Paracoccidioides/Paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is an endemic fungal infection caused by Paracoccidioides brasiliensis and P. lutzii. The fungus is geographically distributed across Mexico and South and Central America. Transmission is by inhalation, and most infections are asymptomatic. The fungus infects the lungs and then spreads to the skin, mucous membranes, and other parts of the body. Primary infection is typically self-limited. However, if infection is not contained by the host, and/or the patient is not treated, life-threatening complications can ensue. Acute infections typically affect younger populations, with findings of lymphadenopathy, hepatosplenomegaly, skin lesions, and signs of bone marrow dysfunction. More commonly, chronic paracoccidioidomycosis is seen, especially in men. Chronic paracoccidioidomycosis represents reactivation of the infection, presenting with lung disease or disseminated infection. Diagnosis is by microscopy, histopathology, culture, and serology. Itraconazole is typically used for mild to moderate disease and amphotericin B for severe and/or CNS disease.

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General Characteristics of Paracoccidioides

Features

Morphology:

  • Thermally dimorphic fungus
    • Mold forms at 22°C–26°C
    • Yeast forms at 37°C
  • Mold form: thin, septated hyphae
  • Yeast form: 
    • Oval/round budding yeast
    • “Pilot’s wheel” or “Captain’s wheel” appearance: large cell surrounded by budding cells
Paracoccidioidomycosis

Histopathology of Paracoccidioides:
Cells with budding daughter cells (blastoconidia) seen in tissue, like a ship’s steering wheel (captain’s or pilot’s wheel)

Image: “Histopathology of paracoccidiodomycoisis” by CDC/Dr. Lucille K. Georg. License: Public Domain

Clinically relevant species

  • P. brasiliensis
  • P. lutzii

Forms of disease

  • Asymptomatic lung infection
  • Acute/subacute
  • Chronic

Epidemiology

  • Endemic in rural areas in the following regions:
    • Southern Mexico to Argentina
    • Brazil
    • Colombia
    • Venezuela
    • Ecuador
    • Paraguay
  • Prevalence in endemic areas:
    • As high as 75% among adults
    • Estimated that only 2% of people develop active infection
  • Chronic form:
    • Most prevalent among men ages 30 to 60 years
    • Estradiol may have a protective effect for women.
  • Morbidity and mortality are dependent on socioeconomic background.

Pathophysiology

Transmission and infectious process

  • Route of entry: inhalation
  • Habitat: unknown, but likely in the soil
  • Animal reservoir: armadillos
  • Rising cases are linked to the following factors:
    • Deforestation (seen in Brazil)
    • Urbanization in peripheral city areas with poor infrastructure
    • Increased soil and air humidity

Pathogenesis

  • Conidia inhaled through the respiratory tract → phagocytized by alveolar macrophages
  • Conversion to yeast form occurs within macrophages → rapid fungal multiplication
  • Typically, infection is limited by nonspecific inflammatory response.
  • Most infected patients have T helper cell type 1 (Th1)–mediated immune response:
    • Alveolitis
    • Compact granuloma formation
    • Latent or asymptomatic infection
  • A deficient Th1 response results in severe disease:
    • Granulomas do not form.
    • Development of Th2 and Th9 responses, leading to the following:
      • B-lymphocyte activation
      • High levels of circulating antibodies
      • Eosinophilia
      • Hypergammaglobulinemia
  • If unresolved → fungus can disseminate via venous and lymphatic system

Host risk factors

  • Agricultural work (especially coffee growers in endemic regions)
  • Smoking
  • Alcohol use
  • HIV and AIDS
  • Immunosuppression

Clinical Presentation

General findings

  • Asymptomatic lung infection is common.
  • < 5% of patients develop clinical disease.
  • 2 patterns of clinical disease:
    • Acute/subacute form (also known as juvenile form): presents ≥ 45 days after infection
    • Chronic form: presents after primary infection is reactivated

Acute/subacute (juvenile) paracoccidioidomycosis

  • Typically observed in:
    • Children
    • Adolescents
    • Adults < 30 years of age
  • Represents < 10% of total cases
  • Signs and symptoms:
    • Constitutional:
      • Fever
      • Weight loss
      • Fatigue
    • Lymphadenopathy
    • Hepatosplenomegaly
    • Manifestations of bone marrow failure (e.g., aplastic anemia)
    • Skin and mucous membrane lesions
    • Bone involvement (less common)
Paracoccidioidomycosis lesions

Paracoccidioidomycosis-caused facial lesions in a Brazilian child:
cells with budding daughter cells (blastoconidia) seen in tissue, like a ship’s steering wheel (captain’s or pilot’s wheel)

Image: “Paracoccidioidomycosis lesions” by CDC/Dr. Martins Castro. License: Public Domain

Chronic paracoccidioidomycosis

  • Represents > 90% of cases
  • Presents months to years after initial infection
  • Primary lung infection:
    • Cough (+/– productive)
    • Hemoptysis (less common)
    • Dyspnea
    • Fever
    • Malaise
    • Weight loss
  • Oropharyngeal and laryngeal mucous membrane lesions:
    • Painful ulcers
    • Odynophagia
    • Dysphagia
    • Dysphonia
    • Stridor
    • Sialorrhea
  • Disseminated disease:
    • Can affect any body site
    • Skin (25% of patients):
      • Crusted papules
      • Ulcers
      • Nodules
      • Plaques
      • Verrucous lesions
    • Lymph nodes: cervical lymphadenopathy most common
    • Adrenal glands: commonly involved but typically asymptomatic
    • CNS:
      • Most common symptom: headache (10%–25% of patients)
      • Meningitis
      • Spinal cord lesion(s)
    • Less common:
      • Bones
      • Joints
      • Genitals
      • Eyes

