Coccidioides/Coccidioidomycosis

Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Patients may present with fever, chills, cough, chest pain, and shortness of breath. The diagnosis is supported by clinical history, radiology, microscopy, fungal culture, and serological data. Management involves antifungals and supportive care. In severe disease, addressing the etiology of immunosuppression is critical.

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General Characteristics and Epidemiology

Basic features of coccidioides

Taxonomy:

  • Order: Onygenales
  • Family: Onygenaceae
  • Genus: Coccidioides

Forms:

  • Dimorphic fungus
  • Exists as both mycelia or as spherules (asexual forms) 

Reproduction:

  • No sexual form has been found.
  • Mycelia and spherules undergo binary fission.
  • Arthroconidia are the infectious particles of the Coccidioides species.
    • Transform into spherules in the lungs and tissues
    • Spherules are filled with endospores that burst and amplify the infection.

Clinically relevant species

Coccidioidomycosis (also known as San Joaquin Valley fever) can be caused by:

  • Coccidioides immitis 
  • Coccidioides posadasii

Epidemiology

  • In North America, Coccidioides is endemic to the southwestern United States:
    • California
    • Arizona
    • Utah
    • Nevada
    • New Mexico
  • Approximately 30%–60% of people who live in endemic areas are exposed at some point.
  • Incidence: approximately 42 cases per 100,000 people
    • Highest incidence in elderly
    • Can cause 15%–30% of community pneumonia in these areas

Pathogenesis

Reservoir

  • Soil in endemic regions
  • Rodents may serve as animal reservoirs (no reported zoonotic transmission to humans).

Transmission

Coccidioides arthroconidia can become airborne when soil is disturbed, allowing transmission via inhalation.

Host risk factors

  • Progressive coccidioidomycosis is uncommon in healthy people, and risk factors include:
    • AIDS infection
    • Use of immunosuppressant medications
    • Chronic steroid use
    • Elderly
    • Pregnant patients
    • History of diabetes mellitus 
    • African American or Filipino ethnicity 
  • Those with high spore exposure are also at an increased risk:
    • Construction workers
    • Farmers
    • Archaeologists

Pathogenesis

  • Inhalation of arthroconidia → develop into tissue-invasive spherules 
    • Enlarge and rupture, releasing thousands of endospores → can form new spherules
    • Can be self-limiting or cause pulmonary disease
    • Can trigger local inflammatory response 
      • Infiltration of neutrophils and eosinophils
      • Granulomatous response with B and T lymphocytes and macrophages
  • Disseminated disease occurs via hematogenous spread (particularly in immunocompromised and pregnant patients)
  • Cutaneous disease can result from either:
    • Dissemination
    • Direct inoculation

Clinical Presentation and Diagnosis

The clinical presentation can vary from asymptomatic to life-threatening. The incubation period is 1–4 weeks after exposure.

Constitutional symptoms

  • Low-grade fever
  • Night sweats
  • Anorexia
  • Weight loss
  • Weakness
  • Chills

Pulmonary involvement

  • Chest pain
  • Dyspnea
  • Cough
    • Dry or with sputum 
    • May present with hemoptysis

Cutaneous involvement

Cutaneous involvement may occur in conjunction with pulmonary involvement, with direct inoculation, or from disseminated disease.

  • Single or multiple granulomatous skin lesions
  • Abscesses
  • Draining sinus tracts
  • Immunologically induced eruptions:
    • Erythema multiforme
    • Erythema nodosum

Disseminated infection

Disseminated infection is defined as disease outside the thoracic cavity and is considered an AIDS-defining illness. Patients can present with the following (this list is not exhaustive):

  • Meningitis 
  • Muscle pain
  • Arthritis (particularly involving the knee)
  • Osteomyelitis

Classic triad of coccidioidomycosis

“Desert rheumatism” is often defined by the presence of:

  • Fever
  • Arthralgia
  • Erythema nodosum

Diagnosis

The diagnosis is made based on history and physical exam with supporting imaging and laboratory data.

Laboratory investigations

  • Fungal cultures
  • Microscopy for spherules in body fluid samples
  • Serologic testing
    • Enzyme immunoassay
    • Complement fixation (IgG antibodies)
    • Immunodiffusion kit (IgM or IgG antibodies)
  • PCR for lower respiratory tract samples (not widely available)
  • Urine antigen testing

Imaging modalities

  • Chest radiography
    • Pulmonary infiltrates, nodules, and cavities
    • Pleural effusions
    • Adenopathy
  • CT chest
    • Pleural infiltrates
      • Micronodular
      • Tree-in-bud sign
      • Multifocal ground-glass opacities
    • Pleural effusions
    • Hilar adenopathy
    • Cavities
    • Diffuse miliary pattern in immunosuppressed
anteroposterior chest x-ray pulmonary fibrosis coccidioidomycosis

This anteroposterior chest X-ray revealed pulmonary changes indicative of pulmonary fibrosis in a case of coccidioidomycosis, caused by fungal organisms of the genus Coccidioides:
Because these changes also resemble those seen in other lung infections, including tuberculosis, the findings uncovered with a chest X-ray need to be coupled with serologic testing as well as possible tissue biopsy. The degree of fibrotic changes, indicative of scarring found on X-ray, can be directly correlated to the severity of the fungal infection.

