INTRODUCTION — Coccidioidomycosis is caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Since these species are not distinguishable based on clinical presentation or through routine microbiologic testing, the fungus will henceforth be referred to as Coccidioides. These organisms are endemic to certain arid regions of the Western Hemisphere. Infection is usually acquired by inhalation, and primary pulmonary infection frequently goes unrecognized. Dissemination of infection beyond the lungs occurs in a small number of cases, although the precise incidence is unknown. An overview of the different manifestations of coccidioidomycosis is found in the table (table 1).

The manifestations and treatment of nonmeningeal, disseminated, extrathoracic coccidioidomycosis will be reviewed here. Primary pulmonary infection, laboratory diagnosis, pulmonary sequelae, coccidioidal meningitis, and infection in immunocompromised hosts are discussed separately:

●(See "Primary pulmonary coccidioidal infection".)

●(See "Coccidioidomycosis: Laboratory diagnosis and screening".)

●(See "Management of pulmonary sequelae and complications of coccidioidomycosis".)

●(See "Coccidioidal meningitis".)

●(See "Coccidioidomycosis in immunocompromised and pregnant persons".)

INCIDENCE OF DISSEMINATED INFECTIONS — By definition, dissemination is coccidioidal infection that is clinically apparent outside the thoracic cavity. Infection of the pleural cavity, as may occur in a ruptured coccidioidal cavity, is not considered disseminated disease. However, some clinicians feel that diffuse pulmonary disease is a manifestation of dissemination. (See "Primary pulmonary coccidioidal infection", section on 'Pulmonary manifestations'.)

The estimated risk of dissemination has varied from approximately 4.7 percent of recognized infections during an epidemic exposure [1] to 0.2 percent of all coccidioidal respiratory infections (both symptomatic and asymptomatic) [2]. It is likely that the number is <1 percent of all infections. Patient groups at increased risk for extrathoracic infection include those who are:

●Of African or Filipino ancestry, particularly men

●Pregnant women who contract coccidioidal infection during and after the second trimester

●Those who have suppressed cellular immunity, including those with advanced HIV-1 infection, transplantation recipients, and those receiving chronic immunosuppressive medications such as glucocorticoids

PATHOGENESIS — Coccidioidomycosis may manifest clinically beyond the initial pulmonary lesion to other parts of the body. Extrathoracic dissemination appears to be the result of hematogenous spread of the organism. While there is also local lymphatic spread from pulmonary infection, it is not established that this results in disease outside the thorax.

CLINICAL MANIFESTATIONS — When extrathoracic dissemination occurs, it is usually evident within weeks to months after the initial exposure. Thus, it is not uncommon for dissemination to be clinically apparent at the time infection is first diagnosed [3]. In patients who do not receive treatment for early coccidioidal infection, disseminated disease occurring six months to one year after initial infection is very uncommon. However, in patients who have received early antifungal treatment, there are reports of delayed presentation of dissemination until up to two years after treatment is stopped [4].

The nature of the symptoms depends upon the exact location and number of individual lesions. The most common sites of disseminated lesions are [5-8]:

●Skin or subcutaneous soft tissue – Skin or subcutaneous soft tissue involvement includes cutaneous granulomatous lesions, subcutaneous soft tissue abscesses (picture 1), and supraclavicular adenopathy.

●Skeleton

•Joint involvement – Disseminated coccidioidomycosis frequently involves only a single joint (eg, knee, wrist, or ankle). Monoarticular infection of the knee is the most common, with a presentation that mimics a degenerative or traumatically injured joint.

•Vertebral infection – For patients with vertebral infection, lesions may be single or multiple, occasionally involving the sacrum and ileum. Unlike bacterial vertebral osteomyelitis, coccidioidal infection may occur in the vertebral body without involvement of the end plate and adjacent disk space. Radionuclide bone scans are useful to identify possible areas of infection [9]. Magnetic resonance imaging (MRI) with gadolinium enhancement can be especially helpful in defining the extent of individual lesions [10]. (See 'Diagnosis' below.)

