Background: Infection with Coccidioides immitis, a soil-inhabiting fungus, causes an illness in humans called coccidioidomycosis.

C immitis is a fungus that thrives in soil, and its growth occurs in either of 2 phases: the mycelial arthrospore phase in the soil and the spherule endospore phase in infected tissues. The mycelia are the least infectious but the hyphae develop into arthrospores that become airborne and are highly infectious.

After the organism is inhaled into the lungs, the arthrospore develops into a thick-walled spherule filled with endospores. Once released, each endospore can start the development of a new spherule and the infection in the host progresses. Coccidioidomycosis is not known to transmit from person to person.

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 critical in acquiring the infection with this organism. Individuals who dig in the soil or who are exposed to the disrupted earth are at the greatest risk.

Pathophysiology: Depending on the immune response of the host, an infection with C immitis may evolve into one of the many clinical syndromes. Most patients with primary pulmonary coccidioidomycosis are asymptomatic, and the infection resolves spontaneously. In approximately 5% of patients, a persistent pulmonary focus of coccidioidomycosis may be manifested as a nodule, cavity, or chronic progressive pneumonia. In approximately 5-7% of cases, coccidioidal pneumonia evolves to form a sharply circumscribed and usually noncalcified pulmonary nodule.

Cavity formation occurs in approximately 5% of patients, these cavities are commonly asymptomatic, and approximately 50% of them disappear within 2 years of occurrence. Some patients develop chronic progressive coccidioidal pneumonia, which manifests with chronic systemic symptoms such as low-grade fever, weight loss, cough, chest pain, and hemoptysis.

In addition, 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 to months of the primary pneumonia. However, in some patients with disseminated disease, radiographs may not show evidence of previous pulmonary disease, and patients have no history of a preceding respiratory illness. Individuals belonging to certain ethnic groups such as African Americans and Filipinos or patients with depressed cellular immunity are more likely to have dissemination; examples of these patients include those with lymphoma, HIV infection, organ transplants and patients receiving high-dose corticosteroids.

Frequency:

• In the US: Coccidioidomycosis affects an estimated 100,000 people each year in the United States. Endemic areas in the United States include Arizona, south central California, Nevada, and New Mexico, as well as the western half of Texas. Although usually affecting those in endemic areas, coccidioidomycosis is increasingly recognized outside these areas, as travelers pass through endemic areas.

• Internationally: The fungus is endemic to certain regions of North America and South America. Affected areas are in the lower Sonoran areas, which are characterized by semiarid regions with hot summers and alkaline soils. These areas include northern Mexico and Central America and South America. Central American countries in which this fungus is ubiquitous include regions of Mexico bordering western United States, Guatemala, Honduras, and Nicaragua. The disease also is endemic in other areas such as the desert regions of South America, which encompasses Argentina, Paraguay, and Venezuela.

Mortality/Morbidity: Infection is directly related to the degree of exposure to airborne arthrospores. Persons exposed to large amounts of dust in endemic areas (eg, farmers, archeologists) have higher rates of infections. Infection rates usually are calculated from coccal skin test results.

Approximately 40% of those infected have symptomatic disease, usually pulmonary. In a majority (approximately 90%) the pulmonary infection resolve without sequelae; however, 5-10% of patients develop chronic disease with pneumonia, cavitary lesions, and nodules. In less than 1%, the disease progresses to dissemination.

Race: The primary pulmonary disease shows no racial predilection, however, disseminated disease occurs more commonly in races with dark skin. Filipinos, African Americans, Hispanics, Native Americans, and Asians have a susceptibility for dissemination, in a descending order. Compared with whites, blacks have 5 times the risk of meningitis and 5 times the risk of death. Filipinos have 10 times the risk of meningitis compared with whites.

Sex: Pregnant women are predisposed to progressive and disseminated infections, particularly in the third trimester. This likely occurs because pregnancy is associated with weakening of cell-mediated immunity. Pregnancy increases risk of dissemination to 40-100 times that of the general population.

Clinical Details: After C immitis is inhaled, an initial pyogenic infection develops. This is followed by a granulomatous respiratory infection. In most patients, the asymptomatic pulmonary infection resolves spontaneously. However, in approximately 5% of patients, a persistent pulmonary focus or dissemination to other parts of the body (eg, bone, joints, skin, meninges) occurs. The infection also may spread to the bone marrow, myocardium, and kidneys.

