Approach

The diagnosis of coccidioidomycosis often depends on maintaining a high degree of clinical suspicion, as symptoms and laboratory studies can be nonspecific. Initial investigation of all patients should include a chest x-ray, sputum culture, coccidioidal serology, complete blood count (CBC), and erythrocyte sedimentation rate (ESR). Further evaluation will depend on the site and severity of the disease.

Clinical evaluation: acute coccidioidomycosis

In acute coccidioidomycosis‚ symptoms begin 7 to 21 days following an exposure. The onset may be abrupt or subacute, and symptoms include one or more of the following: fever, headache, nonproductive cough, shortness of breath, inspiratory chest pain, fatigue, dyspnea, myalgia or arthralgia, and rash.[24] These symptoms can be mild or severe.

Severe symptoms and signs (plus investigation results) include:

  • Multiple symptoms lasting >2 months

  • Weight loss of >10%

  • Night sweats lasting >3 weeks

  • Extensive pulmonary infiltrates (bilateral disease, persistent hilar adenopathy)

  • Inability to work

  • Age >55 years

  • Serology titer >1:16.

Often symptoms resemble community-acquired pneumonia (CAP), and within endemic areas‚ acute pulmonary coccidioidomycosis accounts for nearly 30% of all CAP.[25] Features which may help to differentiate coccidioidomycosis from bacterial CAP include hilar or mediastinal adenopathy, upper lobe infiltrates, nodules, and peripheral blood eosinophilia.[23]

Symptoms may be self-limited or prolonged, lasting weeks to months.

Physical examination is notable for presence or absence of rash and signs of lung consolidation.

Clinical evaluation: diffuse coccidioidomycosis

These patients have bilateral reticulonodular or miliary infiltrates on imaging, a pattern that suggests fungemia. Often patients have either underlying immunosuppression or a high inoculum of inspired arthroconidia (spores).

Clinical evaluation: chronic fibrocavitary coccidioidomycosis

Some patients develop chronic infiltrates and cavities, often in more than one lobe. Nodules may develop following a pulmonary infiltrate, and cavities may form within these nodules. Nodules and cavities may be asymptomatic or associated with cough, hemoptysis, and pleuritic pain. Infrequently, a cavity may rupture, causing a pyopneumothorax.[24]

People with chronic fibrocavitary pneumonia may have weight loss and night sweats in addition to pulmonary symptoms.

Physical exam of the lung may identify rales, rhonchi, wheeze, or rub.

Clinical evaluation: disseminated coccidioidomycosis

The most common sites of extrapulmonary (disseminated) infection include lymph nodes, skin and soft tissue, bones and joints, and meninges. The location of the infection dictates the symptoms and physical findings; most patients will also experience fever, night sweats, and chills.[24] Less than 5% of people with coccidioidomycosis experience extrapulmonary spread of infection.[24]

Laboratory evaluation

Initial investigation of all patients should include a sputum culture, coccidioidal serology, CBC and ESR. Because no particular test has perfect sensitivity and specificity, multiple diagnostic tests should be considered.[26]​

Sputum culture

A positive sputum culture gives a definitive diagnosis of coccidioidomycosis, because there is no colonized state; however, sputum can be difficult to obtain for culture, since patients’ coughs are often nonproductive.[27]​​

Coccidioidal serology

Serologic testing is the most frequently used method for diagnosing coccidioidomycosis.[28][29][30]​ Both qualitative and quantitative antibody-detection methods are available:

1) Qualitative serology

  • Enzyme immunoassay (EIA) is widely available and has the highest early (within 1 to 2 months of presentation) sensitivity of any method so is often used for initial screening.[5][28]​ This method detects specific IgM and IgG antibodies against Coccidioides. Typically, IgM EIA testing is positive early in the course of illness, while IgG arises later. While detection of antibodies by EIA is more sensitive than other available tests for detecting early disease (immunodiffusion tube precipitin test (IDTP), complement fixation titers), it is less specific.[28] Furthermore, an isolated positive IgM needs confirmation with another serologic test (positive EIA IgG, immunodiffusion‚ or complement fixing) as false positives are possible.[23][24]​​​[26][31]​ Sensitivity of EIA is 87% in immunocompetent patients, but only 67% in immunosuppressed patients.[32]​​​

  • Immunodiffusion (ID) tests are less sensitive but more specific than EIA.[33]​ Due to their specificity, they are performed to confirm positive EIA and complement fixation results.[1][23]​​

    • The IDTP assay tests for the presence of IgM antibodies directed against the tube precipitin (TP) antigen, a heat-stable carbohydrate antigen of the fungal cell wall. These antibodies form early in the infection, with around 90% of patients developing them in the first 3 weeks of symptomatic disease.[34]​​​