In some cases when multiple vertebral lesions are present, there may be no other identified lesions of disseminated infection. This suggests either a predilection for vertebral osteomyelitis in certain patients, a tropism for the spine among certain strains of Coccidioides, or spread to the vertebrae through venous channels of Batson's plexus.

●Meninges of the brain and spinal cord – Of all sites of dissemination, meningitis is the most uniformly serious and poses special problems in management that are addressed separately. (See "Coccidioidal meningitis".)

●Other sites – Other sites of dissemination that occur less frequently include the endocrine glands [11,12], the eye [13-15], the liver [16], the kidneys [17,18], the genital organs [19-23], the prostate [24,25], and the peritoneal cavity [26]. Rarely, lesions have been noted in the subserosal intestines, the heart and pericardium, and the urinary bladder. In children, mediastinitis with radiographic evidence of lymph node purulence and abscess has been reported [27] and is considered, by some, a manifestation of dissemination.

Symptoms of extrathoracic coccidioidomycosis are often indistinguishable from infection due to other pathogens, cancer, or degenerative processes. Because of the indolent nature of the infection and lack of specificity of symptoms, the diagnosis of extrathoracic coccidioidomycosis is frequently delayed by weeks or even months. This is especially true if the initial pulmonary infection has not been recognized.

DIAGNOSIS

Initial evaluation — For patients with suspected extrathoracic coccidioidomycosis, the initial evaluation includes serologic testing and imaging of clinically suspicious areas. Testing for serum or urine antigen can also be useful in this situation (table 1) [28,29]. A detailed discussion of diagnostic testing is found elsewhere. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Diagnostic tests'.):

We image specific anatomic sites as directed by findings on clinical examination. Imaging studies to detect deep lesions include nuclear scintigraphy, computed tomography (CT) scan, and magnetic resonance imaging (MRI). The latter two are preferred as they provide far more detail. The role of performing imaging in persons without clinically evident dissemination is unclear.

Confirming the diagnosis — The diagnosis of disseminated coccidioidomycosis should be confirmed by identifying Coccidioides in one or more sites outside the chest, either by visualizing spherules in histopathology specimens or by culture of a lesion in the affected organ. A possible exception to obtaining tissue is when the lesions are deemed too difficult or too unsafe for biopsy and the patient has demonstrable destructive lesions on imaging and positive coccidioidal serologic results. Although patients with disseminated coccidioidal infection generally have complement-fixing antibody titers of 1:16 or greater, an elevated complement-fixing antibody titer without demonstrable extrathoracic lesions is not sufficient to diagnose disseminated infection. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Recovery of Coccidioides from clinical specimens'.)

MANAGEMENT — The management of nonpregnant patients with nonmeningeal extrathoracic infection will be reviewed here. Special considerations regarding the management of pregnant women are discussed elsewhere. (See "Coccidioidomycosis in immunocompromised and pregnant persons".)

General principles — Nearly all patients with disseminated infections should be treated with antifungal therapy. An exception may include children with isolated skin lesions. (See 'Disease-specific recommendations' below.)

Approach to treatment — Our general approach to treatment is as follows:

●We administer itraconazole or fluconazole for initial therapy in nonpregnant patients who present with extrathoracic nonmeningeal coccidioidomycosis and are without lesions that pose an emergency. Other azoles, such as posaconazole, voriconazole, and isavuconazole, may be useful in patients who cannot tolerate the recommended azole agents and in those who have refractory disease that is neither rapid nor life-threatening. The choice of azole, as well as the dose and duration, depend in part upon the site of infection. (See 'Disease-specific recommendations' below and 'Choice of azole' below.)

●Amphotericin B should be administered to patients with azole failure and/or those who have severe disease, particularly when the disease is rapidly progressive or located in a critical anatomic location, such as the spine. It is also the treatment of choice for pregnant women during the first trimester. (See 'Management of pregnant women' below.)

●Surgical debridement or stabilization is important and even critical as adjunctive treatment in some cases. (See 'Determining the need for surgery' below.)