Risk factors

Disseminated coccidioidomycosis may occur in an otherwise healthy individual, but several risk factors have been identified:

• Male sex

   

• Ethnicity (eg, African American, Filipino race)

   

• Pregnancy

   

• Diabetes

   

• Depressed cellular immunity, as in patients with lymphoma, HIV infection, or organ transplants and in patients receiving high-dose corticosteroids

Medical history

Approximately 30-40% of individuals have clinical symptoms after infection. The incubation period, after infection and before symptoms appear is usually 7-21 days. The disease spectrum ranges from a mild flulike illness to subacute pneumonia. Most patients have a cough, chest pain, fever, and fatigue.

Physical examination

More than half of the cases in people residing in high-risk endemic areas are subclinical. Consider coccidioidomycosis in individuals who are at risk for infection and in those who have a constellation of nonspecific signs or unusual rashes, such as erythema nodosum, erythema multiforme, toxic erythema, and arthralgias.

Signs of synovitis, bony tenderness, osteomyelitis, meningitis, hydrocephalus, lymphadenopathy, and abdominal masses or tenderness may indicate a coccidioidal infection. Other systemic organ involvements include the following:

• Skin

   

  • A wide variety of rashes, including maculopapular lesions, erythema multiforme, and erythema nodosum, may develop.

     

  • The development of erythema nodosum is an indicator of a good prognosis.

   

• Pulmonary

   

  • Bronchitis, bronchiolitis, reactive airways disease, pneumonia, and pleural effusions may develop.

     

  • Frank empyemas and bronchopleural fistulas are possible.

   

• Musculoskeletal

   

  • One third of patients with dissemination have musculoskeletal involvement.

     

  • Bone lesions are unifocal in 60% of cases, and joint lesions are unifocal in 90% of cases.

     

  • Multiple lesions or vertebral lesions are associated with a poor prognosis.

   

• Central nervous system

   

  • Acute or chronic meningitis is possible.

     

  • Acute hydrocephalus may be the first sign of disseminated coccidioidomycosis.

Laboratory studies

The 2 tests used to diagnose pulmonary coccidioidomycosis are sputum cultures and serum coccidioidal antibody tests.

• Sputum culture

   

  • The isolation of C immitis from a sputum specimen establishes the diagnosis.

     

  • The identification of spherules in the direct examination of sputum also is diagnostic, but this is less sensitive than a culture finding.

     

  • The organism usually grows within 5 days on most routine microbiologic media.

     

  • A negative culture finding does not rule out coccidioidomycosis.

   

• Coccidioidal antibody tests

   

  • Two serologic tests are available to detect immunoglobulin (IgG) antibodies: the precipitin test (TP) and the complement fixation (CF) test.

     

  • A negative antibody test result does not rule out the disease.

Preferred Examination: Chest radiography is readily available and 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.

Asymptomatic patients may have normal chest radiographic findings, and a normal result generally excludes significant clinical disease. The chest radiographic findings may progress from single or multiple areas of air space consolidation to formation of nodules or cavities, which may further progress to diffuse reticulonodular lung disease and to upper-lobe scarring.

In a patient who is either living or has visited an endemic area, the chest radiographic findings described in the following sections is highly suggestive of thoracic coccidioidomycosis. The diagnosis must be established by means of cultures, histopathologic examination, or serologic tests.

Limitations of Techniques: Chest radiographic findings alone are not diagnostic of thoracic coccidioidomycosis because other infectious diseases and neoplastic processes may mimic coccidioidomycosis.

DIFFERENTIALS

Blastomycosis, Thoracic
Histoplasmosis, Thoracic
Lung Cancer, Non-Small Cell
Lung Cancer, Small Cell
Lung, Metastases
Lung, Nontuberculous Mycobacterial Infections
Lung, Postprimary Tuberculosis
Lung, Primary Tuberculosis
Lymphangitic Carcinomatosis
Pneumonia, Atypical Bacterial
Pneumonia, Typical Bacterial
Pneumonia, Viral
Sarcoidosis, Thoracic

Other Problems to be Considered:

Other fungal infections
Lymphoma
Other causes of cough, fever, and fatigue
Old granuloma

X-RAY

Findings: Asymptomatic patients may have normal chest radiographic findings. Images may depict a small calcified granuloma and, rarely, areas of lung scaring or pleural thickening.

Primary pulmonary coccidioidomycosis

The thoracic manifestations of primary infection include parenchymal disease, intrathoracic adenopathy, and pleural effusion.

