Coccidioides immitis : General Characteristics, Pathogenesis, Clinical Findings, Laboratory Diagnosis, Epidemiology, Prevention and Control

Coccidioides immitis : General Characteristics, Pathogenesis, Clinical Findings, Laboratory Diagnosis, Epidemiology, Prevention and Control

Introduction of Coccidioides immitis

Coccidioides immitis is a dimorphic fungus with septate hyphae. The fungus causing endemic mycosis –Coccidioidomycosis. It is also known as Valley fever or cocci or California fever, or desert rheumatism, or San Joaquin Valley fever. In endemic areas, the spores of the causative agents are usually found in soil where they are dispersed into the air. It commonly occurs in gardening areas, construction, farming, wind areas. Endemic areas affected are the arid areas of the United States in Arizona, California, Nevada, New Mexico, Texas, Utah, and Northern Mexico. It has two forms. White fluffy mold on most cultural media (Sabouraund dextrose agar) and non-budding spherical form- a spherule, in host tissue. C. Imitis reproduces within mature spherules in the host tissue by forming small endospores. Through the formation of thick-walled barrel-shaped spores, called arthrospores, the fungus is identified by its appearance. The fungus is identified by its appearance by the formation of thick-walled barrel-shaped spores, called arthrospores.

Classification of Coccidioides immitis

Taxonomic Classification

(described by Rixford and Gilchrist in 1896)
Kingdom: Fungi
Phylum: Ascomycota
Class: Euascomycetes
Order: Onygenales
Family: Onygenaceae
Genus: Coccidioides

Species: Coccidioides immitis

Causative agents of Coccidioidomycosis

Dimorphic Fungi, Coccidioides is the causative agent of Coccidioidomycosis. Coccidioides are a genus of dimorphic fungi that exist as mycelia or as spherules of asexual forms and lack the reproduction and structures of the sexual form. The two species of Coccidioides are Coccidioides immitis and Coccidioides posadasii. They are known to cause Coccidioidomycosis in different regions in the endemic areas. These two species are phenotypically similar and can only be identified and differentiated on the basis of molecular tests. Infective spores known as arthroconidia are produced by Coccidioides. During inhalation, the arthroconidia get deposited into the lungs. They then germinate and grow into spherules within the lungs and tissues. Spherules are filled with tiny endospores of about 2µm-5µm, which burst into the tissues releasing the endospores which cause severe disease.

Pathogenesis of Coccidioidomycosis

Transmission: Infection is acquired by dust containing arthrospores. Risk factors of Coccidioidomycosis infection People that are living or traveling into endemic areas where the Coccidioides fungus occurs are at risk of infection. Dust storms containing infected soil fungal spores such as farms or building sites raise the risk of exposure and infection. People who have compromised immune systems are at greater risk of contracting a serious or disseminated disease. These include:

  • HIV/AIDS patients
  • Organ transplant recipients
  • Autoimmune patients and rheumatoid disease patients taking immune-suppressing drugs
  • Pregnant women
  • Diabetic patients

Virulence factors of the causative agents

Adherence: Autolysis and thinning processes of the spores leave certain barred-shaped cells with the ability to bind to epithelial cells and tissues during mycelial growth and development of the septae. Arthroconidia, light and loosely chained allows them to quickly become airborne and bind to surfaces, and to be inhaled by hosts.

Specialization and remodeling: The arthroconidia undergo remodeling when in the host cells shedding off the outer layer of the spore, to form the spherules. The spherules which divide internally through the formation of an internal septate divide the spherules into compartments and each compartment contains several small endospores. In the epithelial cells, alveolar sacs, and alveolar macrophages, a completely impregnated spherule with endospores raptures and releases the endospores. The alveolar macrophages select the endospores that induce an acute inflammatory response as a host response to the endospores due to the aggregation of neutrophils and eosinophils. The endospores can further multiply within the cells and tissues and spread by causing mycelial growth in the tissues.