There are no trials comparing amphotericin B with triazole therapy. The decision to use an azole rather than amphotericin B for most patients with extrathoracic disease is based upon the observed efficacy of these agents in uncontrolled studies [30,31] and the reduced toxicity of azoles compared with amphotericin B. The use of amphotericin B instead of an azole for more severe disease is based upon expert opinion that amphotericin B may exert an antifungal effect more quickly [32]. There are no comparative trials of deoxycholate amphotericin B versus lipid formulations for the treatment of coccidioidomycosis, and either formulation is appropriate. However, there is an emerging preference to use liposomal amphotericin B because of reduced renal toxicity [33] and evidence of increased efficacy in other fungal infections [34,35]. This approach is consistent with guidelines published by Infectious Diseases Society of America (IDSA) [32].

Because cellular immunity is important in the immune control of coccidioidal infection, there has been interest in using interferon-gamma for patients with disseminated infection or other serious complications. Although case reports suggest the use of interferon alone, or in combination with other immunomodulatory agents, may lead to clinical improvement [36-38], the efficacy of this approach has not been proven.

Choice of azole — In general, we suggest fluconazole or itraconazole for initial therapy of extrathoracic coccidioidomycosis. Although several prospective studies support the use of either agent [39-41], limited data suggest that itraconazole may have some advantage over fluconazole, especially in the setting of bone and joint disease, as described in the study below [41]. However, the potential improved efficacy has to be tempered with other issues. As an example, itraconazole is not routinely absorbed in all patients, making a serum level imperative. In addition, its use may be associated with hypokalemia and hypertension [42], as well as decreased cardiac inotropy [43]. There may also be cost considerations, since some insurance providers are more likely to approve fluconazole than itraconazole for the treatment of coccidioidomycosis. Additional considerations in immunocompromised hosts at high risk for drug interactions are presented elsewhere. (See "Coccidioidomycosis in immunocompromised and pregnant persons".)

The efficacy of itraconazole (200 mg twice daily) and fluconazole (400 mg once daily) in patients with nonmeningeal extrathoracic coccidioidomycosis was evaluated in a randomized, blinded trial of 191 patients with progressive coccidioidal infections (chronic pulmonary, soft tissue, or skeletal lesions) [41]. After eight months of therapy, there was a nonsignificant increase in the number of patients who responded to itraconazole compared with fluconazole (63 versus 47 percent). In a secondary analysis, most of the apparent difference in response rates occurred in patients with skeletal lesions, in whom 52 percent receiving itraconazole responded compared with only 26 percent among those receiving fluconazole. In this trial, relapse rates following the completion of 12 months of itraconazole or fluconazole were 18 and 28 percent, respectively. However, relapse rates might be even higher than those recorded, since many responding patients continued therapy off protocol. Moreover, a subanalysis indicated that patients continuing therapy were more likely to have had prior relapses, higher serologic titers, and greater extent of disease. An additional discussion of relapse after treatment discontinuation is found below. (See 'Risk of relapse after treatment' below.)

There is less experience with the newer triazole azoles, such as posaconazole and voriconazole; however, they appear to be effective in patients who fail to respond to other azoles [7,44-50]. In an open-label study of 15 patients with chronic refractory coccidioidomycosis, posaconazole (800 mg/day in divided doses) produced a complete response in four and a partial response in seven [47]. The sites of involvement included lungs, bones, joints, skin, soft tissue, lymph nodes, central nervous system, eye, and heart valves. Similar findings were noted in a series of 20 patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis who were treated with a different formulation of posaconazole that is not commercially available [44]. Voriconazole has also been used in patients with coccidioidomycosis, especially those with refractory infections. In a review of disseminated coccidioidal infections, some patients were managed successfully with voriconazole treatment [7]. Similarly, a retrospective study that included 21 patients who received voriconazole for the treatment of refractory coccidioidomycosis found that many, but not all, patients experienced improvement [45]. There are very limited data describing the use of isavuconazole in coccidioidomycosis [51,52].

