INTRODUCTION — Approximately two-thirds of people experience few or no symptoms following respiratory exposure to arthroconidia of Coccidioides spp. Those who become ill typically develop symptoms, such as cough, pleurisy, fever, and weight loss, one to three weeks after exposure; these symptoms generally resolve over the ensuing several months [1,2]. Marked fatigue, one of the common manifestations of the primary infection, may be especially prolonged and slow to resolve.

Whether or not the primary exposure is recognized, most infections are self-limited without additional events or complications. However, occasional patients have persistent pulmonary consequences of coccidioidomycosis that require medical and/or surgical management. These include residual pulmonary nodules, coccidioidal cavities, and diffuse reticulonodular pneumonia.

The clinical manifestations and management of these sequelae will be reviewed here. Primary and disseminated coccidioidomycosis are discussed separately. (See "Primary pulmonary coccidioidal infection" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Coccidioidal meningitis".)

RESIDUAL PULMONARY NODULES — In approximately 4 percent of patients with primary coccidioidal pneumonia, infiltrates do not completely resolve and radiographic findings may persist for months to years following the disappearance of symptoms [3]. These pulmonary nodules range up to several centimeters in diameter, are often solitary, and are frequently located in the periphery of the lung, close to or abutting the pleura.

Confirming the diagnosis — A residual nodule usually poses no problems and requires no treatment if it is known to be the consequence of an initial coccidioidal infection. However, in many cases, coccidioidal nodules are discovered incidentally and can be difficult to distinguish from malignancy.

Testing to differentiate a residual nodule versus malignancy includes:

●Additional radiographic imaging – If residual pulmonary nodules are discovered incidentally, prior chest radiographs should be obtained to look for a previously detected lesion to assess stability. Uptake of fluorodeoxyglucose by positron emission tomography with computed axial tomography is frequently positive in coccidioidal nodules and may not assist in distinguishing these from malignant lesions [4].

●Serology – Testing for anti-coccidioidal antibodies may be useful. A positive result might suggest that the lung lesion represents coccidioidomycosis, since these tests become negative in most patients whose pulmonary lesions completely resolve. However, standard tests for anti-coccidioidal antibodies are negative in more than 65 percent of patients with coccidioidal nodules [5]. In addition, a positive serologic test does not exclude the possibility that the pulmonary lesion is due to malignancy. (See "Coccidioidomycosis: Laboratory diagnosis and screening".)

If malignancy cannot be excluded, the nodule should be sampled for microscopic examination and culture, either by percutaneous aspiration [6] or by transbronchial biopsy. Percutaneous aspiration of coccidioidal pulmonary nodules does not pose a significant risk of creating a granulomatous track to the skin or reactivating clinical disease within the lesion.

If such procedures are not possible or are unsuccessful, then the nodule should be surgically resected in order to perform histopathological examination, including stains for fungal organisms and culture (picture 1A-B and picture 2A-C). Resection of nodules can most often be accomplished by a minimally invasive approach using thoracoscopy and typically involves en bloc resection of the lesion and margin of normal lung (picture 3). The thoracoscopic approach has a low morbidity and short hospital stay [7]. (See "Overview of minimally invasive thoracic surgery", section on 'Types of pulmonary resection'.)

More detailed discussions of the evaluation of a patient with a pulmonary nodule is found elsewhere. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

Indications for antifungal therapy — Once the diagnosis has been established, further treatment of a residual coccidioidal nodule in an otherwise asymptomatic patient is typically unnecessary.

However, reactivation of residual infection can occur due to lesion disruption in the setting of incomplete surgical resection. This may lead to formation of a local abscess or fistula. Although there are no published data on how to manage incomplete resection, one approach is to treat the patient postoperatively with an oral antifungal agent such as fluconazole (400 mg once daily) or itraconazole (200 mg twice daily) for three to six months to reduce the chances of local complications. (See "Pharmacology of azoles".)

If local complications occur, antifungal treatment, with or without local debridement, is reasonable. Optimal management may require consultation with infectious disease specialists and thoracic surgeons familiar with this problem.