Antigenic Variation: Two antigens known as coccidiodin and spherulin are generated by Coccidiodes. Coccidiodin is derived from the mycelial cultures of coccidiodes, and broth cultures contain spherulin antigens. They contribute to the immune responses of the fungi.

Clinical manifestations of Coccidioidomycosis

Most of the infections are asymptomatic pulmonary nodules. Many persons develop self-limited influenza-like fever → Valley fever or desert rheumatism (In women reddish, painful, tender lumps known as erythema nodosum or erythema multiforme occur on the legs just below the knees.  most commonly located in the front of the legs below the knees, associated with migratory arthralgias, a form of pain the spreads from the joints to other parts of the body. These symptoms are collectively known as desert rheumatism).

  • Acute pneumonia
  • Chronic fibrocavitatory pneumonia
  • Chronic dissemination:
  • Bone
  • Meninges
  • Skin
  • Joints Subcutaneous tissue

Some of the major clinical manifestations of coccidioidomycosis include:

  • Acute and chronic inflammation is associated with the production of neutrophils and eosinophils in response to endospore exposure in the alveolar sacs and the lung tissues. Neutrophils and eosinophils get attracted to the site where the spherules rupture and release endospores.
  • Chronic granulomatous infection occurs when mature spherules do not rupture, which is an indication of Coccidiodes’ control.
  • Progressive lung coccidioidomycosis, which is typically chronic with nodules or/and cavity multiplication and enlargement.
  • Disseminated coccidioidomycosis, which is crippling and life-threatening; except for pregnant women, it usually affects men than women. Men most affected are the elderly, those with underlying conditions, HIV/AIDS patients. Majorly caused by C. immitis which has estrogen-binding proteins, and elevated levels of estradiol and progesterone stimulate its growth.
  • Coccidioides meningitis is a disseminated infection commonly affecting the Central Nervous system and brain of AIDS patients.

Diagnosis of Coccidioidomycosis

Clinical diagnosis of Coccidiodimycosis: Physical examination and history of patients for extrathoracic by chest X-rays that indicate unilateral infiltration, lobar consolidation, nodular infiltrate, cavitation, and hilar and peritracheal adenopathy or mediastinal lymphadenopathy.

Laboratory Diagnosis of Coccidioidomycosis

Specimen: It depends on the site of infections and the most common specimens are sputum, pleural fluid, lesion exudates, cerebrospinal fluid, biopsy

KOH mount:  KOH Wet mount and calcofluor stains are used for observation of spherules which are usually 20 to 80 micrometers in diameter, thick-walled, and small endospores of 2 to 4µm for C. immitis.

Culture Characteristics: Culturing Coccidioides in mycological and/or bacterial media produces white to tan cottony colonies within 5-7 days. On SDA, the colonies have hyphae with chains of arthroconidia which independently form hyphal cells. Bacterial media can be prepared with or without antibacterial antibiotics and cycloheximide to inhibit contaminating bacteria or saprophytic molds, respectively. Since arthroconidia are extremely contagious, only in a biosafety cabinet are suspect cultures examined. A complex medium can be used to cultivate and produce spherules of these fungi.

LPCB preparation: It shows hyaline, septate, and thin hyphae and arthroconidia from the plate incubated at 25°C, and also racquet hyphae may occasionally be observed from young cultures. Whereas from the plate incubated at 37°C shows large, round, thick-walled spherules (10-80 µm in diameter) filled with endospores (2-5 µm in diameter). Note:  Organism comes at-risk group III and thus strict precautions should be taken.

Histological diagnosis: Using sputum or tissue samples to diagnose thick fungal spherules with a double refractile wall of 80 μm in diameter as shown above image.