A more detailed discussion of the different azoles is found in a separate topic review. (See "Pharmacology of azoles".)

Management of pregnant women — Pregnant women with extrathoracic coccidioidomycosis should be managed in conjunction with an infectious disease specialist. The approach to treatment during pregnancy depends upon fetal maturity and can be complex. Amphotericin B is the treatment of choice for pregnant women during the first trimester. Azole antifungals are contraindicated during the first trimester because of the risk of teratogenicity. Triazole therapy may be reasonable for the treatment of coccidioidomycosis after that time. A more detailed discussion of the management of pregnant women is found in a separate topic review. (See "Coccidioidomycosis in immunocompromised and pregnant persons", section on 'Pregnancy'.)

Disease-specific recommendations

Soft tissue infection without bone involvement — An oral triazole antifungal (fluconazole 400 mg once daily or itraconazole 200 mg twice daily) is appropriate for most nonpregnant patients with skin and soft tissue infection. The choice of azole is discussed above. (See 'Choice of azole' above.)

The duration of treatment is generally 6 to 12 months but may be longer. Relapses after therapy can occur. (See 'Risk of relapse after treatment' below.)

Amphotericin B formulations should be used for those lesions that, because of their anatomic location, pose an emergency. An example of this might be a peritracheal abscess threatening to obstruct the airway (see 'Retropharyngeal abscess' below). Patients can be switched to oral therapy to complete the course when clinically stable.

For patients with disease refractory to either fluconazole or itraconazole, either posaconazole or voriconazole can be considered when disease is neither rapid nor life-threatening. Isavuconazole is another possible consideration, but data are limited for its use in coccidioidomycosis. In rare cases of triazole refractory disease, an amphotericin B formulation is the only option.

Bone and joint infection

Antifungal therapy — All patients with bone and joint infection require antifungal therapy. In addition, certain patients with vertebral disease may require surgical intervention as well.

●For most nonpregnant patients, an oral triazole is appropriate. As discussed above, data suggest that itraconazole (200 mg twice daily) may be superior to fluconazole in this setting [41,53]. (See 'Choice of azole' above.)

●If fluconazole is used, doses higher than 400 mg daily are typically employed (eg, 800 mg once daily).

●For patients with severe bone and/or joint disease, such as limb-threatening skeletal disease or vertebral infection causing imminent cord compromise, we initiate amphotericin B. We generally prefer a lipid formulation, such as liposomal amphotericin B at 3 to 5 mg/kg intravenously per day. We administer amphotericin B therapy daily for at least 10 days. After that, the dose of amphotericin B can be reduced to three times weekly. We continue that dose until the most serious lesions have started to improve.

We combine a triazole antifungal (eg, itraconazole 200 mg orally twice daily) with the amphotericin B, unless pharmacologic factors or untoward reactions weigh against that choice. Based on clinical observations, combined therapy with a triazole and amphotericin B appears to speed recovery and simplify the transition to triazole therapy alone. There is no evidence for antagonism in this situation.

The triazole agent should be continued after the course of amphotericin B is completed. The duration of antifungal treatment for patients with bone and joint infections is prolonged and should be individualized based on response to therapy. Courses of treatment with triazole antifungals are usually continued for several years and, in some cases, are lifelong, since relapse following the discontinuation of treatment can never be excluded. (See 'Risk of relapse after treatment' below.)

Determining the need for surgery — For patients with bone and joint infection, optimal management may require combined medical and surgical interventions. However, it is frequently difficult to determine the need for surgery. Examples of our approach in certain settings include:

●Monoarticular arthritis – Monoarticular arthritis can be an unexpected diagnosis at the time of arthroscopy. The infection may be limited completely to the synovium, and, in such cases, antifungal treatment without surgical intervention is often quite effective in completely resolving the signs and symptoms of infection.

●Vertebral osteomyelitis – We obtain surgical consultation for most patients with vertebral coccidioidal infection to help assess the need for surgical intervention. The management of these lesions is especially important because of their potential impact on the spinal cord and mobility. For those with evidence of cord impingement, immediate surgical decompression is usually recommended.