    • The immunodiffusion complement fixation (IDCF) assay detects IgG antibodies directed against the chitinase antigen (an enzyme of the fungal cell wall), which are often detectable while the disease is active.[35] These antibodies arise later in illness (typically 8-10 weeks after symptom onset) and stay positive for longer than IgM antibodies.[36] If the IDCF is positive, quantification should be requested; a titer can be obtained by a quantitative ID test or by using a conventional CF assay.[35]​​​

2) Quantitative serology

  • The complement fixation (CF) assay detects complement-binding IgG antibodies and can be performed on body fluids other than serum. CF titers should be ordered in all cases of coccidioidomycosis and are important in assessing the burden of fungal infection and monitoring treatment responses.[28]​ IgG antibodies rise within the first 2 months of infection and fall over time, reflecting progress of convalescence. The titer is proportional to the severity of infection.[1]​ A titer >1:16 should alert one to the possibility of disseminated (extrapulmonary) infection.[1]​ Sensitivity in immunocompetent hosts is 75%.[32]​ CF levels of 1:2 to 1:4 may be due to a cross-reacting antibody; therefore, serologic results should be confirmed with another modality (generally immunodiffusion, but EIA would also be indicative).[1][23]​ When following up a patient with coccidioidomycosis, the CF test is repeated every few months to assure declining titer.

High antibody titers in asymptomatic patients with advanced HIV may be predictive of subsequent symptomatic disease.[23]​ None of these serologic tests are considered definitive in the diagnosis of coccidioidomycosis.[23] It is recommended that all three serology methods are performed at initial evaluation, as performing multiple methods increases the sensitivity of the serologic assay.[32] Repeat serology every 1 to 2 weeks should be considered in symptomatic patients with negative results until a diagnosis is established.[23] Sensitivity of the tests is higher in immunocompetent hosts than in immunosuppressed hosts.[32]

Any positive test result for anticoccidioidal antibodies is usually associated with a recent or active (as opposed to past) coccidioidal infection. This is true for tests that detect either IgG and IgM antibodies, as in most patients these tests return to negative as the infection resolves. This interpretation differs from that of serologic tests for many other types of infection where IgG antibodies are often detectable for life.[5]​

Coccidioidal antigen testing

Coccidioidal antigen testing has been found helpful for immunosuppressed patients with disseminated infection or as an adjunctive cerebrospinal fluid (CSF) test in suspected coccidioidal meningitis.[23][26]​ It can be performed on body fluid samples including urine, serum, and CSF.[23]​ 

Polymerase chain reaction (PCR) testing

A real-time PCR assay for detection of Coccidioides directly from lower respiratory specimens has been approved by the US Food and Drug Administration.[27] It can provide results from an extracted sample in approximately 1.5 hours (compared to traditional fungal culture which may take up to 3 weeks to return results). Compared to fungal culture, the assay has demonstrated sensitivity of 100%, and specificity of 93.8% to 100%.[37]​​

Cerebrospinal fluid (CSF) analysis

For any patient with symptoms or signs of meningitis, a lumbar puncture for CSF analysis is recommended.[4]​ CSF leukocytosis with positive serology identifies coccidioidal meningitis. Other CSF findings may include low glucose and elevated protein levels.

Blood tests

Nonspecific findings may include eosinophilia on CBC or an elevated erythrocyte sedimentation rate.[31]

Imaging

Initial investigation of all patients should include a chest x-ray. This may show a variety of findings, including single or multilobe consolidation, mass, nodules, or, less often, miliary infiltrates with or without cavities.[24] Hilar, paratracheal, and mediastinal adenopathy may be identified.[24] Extensive pulmonary infiltrates (bilateral disease, persistent hilar adenopathy) are indicative of severe disease.

Chest CT may be more sensitive to identify abnormalities, and is indicated when the chest x-ray does not provide adequate detail (e.g., to follow a nodule or cavity size that cannot be seen on chest x-ray, or when looking for characteristics that may distinguish between infection and tumor).

Bone scans may identify abnormalities in skeletal infections. MRI may define bone and soft tissue abnormalities in soft tissue infections.

Histopathology

This is a definitive test. A lung biopsy is indicated when the clinical presentation‚ together with radiographic and serologic results‚ is inconclusive, or when treatment or observation for a presumptive diagnosis (e.g., seropositive patients) is not resulting in expected improvement. Positive histopathology gives a definitive diagnosis of coccidioidomycosis, because there is no colonized state. Spherules are identified using microscopy.

Emerging tests

Lateral flow assay

A lateral flow assay (LFA) to detect the presence of total antibodies against Coccidioides species (IgM or IgG) in serum became commercially available in 2018‚ but is not yet in widespread use.[8] While the LFA can yield rapid point-of-care results, low sensitivity is a limiting factor in its use; in a prospective study, LFA showed only 31% sensitivity compared to EIA.[38]​​

Use of this content is subject to our disclaimer