Coccidioidomycosis (Valley Fever) Imaging

Infection with Coccidioides immitis, a soil-inhabiting fungus native to the San Joaquin Valley in California, causes an illness in humans called coccidioidomycosis. Coccidioidomycosis (also called Valley Fever, derived from San Joaquin Valley) is found in Arizona, California, Nevada, Utah, New Mexico, Texas, northern Mexico, and other areas with a climate similar to that of South America. ^{[1, 2]} In total, coccidioidomycosis has been reported in 22 states. Each year, about 60% of the cases in the United States are diagnosed in Arizona. ^{[3, 4, 5, 6, 7]}  Of particular concern is the emergence of locally acquired coccidioidomycosis in Washington State. ^[8]  In a study of increased infections in southwestern Utah, mean annual temperature, increased population, and new construction were identified as likely contributing environmental factors. ^[3]  An increase in events such as dust storms, hurricanes, mudslides, and tornadoes have been cited as drivers of aerosolization and resulting increased fungal infection outbreaks. Climate change has been proposed as a possible source of outbreaks. ^{[9, 10, 11, 2, 12, 13]}

Approximately 60% of  infections are asymptomatic; when symptoms do occur, coccidioidomycosis can resemble community-acquired bacterial pneumonia. Symptoms occur 7-21 days after exposure, with fever, cough, shortness of breath, and chest pain being the most common. ^[14]

After the organism is inhaled into the lungs, the arthrospore develops into a thick-walled spherule that is filled with endospores (see the image below). Once the endospore is released, it can start the development of a new spherule, allowing the infection in the host to progress. Coccidioidomycosis is not known to be transmitted from person to person.

(See the images below.)

On the basis of clinical presentation and imaging abnormalities, pulmonary involvement of coccidioidomycosis is categorized into acute, disseminated, and chronic forms. In patients with acute disease, the most common findings are lobar or segmental consolidation, multifocal consolidation, and nodules. Adenopathy and pleural effusions are also seen, usually in association with parenchymal disease. ^[15]

The risk of infection is highest in the dry summer months; a secondary period of high risk usually occurs in the late fall, terminating with winter rains. Dust exposure is a critical route for C immitis infection; individuals who dig in the soil or who are exposed to the disrupted earth are at greatest risk. ^[6]

C immitis can disseminate from the lungs and thoracic cavity to infect other organs, such as bone, joints, skin, and meninges. Dissemination usually occurs within weeks or months after the primary pneumonia.

Imaging modalities

Imaging studies in patients with suspected or confirmed coccidioidomycosis include plain chest radiography, computed tomography (CT), magnetic resonance imaging (MRI), and, possibly, positron-emission tomography (PET). ^[16]

Chest radiography is readily available and is usually the first imaging study performed. It assists in clinical staging of the disease and is useful in following up the progression or resolution of the disease. However, chest radiographic findings are nonspecific and variable. Chest radiographic findings alone are not diagnostic of thoracic coccidioidomycosis, because other infectious diseases and neoplastic processes may mimic the disorder.

Chest radiography should be performed in all patients in whom coccidioidomycosis is suspected or confirmed, because of the possibility of pulmonary infection. In patients with suspected coccidioidal osteoporosis, plain radiographs of the affected bone are indicated.

Asymptomatic patients may have normal chest radiographic findings; a normal result generally excludes significant clinical disease. The chest radiographic findings may progress from single or multiple areas of airspace consolidation to the formation of nodules or cavities, which may further progress to diffuse reticulonodular lung disease and upper lobe scarring. In some patients with disseminated disease, radiographs may not show evidence of previous pulmonary disease, and the patients will have no history of a preceding respiratory illness.