Patients who do not require initial surgery should be followed closely on treatment. Subsequent management depends upon the evolution of lesions as evidenced by symptoms, neurologic examination, and repeated magnetic resonance imaging (MRI), which should generally be obtained within one or two months. For progressive lesions, surgical options are reconsidered. For those that are stable or show improvement, medical management alone is continued with repeated MRI at progressively longer intervals.

Less common manifestations — Because of the diversity of possible locations and severity of coccidioidal lesions, guidelines cannot address all of the various situations that might be seen. The following specific examples have been commonly encountered by clinicians practicing within the endemic area and provide illustrative examples of treatment approaches.

Supraclavicular adenopathy — One or more involved supraclavicular lymph nodes may be evident at the time of diagnosis. Patients with supraclavicular adenopathy are usually treated in a similar fashion to those with disseminated skin and soft tissue lesions. (See 'Soft tissue infection without bone involvement' above.)

Although these lymph nodes usually resolve with antifungal therapy, surgical resection may be required in some cases.

The presence of enlarged supraclavicular nodes probably represents lymphatic drainage from the lung rather than hematogenous spread. However, the fact that infection has spread to involve the supraclavicular region suggests exceptional progression of infection along the lymphatic chain, indicating that host defenses are not effectively limiting the infection to the lungs.

Retropharyngeal abscess — Retropharyngeal abscesses occur, but most likely represent extension of cervical osteomyelitis rather than lymphangitic spread from the mediastinum. Initial therapy with amphotericin B is often administered in this setting given the risk of airway compromise.

Solitary cutaneous lesions in children — A single small skin lesion is occasionally biopsied or excised and found on histopathology to be the result of coccidioidal infection. Most clinicians would recommend antifungal therapy in adults based upon this finding alone. However, in an otherwise healthy child with no other evidence of disseminated infection, some pediatricians familiar with coccidioidomycosis have elected to observe the patient closely rather than initiate therapy.

Prostatic infection — Occasional patients have been discovered to have asymptomatic coccidioidal infection of the prostate. Such infections are usually discovered during the evaluation of an elevated serum prostate-specific antigen level, or less commonly during a fine needle biopsy of a palpable prostatic nodule. For patients with prostatic infection, the approach to treatment depends upon how the infection is identified.

For patients who are diagnosed using serology or fine needle biopsy, we typically follow them without treatment and monitor them with periodic office visits and coccidioidal serologies yearly or twice yearly. To date, none of the prostatic lesions have become symptomatic, nor has any patient developed a new lesion elsewhere.

By contrast, if coccidioidal involvement of the prostate is discovered as the result of a transurethral or radical prostatectomy, the greater anatomic disruption of these procedures compared with a fine needle biopsy greatly increases the risk of subsequent complications from the infection. In these situations, antifungal therapy with fluconazole (400 mg daily) or itraconazole (200 mg twice daily) would be appropriate [54]. The length of such therapy is unclear and should be at least six months and directed by change in serologic titer.

Monitoring — Monitoring the complement fixation titer is an important tool in assessing response to treatment. In general, this test should be repeated about every 12 weeks while on therapy with subsequent monitoring for at least one year after antifungal therapy is stopped [55]. An increasing titer suggests increasingly active disease. (See 'Risk of relapse after treatment' below.)

Patients should also be monitored for toxicity related to antifungal therapy, and those receiving itraconazole should have levels measured. (See "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of azoles", section on 'Itraconazole'.)

Risk of relapse after treatment — Antifungal agents suppress but do not eradicate coccidioidal infection; thus, there is potential for relapse once treatment is discontinued in patients who respond to therapy. In the trial comparing fluconazole and itraconazole treatment described above, relapse rates following the completion of 12 months of therapy were 28 and 18 percent, respectively [41]. However, these relapse rates are likely underestimates, because many treating providers were unwilling to stop treatment at the end of the study. (See 'General principles' above.)

