Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis

INTRODUCTION — Coccidioidomycosis is caused by the dimorphic fungus Coccidioides. Based on genomic analysis [1], it consists of two species, Coccidioides immitis and Coccidioides posadasii. However, these species are not distinguishable on either clinical presentation or through routine microbiologic testing. The fungus is endemic to certain regions of the Western Hemisphere, and infection is usually acquired by inhalation of airborne arthroconidia. Most cases are recognized as pulmonary infection, and infection beyond the thoracic cavity occurs in a small number of cases. An overview of the different manifestations of coccidioidomycosis is found in the table (table 1).

The manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis will be reviewed here. Primary pulmonary infection, laboratory diagnosis, pulmonary sequelae, coccidioidal meningitis, and management considerations, screening, and prevention in immunocompromised hosts and pregnant patients 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 "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

DEFINITION AND INCIDENCE OF DISSEMINATED INFECTIONS

Definition of extrathoracic coccidioidomycosis — Extrathoracic coccidioidomycosis is coccidioidal infection that is clinically apparent outside the thoracic cavity. Infection of the pleura or pleural space, as may occur in a ruptured coccidioidal cavity, is not considered disseminated disease. However, some clinicians feel that diffuse or reticulonodular pulmonary disease is a manifestation of dissemination since it is frequently associated with fungemia [2]. Extrapulmonary immunologic manifestations of primary pulmonary coccidioidomycosis, such as diffuse arthralgias or rashes, are also not considered manifestations of extrathoracic dissemination. (See "Primary pulmonary coccidioidal infection", section on 'Signs and symptoms'.)

Incidence and risk factors for disseminated infection — The risk of dissemination has been estimated to be 0.2 percent of all coccidioidal infections, including those with symptomatic and asymptomatic infection [3], but is likely higher in epidemic settings [4]. Patient groups at increased risk for extrathoracic dissemination include those who are:

●Of African or Filipino ancestry, particularly males

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

●Those who have suppressed cellular immunity, including (but not limited to) those with advanced human immunodeficiency virus (HIV) infection, transplant recipients, and those receiving chronic immunosuppressive medications such as glucocorticoids and anti-cytokine therapies (see "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Immunocompromised patients')

PATHOGENESIS — In most instances, extrathoracic dissemination appears to be the result of hematogenous spread of the organism and generally occurs early in the disease course. While there is also local lymphatic spread from pulmonary infection resulting in enlarged supraclavicular nodes, it is not established that this commonly results in disease outside the thorax [5]. Nevertheless, 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.

CLINICAL MANIFESTATIONS

Spectrum of disease — When extrathoracic dissemination occurs, it is usually evident within weeks to months after the initial exposure. Often, dissemination is clinically apparent at the time infection is first diagnosed [6]. In patients who do not receive treatment for early coccidioidal infection, disseminated disease occurring six or more months after initial infection is uncommon. However, in patients who have received early antifungal treatment, there are reports of delayed presentation of dissemination up to two years after treatment is stopped [7].

The nature of the symptoms depends upon the location and number of lesions. Although extrathoracic dissemination may affect nearly every organ system [8], the most common anatomic sites of disseminated lesions include skin and soft tissues, genital tract, peritoneum, and the central nervous system. In the immunocompromised host, extrathoracic disseminated coccidioidal lesions may occur more commonly and in less common anatomic sites, such as inguinal lymph nodes and the liver [9,10]. As an example, in renal transplant recipients without antifungal prophylaxis, approximately three-quarters of diagnosed infections result in extrathoracic lesions, more than 50-fold higher than in immunocompetent populations [11]. Patients with HIV and CD4 counts <250 cells/microL can also present with fever and weight loss without any clear organ involvement in association with a positive coccidioidal serology [12,13].

Symptoms of extrathoracic coccidioidomycosis may be indistinguishable from infection due to other granulomatous 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. This is especially true if the initial pulmonary infection has not been recognized.

Skin and subcutaneous soft tissue — Skin or subcutaneous soft tissue involvement includes cutaneous granulomatous lesions, subcutaneous soft tissue abscesses (picture 1), and extrathoracic lymphadenopathy. Cutaneous coccidioidomycosis often presents with a persistent papule or verrucous lesion that may ulcerate.

Bone and joints — Coccidioides spp can affect joints, tendons, as well as bone.

●Joint and tendon involvement – Articular coccidioidomycosis is usually monoarticular and may involve any joint, although the knee is most commonly involved. It usually presents in a subacute manner, with persistent localized pain and swelling of the involved joint. Other commonly involved joints include the ankles, wrists, and hips. It may be associated with contiguous osteomyelitis. Arthrocentesis reveals a lymphocytic pleocytosis, and complement-fixation antibody titer is often higher than in serum.

●Bone involvement – In one survey, the most common sites of coccidioidal osteomyelitis were the hand and wrist, pelvis, and knee [14]. Other sites include the elbow, calcaneum, and sternum, but any bone may be involved. Patients present with swelling and pain overlying the involved bone. In chronic cases, there may be development of a fistulous tract with purulent drainage.

Infection of the axial skeleton is a special case. It usually involves the lumbar spine [15]. In contrast to bacterial vertebral osteomyelitis, infection generally begins within the vertebral body and without involvement of the end plate and adjacent disk space. In severe cases, axial coccidioidomycosis can result in vertebral collapse and nerve impingement.