COCCIDIOIDAL CAVITIES — The pulmonary sequelae of primary coccidioidal infection includes the development of cavities. Half of these cavities will resolve within the first two years, and many are asymptomatic.

Thin-walled cavities — The inflammatory pulmonary process that develops during the initial coccidioidal infection results in areas of infarction that leads to cavitation in some patients. A cavity can also occur when a previously stable coccidioidal nodule liquefies and erodes into a bronchiole. These cavities often have the same dimensions as the original nodule.

Residual cavities are commonly solitary and peripheral in location on chest x-ray. Their walls are often thin with little or no discernible surrounding infiltrate. In the absence of symptoms, treatment is not recommended. Since it is possible for coccidioidal cavities to change appearance, repeat chest x-rays at intervals ranging from six months to two years are helpful to determine whether the lesion is enlarging or regressing. Sequential posterior-anterior and lateral chest x-rays are often sufficient for assessment without the need for multiple computed tomography (CT) scans.

The management of thin-walled cavities depends upon the host and the presence or absence of symptoms.

●We do not administer antifungal therapy to most immunocompetent patients who are asymptomatic [2]. Such patients should be monitored periodically (every one to two years) to evaluate the size of the lesion and the presence of other complications, such as bacterial or fungal superinfection.

●Patients who develop symptoms such as pleural discomfort and hemoptysis, as well as those who are immunocompromised, should be treated with oral antifungal agents (eg, fluconazole or itraconazole) for at least one year [2]. If symptoms recur after stopping, subsequent retreatment for longer periods or even indefinitely might be needed.

●For asymptomatic patients whose cavity persistently enlarges, fluconazole 400 mg daily is reasonable. The optimal treatment duration is not established.

Surgical resection is rarely indicated because of the efficacy of oral azoles. However, resection is reasonable for young, otherwise healthy patients whose symptoms persist or recur after a two-year trial of azoles, as well as those who have cavity growth despite antifungal treatment.

Although surgical resection may be curative, it can be technically difficult. If the lesion is peripheral, there are often extensive adhesions within the pleura. More central and more acutely inflamed lesions will have a significant area of inflamed lung surrounding the cavity, which is generally underappreciated on CT scan. This often mandates large wedge resections and even lobectomy to obtain an adequate margin to allow stapling in an area of relatively normal parenchyma. Careful attention must be paid not to enter or rupture the cavity since this can lead to spread throughout the pleural space and possible empyema. In general, minimally invasive surgery is an option for these more complicated resections, although the experience of the surgeon is an important consideration.

Ruptured cavities — Despite their frequent proximity to the pleura, it is rare for coccidioidal cavities to rupture out into the pleural space. Moreover, there are no data regarding whether antifungal therapy prevents such rupture. Thus, we do not treat cavities based on whether they are pleural based.

When rupture does occur, a bronchopleural fistula and contamination of the plural space occurs. Dyspnea and chest pain are the most common manifestations. Ruptured coccidioidal cavities are most frequent in young, otherwise healthy, athletic males and are not associated with immunosuppression [8]. They are also seen more frequently in patients with underlying diabetes.

In approximately half of patients with ruptured cavities, symptoms associated with rupture are the first symptoms of the coccidioidal infection. A pneumothorax with associated effusion/air-fluid level is frequently seen on upright chest imaging and is useful to distinguish this problem from a spontaneous pneumothorax (image 1). (See "Treatment of secondary spontaneous pneumothorax in adults".)

If a ruptured coccidioidal cavity is diagnosed, the preferred therapy is prompt decortication and surgical resection of the cavity. More proximally located cavities may require a lobectomy due to the surrounding inflammation, and decortication to facilitate re-expansion of the remaining lung. Oral antifungal therapy with fluconazole (400 mg daily) is commonly administered in conjunction with the surgery, but is likely the minor part of management if the surgery is successful [8].

If the diagnosis is delayed for one week or more, the morbidity and mortality of the rupture and the interventions increase significantly [7]. Surgical repair becomes a greater technical challenge with delayed diagnosis and resection may not be possible due to inflammation and infection. In this case, consideration should be given to decortication without attempt at resection, accepting the need for longer term chest tubes. With oral antifungal therapy, many cavities will respond to the point that the air leak resolves and chest tubes can be removed.