Patients suspected of having meningitis should undergo neuroimaging studies. MRI is more sensitive than other studies to identify central nervous system involvement, and it is the preferred modality if spinal cord impingement is suspected. ^[1]

Lammering et al conducted a retrospective imaging review of 23 patients with proven coccidioidal CNS meningitis and evaluated the prevalence and significance of concurrent coccidioidal brain and intraspinal disease. All patients had intracranial abnormalities, and 86% (19/22) who underwent spinal imaging had signs of intraspinal disease, including leptomeningeal enhancement (84%), arachnoiditis (63%), and cord signal abnormalities (37%). Seven of 15 patients (47%) who underwent myelography had complete spinal blocks. ^[17]

PET scans are increasingly used in the diagnosis and staging of invasive fungal infections, including coccidioidomycosis, and may be able to detect lesions that are not otherwise visualized with CT.

In patients with confirmed skeletal involvement or highly suspected osseous dissemination, a bone scan should be obtained to assess concurrent silent or multifocal osteomyelitis. ^[18]

Osteomyelitis

Osteomyelitis may result from hematogenous spread of coccidioidomycosis. It may involve any part of the skeleton but disproportionately affects the vertebrae; paraspinal abscesses are a possible complication. Other common sites of involvement include the tibia, femur, skull, and bones of the hands and feet.

In patients with osteomyelitis, bone radiographs may show lytic lesions, periosteal elevation, and bony destruction (see the image below.)

In patients with confirmed skeletal involvement or highly suspected osseous dissemination, a bone scan should be obtained to assess concurrent silent or multifocal osteomyelitis. Abnormal uptake on a bone scan should be investigated further with additional imaging modalities, such as CT scanning or MRI. ^[18]

Findings on chest radiography may be normal or may include the following nonspecific changes ^{[19, 20, 21, 22, 23, 24, 25, 26, 27]} :

• Infiltrates
• Nodules
• Cavities
• Mediastinal or hilar adenopathy
• Pleural effusion

The most common finding is a localized infiltrate. Less-common findings include diffuse reticulonodular disease, pleural effusion, hilar adenopathy, single or multiple cavities (thin-walled and usually apical), miliary disease, and pneumothorax with associated pleural effusion.

Although the sensitivity of a chest radiographic finding is high in a patient from an area with endemic disease, the specificity is low. The chest radiograph may suggest coccidioidomycosis, but confirmation with another diagnostic test is mandatory. The chest radiographic patterns of coccidioidomycosis have a broad differential diagnosis; therefore, careful clinical evaluation and workup are recommended to exclude other disorders.

Calcification in coccidioidomas is much less frequent than it is in tuberculosis and histoplasmosis. In the evaluation of these nodules, malignancy is a primary concern for the clinician. In a review of 200 solitary pulmonary nodules that were surgically resected in patients from endemic areas, 33.5% of the nodules were malignant. ^[28]

Pulmonary nodules may be better defined on CT scans of the lungs than on standard chest radiographs, and they may show marked enhancement after the intravenous administration of contrast material.

Primary coccidioidomycosis

Asymptomatic patients may have a normal chest radiograph or may have residual abnormalities of a previous infection, including parenchymal scarring, pleural thickening, calcified and uncalcified nodules, and lymph nodes (see the images below). Lobar, segmental, or subsegmental infiltrates may be indistinguishable from those seen with acute pneumonia. Radiographic changes in primary coccidioidomycosis often resolve spontaneously, albeit slowly.

Parenchymal consolidation

Parenchymal consolidation is the most common manifestation, being seen in 75% of patients. The segmental or subsegmental consolidation may be single or multiple; it is usually unilateral and in perihilar or basal distribution. It may resolve spontaneously within 1-2 weeks. Calcifications occur in the minority of lesions (< 15%). Parenchymal consolidation can demonstrate a migratory pattern, resolving at one site and appearing at another. This has been termed "phantom infiltrates."

Nodules

In 20% of patients, nodular lung disease is seen (see the images below). The nodules frequently are well-defined, simulating metastases, or they may have ill-defined margins. They have a parahilar and lower-lobe distribution and are 5-25 mm in size.