Parenchymal consolidation is the most common manifestation seen in 75% of patients. The segmental or subsegmental consolidation is single or multiple, usually unilateral and in perihilar or basal distribution. These may resolve spontaneously within 1-2 weeks.

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

In approximately 20% of patients, hilar adenopathy is present. This is usually unilateral and concomitant with parenchymal lesions. Mediastinal adenopathy is seen with severe and prolonged infection and is associated with a higher risk for dissemination.

Pleural effusion is seen in less than 20% of patients, although pleuritic chest pain occurs more frequently (50-75%), as determined clinically. The effusion is usually small, although a massive effusion in children may suggest more severe disease, and it may even represent evidence of acute dissemination.

Scattered patchy infiltrates called persistent coccidioidal pneumonia is a less common presentation and may require as long as 1-2 months to resolve. Hilar lymphadenopathy is present in about 20% of primary infections. Pleural thickening or small pleural effusion may be present in 20% of patients with coccidioidomycosis. Pleural effusion may occur without parenchymal or lymph node involvement.

Persistent or chronic pulmonary coccidioidomycosis

Approximately 5% may develop a persistent pulmonary disease when the primary disease is present for longer than 6 weeks. 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 suggestive of an antecedent acute primary pulmonary coccidioidal illness.

Persistent coccidioidal pneumonia generally occurs in a severely ill patient with dense extensive consolidation. Depending on the size of 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, as in two thirds of cases.

Chronic progressive coccidioidal pneumonia occurs in less than 1% of patients and clinically and radiographically mimics chronic pulmonary tuberculosis or histoplasmosis. However, patients with this finding 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.

Pulmonary nodules from coccidioidomycosis 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 are usually well circumscribed and round, with average size of 1.5-2 cm. They are usually single and tend to occur in the periphery of middle and upper lung zones. In contrast to those in tuberculosis, these nodules may develop in the anterior segment of an upper lobe. These nodules may remain stable for months and eventually regress; only rarely is slow growth is observed.

Calcification in coccidioidoma is much less frequent in comparison to 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% were malignant (Read, 1972).

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.

Cavities

Cavities may develop as a result of necrosis in an area of pneumonia or excavation of a nodule. Those formed by means of excavation have been reported in 10-15% of patients. Usually, these appear singly and are located in the upper lobes. They may have thin or thick walls; thin-walled cavities have a tendency to change in size, which possibly reflects check-valve communication with the bronchial tree.

A rapid change in the size of a cavity suggests coccidioidal infection rather than any other granulomatous infection. A single asymptomatic thin-walled cavity is probably more common than other types. Most of the cavities close spontaneously in 2 years, although some may remain stable in size, but they are not known to produce disseminated disease. Rarely, these cavities may be colonized by Aspergillus organisms and develop a mycetoma. The cavities may wax and wane over the years. A subpleural cavity may also break down into the pleural cavity, causing a pneumothorax, pyopneumothorax, or bronchopleural fistula.

Bronchiectasis may occur in 1-2% of patients with chronic disease. Endobronchial coccidioidal infection can be present in rare cases, or bronchial stenosis from scaring may be evident. Calcified residual lesions in the lungs and lymph nodes contain viable organism and are a potential source for dissemination.

Disseminated pulmonary coccidioidomycosis

Disseminated coccidioidomycosis may occur as a complication of primary illness, a late complication of chronic coccidioidomycosis or the reactivation of latent disease in susceptible individuals. Dissemination of infection occurs hematogenously to both 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. In white patients meningitis is commonly present, and in black patients, lymph node or subcutaneous abscess are commonly associated with disseminated disease.

The radiographic manifestations of dissemination include a miliary pattern that resembles miliary tuberculosis, although the nodules in coccidioidomycosis are less well defined. Hilar and mediastinal adenopathy is almost always associated with disseminated disease. Lung biopsy is usually required for diagnosis. The differential diagnosis for the miliary pattern includes tuberculosis, other mycotic infections, silicosis, sarcoidosis and metastatic disease. Pericardial involvement may lead to pericardial effusion, cardiac tamponade, or constrictive pericarditis.

Degree of Confidence: All chest radiographic patterns of thoracic coccidioidomycosis can occur with several other disease processes.

False Positives/Negatives: 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; however, confirmation with another diagnostic test is mandatory. The chest radiographic patterns of coccidioidomycosis have a broad differential diagnosis; careful clinical evaluation and workup is recommended to exclude other disorders.