Version May 2024
INTRODUCTION — Approximately two-thirds of people experience few or no symptoms following coccidioidal infection. Those who become ill usually present with cough, pleuritic chest pain, fever, night sweats, rash, and weight loss one to three weeks after exposure; these symptoms generally resolve over the ensuing several months [1,2]. Fatigue, one of the common manifestations of the primary infection, may be especially prolonged and slow to resolve.
Most infections are self-limited without complications or additional events whether the primary exposure is recognized or not. However, occasional patients have persistent pulmonary consequences of coccidioidomycosis that require medical and/or surgical management. These include residual pulmonary nodules, coccidioidal cavities, and persistent fibrocavitary pulmonary disease.
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 — Historically, 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]. With widespread use of computed tomography (CT) imaging, residual nodules are likely to be much more common. These pulmonary nodules range from millimeters to several centimeters in diameter and may be solitary or multiple.
Confirming the diagnosis — Residual coccidioidal nodules are not a problem in and of themselves and require no treatment. The issue is determining whether they are due to coccidioidomycosis. In many cases, these nodules are discovered incidentally and can be difficult to distinguish from malignancy.
Testing to ascertain if a nodule is coccidioidal versus malignancy includes:
●Additional radiographic imaging – If residual pulmonary nodules are discovered incidentally, a first step is to see if there are any prior chest imaging studies to look for a previously detected lesion. If there are no available prior images, follow-up imaging can be done in three to six months in patients at low risk for lung cancer. Coccidioidal nodules are generally stable and do not increase in size with time. Assessing for the uptake of fluorodeoxyglucose by positron emission tomography (PET) with computed axial tomography (PET/CT) is discouraged since coccidioidal nodules are frequently positive and the degree of uptake overlaps with that of malignancies [4].
●Serology – Testing for anticoccidioidal antibodies may be useful. A positive result might suggest that the lung lesion represents coccidioidomycosis, because these tests become negative in most patients whose pulmonary lesions completely resolve. However, standard tests for anticoccidioidal antibodies are negative in 30 to 65 percent of patients with coccidioidal nodules [5,6]. In addition, a positive serologic test does not completely 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 biopsied and undergo histologic examination and culture (picture 1A-B and picture 2A-C). Biopsy can be by percutaneous aspiration [7] or by transbronchial biopsy. The use of endobronchial ultrasonography in conjunction with bronchoscopy has improved the ability to successfully identify the etiology of pulmonary nodules [8]. All these methods may result in pneumothorax or bleeding and, because the biopsy sample is small, miss the area of abnormality.
If such procedures are not possible or are unsuccessful, then the nodule can be surgically biopsied. Resection of nodules can 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 [6] but may also be complicated by pneumothorax, bleeding, and other complications. (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".)
Management of patients with residual infection who become immunocompromised and are at increased risk for reactivation is discussed elsewhere. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)
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 include 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 radiograph. 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 radiographs 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 radiographs are often sufficient for assessment without the need for multiple 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 pleuritic chest pain, increasing cough, particularly if productive, and hemoptysis should be further evaluated. A CT scan of the chest without contrast is appropriate and bacterial and fungal cultures of respiratory secretions should be obtained. Cavities may become secondarily infected, either with oral bacterial flora, environmental fungi, such as Aspergillus species, or even by the mycelial form of Coccidioides growing in the cavity. Such infections are often manifested by the development of fluid within the cavity.
●For asymptomatic patients whose cavity persistently enlarges, oral triazole therapy with either fluconazole or itraconazole is appropriate since this can result in reduction of the size or closure of the cavity [9]. The optimal treatment duration is not established.
Surgical resection is sometimes indicated for patients in the following scenarios:
●Persistent or recurrent symptoms after a three- to six-month trial of azoles
●Persistent hemoptysis
●Increased size of cavity despite antifungal treatment
●Systemic intolerance to azole therapy
Resection is also a reasonable alternative in an individual who is hesitant or unwilling to commit to long-term azole therapy.
Although surgical resection may be curative, it can be technically difficult depending on the inflammatory reactivity of the infection. If the lesion is peripheral, there can be extensive adhesions within the pleura. More central and acutely inflamed lesions may have a significant area of inflamed lung surrounding the cavity, which is generally underappreciated on CT scan. This often mandates large wedge resections and potentially 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 into the pleural space. Once ruptured, complications for resection and treatment become significantly higher [6]. There are no data regarding whether antifungal therapy prevents such rupture; therefore, we do not treat cavities based on whether they are pleural based.
When rupture does occur, a bronchopleural fistula and contamination of the pleural space occur. Abrupt onset of 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 [10]. They are also seen more frequently in patients with underlying diabetes mellitus that is not well controlled.
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 a minor part of management [10].
If the diagnosis is delayed for one week or more, the morbidity and mortality of the rupture and the interventions increase significantly [6]. 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 an attempt at resection; in this case, chest tubes will be required for a longer time. 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, diabetes mellitus, or immunosuppression are significantly more likely to develop this complication [11,12].
In general, patients with fibrocavitary coccidioidomycosis are often symptomatic with night sweats, fatigue, and weight loss, in addition to pulmonary symptoms, such as chest pain, hemoptysis, sputum production, and dyspnea. Radiographically, the changes are extensive, including a complex mixture of infiltrates, fibrosis, and cavitation [12].
Symptomatic patients with chronic fibrocavitary pneumonia should undergo treatment, usually with a prolonged course of oral antifungal triazoles [2]. A randomized trial of 198 patients with chronic pulmonary, soft tissue, or skeletal coccidioidal infections directly compared fluconazole (400 mg orally once daily) and itraconazole (200 mg orally twice daily) [13]. The two drugs were equivalent in the overall analysis and in the subset with chronic pulmonary infections (eg, response in 63 and 66 percent, respectively, at 12 months).
Posaconazole has been less well studied but has shown promise in a small open-label trial [14], and as salvage therapy in patients with chronic pulmonary coccidioidomycosis [15,16]. 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 [16].
Amphotericin B can be used for refractory infections but is rarely necessary in these cases. (See "Primary pulmonary coccidioidal infection", section on 'Moderate 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 5th to 6th 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 10th to 12th 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
●Pulmonary sequelae of coccidioidomycosis – Most patients who acquire coccidioidomycosis 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 – Residual pulmonary nodules usually have no clinical consequences and require no treatment. If residual pulmonary nodules are discovered incidentally, prior chest imaging 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.)
●Coccidioidal pulmonary cavities
•Thin-walled cavities – Residual thin-walled cavities are typically asymptomatic and usually require no treatment. Periodic imaging may be used to monitor residual cavities. Treatment is initiated if symptoms, such as persistent cough, pleuritic chest pain, or hemoptysis, occur. Such symptoms often improve with a trial of 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 triazole therapy, as well as in those who have cavity growth despite antifungal treatment. (See 'Thin-walled cavities' above.)
•Ruptured cavities – 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.)
●Chronic fibrocavitary pneumonia – 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. (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.
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