Nodules may have the typical appearance of a granuloma, with smooth, well-circumscribed edges, but they can be indistinguishable from a malignant lesion without surgical resection and histologic examination. In a review of 200 solitary pulmonary nodules surgically resected from patients within endemic areas, 33.5% were found to be malignant. ^[29]

CT imaging may provide better definition of the nodule. Fluorodeoxyglucose positron-emission tomography (FDG-PET) scans may demonstrate intense uptake in nodules, similar to malignancy, but uptake may also be mild; thus, FDG-PET scanning cannot be used to distinguish between malignant and coccidioidomas in an endemic area.

Hilar adenopathy

Hilar adenopathy is seen in approximately 20-25% of patients with coccidioidomycosis. It is usually unilateral and concomitant with parenchymal lesions. The constellation of an infiltrate and hilar adenopathy in a patient from an endemic area should raise suspicion for coccidioidal pneumonia. Paratracheal or mediastinal adenopathy can also be seen, and its appearance is often a precursor to disseminated disease.

Pleural effusion

Pleural effusion is seen in 5-15% of patients, although pleuritic chest pain occurs more frequently (in 50-75% of cases), as determined clinically. The effusion usually is small, although a massive effusion in children may suggest more severe disease, and it may even represent evidence of acute dissemination. Effusions are more often left sided, transudative, and eosinophilic on analysis. Empyema can also occur, with diagnosis confirmed by thoracentesis. Bronchopleural fistulas and secondary spontaneous pneumothoraces have also been reported.

Other findings

Scattered patchy infiltrates called persistent coccidioidal pneumonia are a less common presentation and may require as long as 1-2 months to resolve. Diffuse pneumonia is unusual and may represent a large inhalation of arthrospores or severe underlying immunodeficiency. Findings may suggest acute respiratory distress syndrome or a miliary (ie, resembling millet seed) pattern with multiple, small, bilateral nodular densities. This pattern is also seen in disseminated disease. Diffuse miliary lesions on chest radiography are associated with rapid clinical deterioration and death.

Persistent or chronic coccidioidomycosis

Approximately 5% of patients may develop a persistent pulmonary disease when the primary disease is present for longer than 6 weeks. Persistent disease may last longer than 3 months. This disease may include persistent pneumonia with or without adenopathy, nodules and cavities, pleural disease, bronchiectasis, empyema, or calcifications. Only 25% of patients with chronic changes have a history that is suggestive of an antecedent acute primary pulmonary coccidioidal illness.

Dense segmental and lobar consolidation is the most common finding. It can be unifocal or multifocal and is sometimes bilateral with cavitary regions. Findings of chronic coccidioidomycosis may resemble those seen in pulmonary tuberculosis, with associated infiltrates and fibrosis. Bronchiectasis may be seen in 1-2% of patients.

Coccidioidal pneumonia

Persistent coccidioidal pneumonia generally occurs in a severely ill patient with dense, extensive consolidation. Chronic, progressive coccidioidal pneumonia occurs in less than 1% of patients. It mimics chronic pulmonary tuberculosis or histoplasmosis both clinically and radiographically. However, patients do have the chronic presence of C immitis on sputum cultures. Apical fibronodular lesions with cavities and volume loss are seen on radiographs, which generally show dramatic resolution with amphotericin B treatment.

Depending on the size of the consolidation, 3-21 months may be required for its resolution. Despite the slow resolution, fibrosis is less common. In immunocompromised patients with persistent pneumonia, the clinical symptoms become severe or even fatal in two thirds of cases.

Pulmonary nodules are the most common radiographic findings in persistent pulmonary infection. Nodular lesions (coccidioidomas) represent localized foci of incompletely resolved consolidation. Nodules may also form from filling in of a cavity. Nodules usually are well circumscribed and round, averaging 1.5-2 cm. They usually are single, and they tend to occur in the periphery of middle and upper lung zones. In contrast to the nodules in tuberculosis, these nodules may develop in the anterior segment of an upper lobe. The nodules may remain stable for months and eventually regress; only rarely is slow growth observed.