CHRONIC FIBROCAVITARY PNEUMONIA — On occasion, primary coccidioidal pneumonia does not resolve and evolves into a chronic pulmonary process. Patients with underlying lung disease or diabetes and immunocompromised patients are significantly more likely to develop this complication [9,10].

It can be difficult to distinguish between patients with a symptomatic cavity and those with chronic fibrocavitary pneumonia. In general, fibrocavitary pneumonia is characterized by the presence of systemic symptoms (eg, night sweats, fatigue, and weight loss), in addition to pulmonary symptoms, such as chest pain, hemoptysis, sputum production, and/or shortness of breath. Patients also have more extensive and complex radiographic abnormalities, which can show complex mixtures of infiltrates, fibrosis, and cavitation.

Most patients with chronic fibrocavitary pneumonia are symptomatic and therefore require treatment, usually with oral antifungal azoles for at least one year [2]. A randomized trial of 198 patients with chronic pulmonary, soft tissue, or skeletal coccidioidal infections directly compared fluconazole (400 mg PO once daily) and itraconazole (200 mg PO twice daily) [11]. The two drugs were equivalent in the overall analysis and in the subset with chronic pulmonary infections (eg, response in 63 and 66 percent at 12 months).

Posaconazole has been less well studied but has shown promise in a small open-label trial [12], and as salvage therapy in patients with chronic pulmonary coccidioidomycosis [13,14]. A small retrospective study of patients receiving voriconazole or posaconazole for the treatment of refractory coccidioidomycosis found that many (but not all) patients treated with one of these agents experienced improvement [14].

Amphotericin B can be used for refractory infections. (See "Primary pulmonary coccidioidal infection", section on 'Severe disease'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Coccidioidomycosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Valley Fever (coccidioidomycosis) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Almost all patients exposed to the arthroconidia of Coccidioides spp are asymptomatic or develop symptoms that are self-limited. The occasional pulmonary consequences of coccidioidomycosis include residual pulmonary nodules, coccidioidal cavities, chronic and progressive fibrocavitary pneumonia, and diffuse reticulonodular pneumonia. (See 'Introduction' above.)

●Residual pulmonary nodules usually have no clinical consequences and require no treatment. If residual pulmonary nodules are discovered incidentally, prior chest x-rays should be obtained to look for a previously detected lesion to assess stability, and serologies for anti-coccidioidal antibodies should be sent. If malignancy cannot be excluded, the nodule should be sampled for histopathological examination and culture. (See 'Residual pulmonary nodules' above.)

●Residual thin-walled cavities are typically asymptomatic and usually require no treatment. Periodic imaging may be used to monitor residual cavities. Treatment is generally initiated if symptoms, such as pleural discomfort and hemoptysis, occur. Such symptoms often improve when treated with oral antifungal agents (eg, fluconazole or itraconazole), but relapse may be seen when treatment is discontinued. Oral antifungal therapy is also reasonable in asymptomatic patients whose cavity persistently enlarges. Surgical resection may be necessary in patients whose symptoms persist or recur after a two-year trial of azoles, as well as in those who have cavity growth despite antifungal treatment. (See 'Thin-walled cavities' above.)

●If a cavity ruptures, a bronchopleural fistula and pleural contamination results. If promptly diagnosed, surgical resection of the cavity is the preferred approach. If the diagnosis is delayed for one week or more, surgical resection becomes increasingly challenging with a much higher risk of complications; decortication without resection but with long-term chest tubes should be considered. (See 'Ruptured cavities' above.)

●For patients who develop chronic fibrocavitary pneumonia, we treat with oral antifungal azoles for at least one year. Fluconazole (400 mg once daily) and itraconazole (200 mg twice daily) appear to be equivalent in efficacy. Amphotericin B can be used for refractory infections unresponsive to oral therapy. (See 'Chronic fibrocavitary pneumonia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Shari Meyerson, MD, and John Galgiani, MD, who contributed to an earlier version of this topic review.