Most relapses occur at the site of previously identified lesions rather than at new sites. Although it is reasonable to discontinue therapy at least once for most patients, some clinicians may elect to continue treatment indefinitely if the site of the initial lesion is particularly critical, because a recurrence, even if detected early, might be deleterious to the patient. In some instances, surgical extirpation of a focus of coccidioidal infection may prevent subsequent relapses. (See 'Bone and joint infection' above.)

Certain immunocompromised hosts (eg, transplant recipients who remain on immunosuppressive therapy) may require antifungal therapy indefinitely. Additional information on the management of immunocompromised hosts is presented elsewhere. (See "Coccidioidomycosis in immunocompromised and pregnant persons", section on 'Principles of treatment in immunocompromised patients'.)

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

●Coccidioidomycosis is caused by the dimorphic fungi Coccidioides, which is endemic to certain arid regions of the Western Hemisphere. Infection is usually acquired by inhalation, and primary pulmonary infection frequently goes unrecognized. (See 'Introduction' above and 'Incidence of disseminated infections' above.)

●Dissemination of infection beyond the lungs can occur. Disseminated infection frequently becomes evident within weeks and usually within six months after the initial exposure if antifungal therapy has not been given. Extrathoracic dissemination is usually the result of hematogenous spread. (See 'Pathogenesis' above and 'Clinical manifestations' above.)

●The most common sites of disseminated lesions are skin, subcutaneous soft tissue, meninges, and skeleton. (See 'Clinical manifestations' above.)

•Skin, subcutaneous, and skeletal lesions typically become evident in a subacute or chronic fashion. The timing and nature of the symptoms depends upon the exact location and number of individual lesions.

•Of all sites of dissemination, meningitis is the most serious and poses special problems in management, which are addressed in a separate topic review. (See "Coccidioidal meningitis".)

●For patients with suspected extrathoracic coccidioidomycosis, the initial evaluation includes serologic testing and imaging of suspected areas. Serum or urine antigen testing may also be helpful. The diagnosis of disseminated infection should almost always be confirmed with a biopsy demonstrating evidence of Coccidioides outside the chest. (See 'Diagnosis' above.)

●In general, for nonpregnant patients who present with extrathoracic nonmeningeal coccidioidomycosis and are without lesions that pose an emergency, we recommend initial therapy with fluconazole or itraconazole rather than amphotericin (Grade 1C). Itraconazole may have some advantage over fluconazole, especially in the setting of bone and joint disease. However, data are limited, and the potential improved efficacy has to be tempered with other issues, such as drug interactions and the need to monitor drug levels. (See 'Management' above.)

●Initial therapy with amphotericin B is typically reserved for individuals who have rapidly progressive disease or have lesions that could cause significant compromise. Such patients should be concurrently treated with triazole antifungal therapy (eg, itraconazole 200 mg orally twice daily), which is then continued after the course of amphotericin B is completed. Amphotericin B is also used for pregnant women in the first trimester and those who have failed azole therapy. (See 'Management' above.)

●The approach to treatment of coccidioidomycosis during pregnancy depends upon fetal maturity and can be complex given the potential risk of teratogenicity with azole agents and the risk of toxicity with amphotericin B. This is discussed in detail elsewhere. (See "Coccidioidomycosis in immunocompromised and pregnant persons", section on 'Pregnancy'.)

●Most patients with nonmeningeal extrathoracic coccidioidomycosis can be treated with antifungal therapy alone. However, for certain patients (eg, those with vertebral involvement causing cord compression), surgical debridement or stabilization may be important as adjunctive treatment. (See 'Bone and joint infection' above.)

●The duration of therapy depends upon the site of infection. Treatment can range from 6 to 12 months for soft tissue infections to lifelong therapy if the site of the initial lesion is particularly critical. (See 'Disease-specific recommendations' above.)

●Monitoring of the complement fixation titer is an important tool in assessing response to treatment. In general, this test should be repeated about every 12 weeks while on therapy. Serologic monitoring should continue for at least one year if antifungal therapy is stopped, since there is potential for relapse once treatment is discontinued. (See 'Risk of relapse after treatment' above.)

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