Serological Testing

  • Eosinophilia, increased ESR or CRP.
  • Assay for anti-coccidiodidal antibodies, IgG, and IgM for confirmation
  • ELISA for detection of antibodies against the disease or presence of coccidiododial antigens
  • Immunodiffusion for detection of IgM and IgG antibodies against coccidioidomycosis
  • CFT for IgG for estimation of disease severity, with high titters indication severe disease and low titters, indication less severe disease or decline in severity. CFT also detects the presence of complement-fixing antibodies in the CSF which is an important diagnosis for coccidial meningitis.
  • Urine Antigen Test is used in immunocompromised. Patients with significant forms of infection, including pneumonia and disseminated disease.
  • Delayed cutaneous hypersensitivity is used for endemic epidemiological research, primarily to detect hypersensitivity to coccidioidin or spherulin, which develops in immunocompetent patients within 10 to 21 days after acute infection. Spherulin, however, is absent in progressive diseases.

Test for Skin: The coccidiosis skin test achieves a maximal induration (about 5 mm in diameter) of 0.1 mL standardized dilution between 24 and 48 hours after cutaneous injection.

Molecular Diagnosis: cDNA probing rapidly identifies fungal growth. PCR is used to test for fungal DNA from samples from the lower respiratory tract.

Treatment of Coccidioidomycosis

Fluconazole or itraconazole can be used to treat mild to severe illnesses.  Amphotericin B is treated for serious illnesses. In non-endemic areas where the risk of fungal seeding is low and less hematogenous, patients are treated with less toxic fluconazole. Mild to moderate nonmeningeal extrapulmonary infections are treated with fluconazole or itraconazole are taken orally. Voriconazole can be administered orally or intravenously or treat with oral posaconazole.HIV/AIDS patients with coccidioidomycosis-associated infections use maintained therapy of fluconazole or itraconazole while monitoring the CD4 cell count at about > 250/µl. Meningeal coccidioidomycosis is treated with long-term administration of oral fluconazole. Surgical removal of involved bone to cure osteomyelitis Surgical removal of a lung or pulmonary cavities that cause hemoptysis may be necessary when the disease is diagnosed early to resection the cavity and close pulmonary leaks.

Epidemiology of Coccidioides immitis

Naturally, it exists in many parts of the New World’s soil and air. These are normally dry to semi-arid regions with relatively modest precipitation, mild winters, and prolonged hot seasons. Coccidioidomycosis is typically a disease of both human and non-human inhabitants of these areas; but after entering these areas, tourists may acquire the disease and return home long distances from the endemic areas. Arthroconidia inhalation of C. Immitis leads to an infection that is usually benign, but sometimes serious and sometimes fatal. Recovery from infection or asymptomatic infection leads to reinfection resistance. Exposure to soil indicates that exposure to C. Immitis is more likely for those occupations.  The persistence of the organism in the soil means that especially as long as susceptible newcomers continue to penetrate endemic areas, infections will be encountered in the future.

Prevention and Control of Coccidioidomycosis

Near control of risk classes of opportunistic coccidioidomycosis contractors. By minimizing dust, paving highways and airfields, planting grass or crops, and using oil sprays, certain control measures can be accomplished.

Key Notes on Coccidioides immitis

  • C. immitis is unique because it produces spherules(30 μm- 60 μm in size), containing endospores(2 μm to 5 μm) in tissue, and hyphae at 25°C.
  • Infection of the skin, bones, joints, lymph nodes, adrenal glands, and central nervous system results from the hematogenous spread of the pathogen into the host’s bloodstream.
  • C. Immitis is an anaerobic organism that develops spherules in the presence of COquickly.
  • The majority of infections with Coccidioides have an incubation period of one to four weeks.
  • Without particular treatment, the infection may resolve.

Further Reading

  1. https://ppdictionary.com/mycology/immitis.htm
  2. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/coccidioides-immitis
  3. https://www.msdmanuals.com/professional/infectious-diseases/fungi/coccidioidomycosis
  4. https://jcm.asm.org/content/45/1/26
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702223/
  6. https://emedicine.medscape.com/article/215978-overview
  7. https://www.pathologyoutlines.com/topic/lungnontumorcoccidio.html
  8. https://opentextbc.ca/microbiologyopenstax/chapter/respiratory-mycoses/
  9. https://pubs.rsna.org/doi/full/10.1148/rg.344130134
  10. https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1196/annals.1406.049
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