Diagnosis

Laboratory tests

  • Microscopic visualization of culture growth is required for diagnosis.
  • Direct histologic examination of tissue:
    • Pilot’s wheel: large yeast cell with translucent cell walls and multiple buds
    • Sources:
      • Sputum
      • Bronchial lavage fluid
      • Exudates, skin lesions
      • Biopsies of other tissues
    • Preparation:
      • KOH
      • Gomori methenamine silver (GMS) stain
      • H&E stain
    • May find granulomatous reaction: giant and epithelioid cells
  • Culture: 
    • Sabouraud dextrose agar or yeast extract agar
    • Can require up to 4 weeks for growth
  • Serology:
    • Quantitative immunodiffusion (preferred)
    • Antibody titers monitored to check response to treatment
    • Limitations:
      • Cross reactivity with other fungi
      • Sensitivity can be lower in immunocompromised patients.
  • Additional evaluation:
    • Liver function tests: 
      • Mild elevation of liver function
      • Low albumin (correlated with poor prognosis)
    • CBC: anemia
    • Adrenal dysfunction:
      • Morning cortisol
      • Adrenocorticotropic hormone (ACTH) stimulation test

Radiographic findings

  • Chest X-ray: mixed interstitial and alveolar infiltrates:
    • Usually perihilar, bilateral, and symmetrical
    • Predominantly involve the lower lungs
  • Chest CT:
    • Ground glass attenuations
    • Consolidations
    • Nodules
    • Masses
    • Cavities
    • Septal or interlobular thickening
    • Chronic disease:
      • Fibrosis
      • Bullae
      • Emphysema
  • Neuroimaging:
    • Ring-enhancing lesions in the brain and/or spinal cord
    • Findings may be nonspecific (i.e., solitary or multifocal parenchymal lesions).

Management

  • Sensitive to antifungal agents
  • Itraconazole:
    • Preferred agent for mild to moderate disease
    • Duration of 6–12 months
  • Amphotericin B:
    • Used for severe disease and CNS involvement
    • Duration of 3–6 weeks then → oral agent for prolonged course (> 2 years)
  • Trimethoprim–sulfamethoxazole (TMP-SMX):
    • May be used alternatively for severe and/or CNS disease
    • Requires longer course than itraconazole on average (≥ 2 years)

Differential Diagnosis

  • Blastomycosis: pulmonary disease caused by inhaling the spores of Blastomyces. Although blastomycosis and paracoccidioidomycosis are both endemic to Central and South America, Paracoccidioides is not endemic to the Great Lakes and the Ohio and Mississippi River valleys. Diagnosis is made by cultures and imaging. The yeast of Paracoccidioides are typically smaller with thinner cell walls.
  • Tuberculosis (TB): infectious disease caused by bacteria of Mycobacterium tuberculosis complex. Like Paracoccidioides, the bacteria usually infect the lungs but can also spread to other parts of the body. Both are also associated with a period of latency and can present with similar signs and symptoms. Look for a history of exposure to an environment with TB prevalence (healthcare setting, homeless shelter, etc.). CD4 count < 300/μL is typically associated with TB. The diagnosis is established with tuberculin skin test, blood tests, sputum culture, and lung imaging.
  • Opportunistic fungal infections (aspergillosis, candidiasis, pneumocystis pneumonia, mucormycosis): group of infections that occur in patients with weakened immune systems (especially those with CD4 counts < 200/μL) and typically do not cause disease in healthy patients with normal immune system function. General signs and symptoms can be similar to those of paracoccidioidomycosis. Microscopy and culture of sputum or bronchoalveolar lavage with identification of specific organism can help differentiate.
  • Leishmaniasis: parasitic disease found in tropical, subtropical, and southern Europe regions. The most common findings in leishmaniasis are cutaneous lesions causing skin sores; however, the disease can also involve visceral organs (often the spleen, liver, and bone marrow). 
  • Multiple carcinomas (lymphoma, leukemia, skin, maxillofacial malignancies): have overlapping signs and symptoms with paracoccidioidomycosis (e.g., lymphadenopathy, hepatosplenomegaly, skin lesions, oropharyngeal lesions). Diagnosis is made by histopathology.

References

  1. Centers for Disease Control and Prevention Resources for Health Professionals. (2021). Parasites—leishmaniasis. https://www.cdc.gov/parasites/leishmaniasis/health_professionals
  2. Nucci, M., Colombo, A. L. (2021). Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis. UpToDate. Retrieved June 21, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-acute-subacute-paracoccidioidomycosis
  3. Nucci, M., Colombo, A. L. (2021). Clinical manifestations and diagnosis of chronic paracoccidioidomycosis. UpToDate. Retrieved June 21, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-chronic-paracoccidioidomycosis
  4. Nucci, M., Colombo, A. L. (2021). Mycology and epidemiology of paracoccidioidomycosis. UpToDate. Retrieved June 21, 2021, from https://www.uptodate.com/contents/mycology-and-epidemiology-of-paracoccidioidomycosis
  5. Nucci, M., Colombo, A. L. (2021). Treatment of paracoccidioidomycosis. UpToDate. Retrieved June 21, 2021, from https://www.uptodate.com/contents/treatment-of-paracoccidioidomycosis

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