Cavitary coccidioidomycosis

Cavities may develop as a result of necrosis in an area of pneumonia or may be produced by excavation of a nodule. Cavities that have been created by means of excavation have been reported in 10-15% of patients. A solitary, thin-walled cavity is a common residual finding of coccidioidal infection (see the images below). Many thin-walled cavities on plain chest radiographs prove to be thick-walled cavities when visualized on CT scans. Approximately half of cavities resolve spontaneously within 2 years. Cavities smaller than 2.5 cm are most likely to resolve; large cavities (>5 cm) may persist and may result in symptoms. A rapid change in the size of a cavity suggests coccidioidal infection rather than any other granulomatous infection.

Cavities may produce pleuritic pain, cough, or hemoptysis. Mycetoma may develop in the cavities as a result of infection with mycelia of C immitis or other fungi, such as Aspergillus species. The cavities may wax and wane over the years, possibly due to a check-valve mechanism. This finding is suggestive of coccidioidal infection. ^[30] A subpleural cavity may break down into the pleural cavity, causing a pneumothorax, pyopneumothorax, or bronchopleural fistula. The rupture of a peripheral coccidioidal cavity into the pleural space is a complication that is most common in young male patients. An air-fluid level in the pleural space is a clue that the process is not a spontaneous pneumothorax.

In the past, these cavities often were surgically resected. However, the use of surgical treatment has diminished since the advent of effective antifungal therapy.

Chronic fibrotic coccidioidal pneumonia

Some patients develop a chronic fibrotic pneumonia process characterized by both pulmonary infiltrates and pulmonary cavitation. Involvement of more than one pulmonary lobe is more common. Chronic fibrocavitary pneumonia appears to be associated with diabetes mellitus or preexisting pulmonary fibrosis related to cigarette smoking or other causes. Patients may have systemic symptoms, such as fever, night sweats, and weight loss, as well as local symptoms.

Disseminated coccidioidomycosis

Disseminated coccidioidomycosis may occur as a complication of primary illness, a late complication of chronic coccidioidomycosis, or a reactivation of latent disease in susceptible individuals. Dissemination of infection occurs hematogenously to the lungs and extrathoracic organs. Although the disease may affect any organ of the body, the principal sites of involvement are the skin, bones, joints, kidneys, and meninges.

Hilar and mediastinal adenopathy are almost always associated with disseminated disease. Mediastinal adenopathy is often seen as bulky paratracheal adenopathy (see the image below). Lung biopsy is usually required for diagnosis.

The radiographic manifestations of dissemination include a miliary pattern that resembles miliary tuberculosis, although the nodules in coccidioidomycosis are less well defined. A miliary pattern is an ominous sign that represents the development of small granulomas throughout the lung (and other organs). It can occur in immunocompromised or immunocompetent hosts. The differential diagnoses for the miliary pattern include other mycotic infections, tuberculosis, silicosis, sarcoidosis, and metastatic disease.

Acute respiratory distress syndrome (ARDS) is an infrequent complication in immunocompromised hosts.

Pericardial involvement may lead to pericardial effusion, cardiac tamponade, or constrictive pericarditis. An enlarged cardiac silhouette represents pericardial involvement and a pericardial effusion.

In select cases of coccidioidomycosis, CT scanning (see the images below) is more useful than other modalities in defining the morphology of the lesions that are seen on chest radiographs. ^[31] Examples of abnormalities that chest CT scanning helps better define following chest radiography are airway disease, such as endotracheal or endobronchial coccidioidal granulomas; mediastinal adenopathy (paratracheal and mediastinal); pericardial disease; pulmonary nodules; cavitary disease and pneumatoceles; mycetomas residing in chronic cavities; pleural effusion and empyema; hydropneumothorax; and bronchiectasis.

Neuroimaging studies on CT or MRI should be performed in patients suspected of having meningitis; however, in such cases, CT scanning is considered to be less sensitive than MRI. CT or MRI of the brain in patients with CNS involvement may demonstrate basilar meningeal enhancement, granulomas, or abscesses. CT imaging provides information on bony destruction that is more precise than that of MRI.

