Investigations
1st investigations to order
sputum culture
Test
Definitive test. A positive culture gives a definitive diagnosis of coccidioidomycosis, because there is no colonised state; however, sputum can be difficult to obtain for culture, since patients’ coughs are often non-productive.[27]
Result
growth of Coccidioides species
enzyme immunoassay serology for coccidioidomycosis
Test
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 titres), it is less specific.[28] Furthermore, an isolated positive IgM needs confirmation with another serological 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] If other serological modalities (immunodiffusion and complement fixing) are positive, no further study is needed. If other modalities are negative, repeat serology in 1 to 2 weeks to test for seroconversion in a patient with acute symptoms.[23]
Result
any of the following combinations would be a positive test: IgM positive and IgG positive, or IgM negative and IgG positive; when IgM is positive but IgG negative, there is a chance of a false-positive result
immunodiffusion serology for coccidioidomycosis
Test
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 titre can be obtained by a quantitative ID test or by using a conventional CF assay.[35]
Result
positive for early IgM (IDTP) or late IgG (IDCF) antibodies
complement fixation serology for coccidioidomycosis
Test
The complement fixation (CF) assay detects complement-binding IgG antibodies. It is quantitative and can be performed on body fluids other than serum. CF titres 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 titre is proportional to the severity of infection.[1] A titre >1:16 should alert one to the possibility of disseminated (extra-pulmonary) 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, serological 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 titre.
Result
assay for late IgG antibodies; any positivity indicates present or recent infection; titres >1:16 should prompt evaluation for the possibility of disseminated coccidioidomycosis
FBC
Test
Non-specific test.
Result
eosinophilia
chest x-ray
Test
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.
Result
lobar pneumonia (single site or multifocal); single or multifocal nodular infiltrate; single or multiple cavities; calcified or uncalcified nodule; hilar or mediastinal adenopathy
Investigations to consider
antigen testing
Test
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] Can be performed on body fluid samples including urine‚ serum, and CSF.[23]
Result
positive for coccidioidal antigen
polymerase chain reaction (PCR)
Test
A real-time PCR assay for detection of Coccidioidesdirectly 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]
Result
positive for coccidioidal DNA
lung biopsy
Test
Definitive test. A lung biopsy is indicated when the clinical presentation, together with radiographic and serological 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 colonised state
Result
identification of spherules on microscopy
lumbar puncture
Test
For any patient with symptoms or signs of meningitis, a lumbar puncture for CSF analysis is recommended.[4] Identifies coccidioidal meningitis with positive serology.[23]
Result
low glucose levels, elevated protein levels, leukocytosis; positive coccidioidal serology with complement fixation (CF)
erythrocyte sedimentation rate
Test
Non-specific test.
Result
elevated
CT chest
Test
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 tumour).[42]
Result
acute pulmonary coccidioidomycosis: consolidation, streaky densities, nodular or patchy opacities, hilar and/or mediastinal adenopathy, pleural effusion. chronic pulmonary coccidioidomycosis: nodules, cavities, persistent pneumonia, chronic progressive pneumonia, adenopathy, pleural effusion. regressive end-stage disease: fibrosis, bronchiectasis, calcifications
bone scan
Test
May identify abnormalities in skeletal infections.[43]
Result
single or multifocal lesions, most common on axial skeleton, but can be seen in any bone of the body; lesions may be described as punched-out lytic, permeative/destructive, or involving a joint and/or disc space; generally, lesions have well-demarcated borders, but sometimes have an ill-defined border and diffuse appearance to the bony destruction
MRI
Test
May define bone and soft tissue abnormalities in soft tissue infections.
Result
bone findings can include erosions, abscesses, masses; soft-tissue findings may include non-specific soft-tissue inflammation, swelling, abscess, mass, lymphadenopathy, fat stranding
Emerging tests
lateral flow assay (LFA)
Test
A 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 enzyme immunoassay.[38]
Result
positive for IgM or IgG
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