Image: “A case of pulmonary fibrosis caused by coccidioidomycosis” by CDC/Dr. Lucille K. Georg. License: Public Domain

Invasive sampling

  • Bronchoscopy with bronchoalveolar lavage
  • Cerebral spinal fluid
  • Biopsy of infected site

Management

General treatment strategies

  • Mild asymptomatic cases do not require treatment.
  • Antimicrobials for symptomatic patients or risk factors for disseminated disease 
  • Manage etiology of immunosuppression.
  • Supportive care with respiratory adjuvants and hemodynamic support
  • Surgery may be needed for progressive cavitary disease.

Antimicrobial therapy

  • Fluconazole (preferred) or itraconazole for mild-to-moderate disease
  • Posaconazole and voriconazole are alternative therapies.
  • Amphotericin B:
    • Preferred for severe disease or persistent infections
    • Switch to oral azole therapy once stabilized.

Complications and Prevention

Complications

Listed complications are associated with being immunocompromised and/or delay in treatment:

  • Severe pneumonia, progressing to ARDS
  • Pulmonary cavities 
    • May require surgical resection
    • Secondary bacterial or other fungal pneumonia may result from an existing cavity.
    • Pyopneumothorax can result from a ruptured cavity.
    • Ruptured cavities can lead to bronchopleural fistulas.
  • Chronic fibrocavitary pneumonia 
  • Disseminated disease

Prevention

It is difficult to prevent coccidioidomycosis when living in an endemic area. General strategies include:

  • Avoiding areas of dust (e.g., construction sites or excavation sites)
  • Wearing a respirator if unable to avoid dust
  • Avoiding contact with dirt
  • Avoiding dust storms
  • Addressing etiology of the immunocompromised state

Differential Diagnosis

  • Bacterial pneumonia: patients may present with fever, shortness of breath, cough, and malaise. A thorough history should address risk factors for typical versus atypical bacterial pneumonias. Diagnosis is based on history, exam, imaging, cultures, and antigen testing. Treatments include supportive care, supplemental oxygenation, and antimicrobials. 
  • Blastomycosis: endemic to the Ohio and Mississippi River valleys and the Great Lakes regions of the United States. Blastomycosis can present with pneumonia, skin lesions, osteomyelitis, and meningitis. The diagnosis is made by identifying the organism in sputum or tissue samples, culture, PCR, or antigen testing. Antifungals are used for treatment.
  • Histoplasmosis: endemic to the Mississippi and Ohio River valleys. Patients can present with pneumonia, lymphadenopathy, hepatosplenomegaly, and oral ulcerations. Diagnosis is made with fungal cultures, serology, and antigen testing. Treatment is with antifungals and supportive care.
  • Tuberculosis: an infectious disease caused by the Mycobacterium tuberculosis complex bacteria. Pulmonary disease presents with fever, night sweats, cough, hemoptysis, fatigue, and weight loss. Extrapulmonary manifestations can include pleurisy, meningitis, Pott disease, pericarditis, and miliary disease. The diagnosis is established with tuberculin skin test, sputum culture, and lung imaging. The mainstay of management is anti-mycobacterial drugs.
  • Sarcoidosis: an inflammatory disorder characterized by noncaseating granulomas in the lungs, liver, brain, eyes, and skin. Diagnosis may be suggested radiographically and confirmed by biopsy. Treatment is with corticosteroids and other immunosuppressive agents.

References

  1. Akram, SM. (2021). Coccidioidomycosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK448161/
  2. Ampel, NM, & Hoover, SE. (2015). Pathogenesis of coccidioidomycosis. Current Fungal Infection Reports, 9(4), 253–258. https://doi.org/10.1007/s12281-015-0242-1
  3. Centers for Disease Control and Prevention. (2020). About valley fever. Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/diseases/coccidioidomycosis/definition.html
  4. Galgiani, JN, Ampel, NM, Blair, JE, Catanzaro, A, Johnson, RH, Stevens, DA, & Williams, PL. (2005). Coccidioidomycosis. Clinical Infectious Diseases, 41(9), 1217–1223. https://doi.org/10.1086/496991
  5. Revankar, SG. (2021). Coccidioidomycosis (San Joaquin fever; Valley fever). MSD Manual Professional Version. Retrieved June 11, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/fungi/coccidioidomycosis
  6. Blair, JE, & Ampel, NM. (2020). Primary pulmonary coccidioidal infection. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/primary-pulmonary-coccidioidal-infection
  7. Blair, JE, & Ampel, NM. (2020). Coccidioidomycosis: Laboratory diagnosis and screening. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/coccidioidomycosis-laboratory-diagnosis-and-screening
  8. Jaroszewski, D, Blair, JE, & Ampel, NM. (2019). Management of pulmonary sequelae and complications of coccidioidomycosis. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/management-of-pulmonary-sequelae-and-complications-of-coccidioidomycosis
  9. Hospenthal, DR, Thompson III, GR, Oppenheimer, AP, and Arsura, EL. (2019). Coccidioidomycosis and valley fever. In Bronze, M.S. (Ed.), Medscape. Retrieved June 11, 2021, from https://emedicine.medscape.com/article/215978-overview

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