co-infected with AIDS.)

Rodrigues G da, S, Severo, CB, Oliveira F de, M, Moreira J da, S, Prolla, JC, Severo, LC. "Association between paracoccidioidomycosis and cancer". J Bras Pneumol . vol. 36. 2010. pp. 356-62.

(Reviews the literature about paracoccidioidomycosis and discusses the fact that the diagnosis of paracoccidioidomycosis appears to increase the risk of lung cancer.)

Tobón, AM, Agudelo, CA, Restrepo, CA, Villa, CA, Quiceno, W, Estrada, S, Restrepo, A. "Adrenal function status in patients with paracoccidioidomycosis after prolonged post-therapy follow-up". Am J Trop Med Hyg . vol. 83. 2010. pp. 111-4.

(This study assessed adrenal function in patients with paracoccidioidomycosis who had been treated to determine a possible connection between high antibody titers and adrenal dysfunction.)

Pedroso, VS, Vilela M de, C, Pedroso, ER, Teixeira, AL. "Paracoccidioidomicose com comprometimento do sistema nervoso central: revisão siatemática da literatira". Rev Soc Bras Med Trop . vol. 42. 2009. pp. 691-7.

(This study is the first systematic review of cases of neuroparacoccidioidomycosis available in the literature.)

"Ministério da Saúde". Secretaria de Vigilânica em Saúde. Departamento de Vigilância Epidemiológica. 2008.

(Pocket guide about the most infectious diseases in Brazil.).
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