In a retrospective study of 18 immunocompetent patients with chronic pulmonary coccidioidomycosis, several CT scan abnormalities were reported. Solitary 1- to 2-cm nodules were seen in 17 patients, a focal area of ground-glass attenuation was seen in 1 patient, and focal consolidation was seen in 1 patient. Ten nodules had homogeneous attenuation on the CT scan, 2 showed cavitation, another 2 had foci of calcifications, and 1 had a central lucency. Most nodules (those in 14 patients) were peripheral, and some (those in 3 patients) were central. Ground-glass attenuation, representing granulomatous inflammation, surrounded 3 nodules. ^[31]

In a study by Capone et al of 15 patients evaluated with chest CT scans for acute pulmonary coccidioidomycosis, the main findings were multiple nodules, interlobular septal thickening, consolidation, lymph node enlargement, and, less frequently, pleural effusion. ^[32] Nodules ranged from 0.5-3 cm in diameter and showed ill-defined contours and nodule coalescence. More than 75% of patients presented with more than 20 nodules, and all patients with nodular presentations had more than 10 nodules with cavitation. In 73% of cases, these nodules were adjacent to the pleural surface. None showed calcification. About 40% of the cases showed mediastinal and/or hilar lymph nodes of more than 1 cm in diameter.

CT-guided transthoracic core needle biopsy (CTTCB) has been shown to be a relatively safe method for evaluating lung nodules and  to be highly accurate in evaluating lung nodules caused by coccidioidomycosis in an endemic area. The sensitivity and specificity of CTTCB for a coccidioidomycosis lung nodule was 83% and 100%, respectively, with a positive predictive value of 100%. ^[33]

The MRI appearance of coccidioidomycosis varies; findings may include heterogeneous marrow signal intensity and soft tissue involvement. MRI may help delineate the extent of bone, joint, and overlying soft tissue involvement, including sinus tracts or fistulae. A bone scan may detect multiple sites of bony involvement. ^[1]

Neuroimaging studies, such as CT and MRI scans, should be performed in patients suspected of having meningitis. MRI is more sensitive than other studies for CNS involvement, yielding positive findings in approximately 75% of patients with coccidioidal meningitis, whereas CT scanning yields only 42%. The 3 most common findings include hydrocephalus with ventricular enlargement, basilar meningitis, and vascular occlusion. The detection of hydrocephalus and vascular occlusion has negative prognostic implications.

MRI is the preferred modality if spinal cord impingement is suspected and is useful in establishing the extent of disease and in planning surgical debridement of infected areas. MRI may be better than CT in evaluating the patency of the aqueduct of Sylvius. Cerebral infarctions can also be seen in coccidioidal meningitis.

In a study of MRI images of 41 patients with spinal manifestations of coccidioidal infection, leptomeningeal enhancement was identified in 26 patients (63%), arachnoiditis in 22 patients (54%), osteomyelitis-discitis in 14 patients (34%), cord edema in 11 patients (27%), and true syrinx in 3 patients (7%). In 30 patients (73%), brain involvement was present, most commonly basilar meningitis. ^[1]  

Positron emission tomography (PET) scans are increasingly being used for the diagnosis and staging of invasive fungal infections, including coccidioidomycosis, and may be able to detect lesions not otherwise noted with CT. ^{[34, 35]}

Fluorodeoxyglucose PET (FDG-PET) scanning can help identify areas of active coccidioidal infection. Intense diffuse uptake is seen in patients with disseminated coccidioidomycosis. Solitary nodules may have uptake indistinguishable from malignancy, and long-standing granulomas may have little or no uptake.

Coccidioidal pulmonary nodules can take up significantly less FDG  by PET/CT than nodules associated with malignancies, but there is considerable overlap between granulomatous and malignant lesions at lower maximum standard unit of uptake (SUV_max). ^[35]