Genital tract — In males, epididymal infection manifests as unilateral scrotal swelling, induration, and tenderness. Prostatic infection may present with urinary obstruction or prostatic tenderness. Occasionally, patients are asymptomatic and diagnosis is made incidentally during biopsy or surgical removal of the prostate. Female genital tract coccidioidomycosis is uncommon. It may present as a granulomatous endometritis, an adnexal mass, or as an extension of peritoneal disease [16,17].

Peritoneum — Coccidioidal infection to the peritoneum may occur through lymphatic spread rather than hematogenously. It usually presents with dull abdominal pain and increasing abdominal girth. An antecedent clinical history of pulmonary coccidioidomycosis occurs in fewer than half of the patients [10]. Imaging frequently reveals ascites with a thickened peritoneum, similar to peritoneal carcinomatosis or peritoneal tuberculosis [18].

Central nervous system — Of all sites of dissemination, meningitis is the most uniformly serious and poses special problems in management. It is addressed separately. (See "Coccidioidal meningitis".)

Other sites — Other less frequent sites of dissemination include the eye [19-21] and the pericardium [22], but almost any anatomic site may be involved [23].

DIAGNOSIS

Initial evaluation — For patients with suspected extrathoracic coccidioidomycosis, the initial evaluation includes serologic testing and imaging of clinically suspicious areas. Although less sensitive than antibody testing, obtaining serum or urine antigen may also be useful in this situation to help add to diagnostic certainty when biopsy is either unable to be performed or is negative for coccidioides (table 1) [24-26]. 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 history or findings on clinical examination. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are preferred imaging modalities although positron emission tomography (PET)/CT can also identify sites of dissemination [27]. MRI with gadolinium enhancement can be especially helpful in defining the extent of individual lesions in vertebral osteomyelitis [28]. 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 spp in one or more sites outside the thoracic cavity, 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; in such situations, empiric treatment for nonconfirmed infection must be monitored to assure efficacy.

An elevated complement-fixing antibody titer without demonstrable extrathoracic lesions is not sufficient to diagnose disseminated infection, as it can often be seen in pulmonary coccidioidal disease [29]. Because of this, the diagnosis of extrathoracic disseminated coccidioidomycosis depends on identification of Coccidioides spp outside of the thoracic cavity. (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 females and immunocompromised individuals are discussed separately. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Management considerations for special populations'.)

Approach to treatment — Nearly all patients with disseminated infections should be treated with antifungal therapy; an exception may be children with isolated skin lesions, although any decisions not to treat should be made after consultation with a pediatric infectious disease specialist familiar with managing coccidioidal disease. Surgical debridement or stabilization may be critical as adjunctive treatment in some cases, particularly when there is vertebral involvement. If left untreated, patients can develop severe infection, including limb-threatening skeletal disease, vertebral infection causing cord compromise, and airway obstruction due to paratracheal abscess. (See 'Determining the need for surgery' below.).

Mild to moderate disease — For patients with extrathoracic nonmeningeal coccidioidomycosis who are clinically stable and do not have lesions that pose an emergency, we suggest the use of fluconazole or itraconazole. Other triazole antifungals, such as voriconazole, posaconazole, 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 triazole depends upon many issues, including the site of infection, cost, availability, adverse effects, and drug-drug interactions. Because of this, all triazole antifungal agents are appropriate therapy and we cannot recommend one over another at this time. The triazole dose and duration of therapy depend upon the site of infection. (See 'Issues related to certain clinical manifestations' below.)

Early prospective studies support the use of either fluconazole or itraconazole [30,31]. However, data from a comparative trial comparing fluconazole to itraconazole for nonmeningeal coccidioidomycosis suggest that patients who received itraconazole may have a higher response rate compared with fluconazole (63 versus 50 percent), especially in the setting of bone and joint disease (52 versus 26 percent). Moreover, relapse rates after discontinuation were lower but not statistically significant with itraconazole compared with fluconazole (18 versus 28 percent) [32]. However, the potential improved efficacy should be tempered with other issues. Itraconazole is not routinely absorbed in all patients, making a serum level imperative. In addition, its use may be associated with hypokalemia and hypertension [33], as well as decreased cardiac inotropy [34]. There may also be cost and insurance considerations. Additional considerations, such as increased risk for drug interactions, are presented elsewhere. (See "Pharmacology of azoles", section on 'Drug interactions'.)

There is less experience with the newer triazole antifungals voriconazole, posaconazole and isavuconazole. However, both voriconazole and posaconazole appear to be effective in patients who fail to respond to other either fluconazole or itraconazole therapy [35]. An older formulation of posaconazole was shown to produce both complete and partial responses in patients who were refractory to prior antifungal therapy [36]. The newer delayed release posaconazole formulation also appears to be effective. Similarly, a study of isavuconazole, conjugated as isavuconazonium, demonstrated efficacy in refractory cases of nonmeningeal coccidioidomycosis [37].

There are no trials comparing amphotericin B with triazole antifungal therapy. The decision to use a triazole rather than amphotericin B for patients with mild extrathoracic disease is based upon the observed efficacy of these agents and their reduced toxicity compared with amphotericin B.

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

Severe or refractory disease — For patients with severe extrathoracic nonmeningeal coccidioidomycosis (eg, clinically unstable, rapidly progressive disease, lesions in critical anatomic locations such as the spine) or those who have not improved with azole therapy, we suggest liposomal amphotericin B along with a triazole antifungal. Although the combination of amphotericin B plus triazoles has been suggested to be antagonistic for some fungal infections [38], this is not the case in candidiasis [39] and not the clinical experience in coccidioidomycosis. Because of this, we advocate using the combination in cases of severe coccidioidomycosis. Once the patient is clinically improving (usually after one to three weeks of therapy), we transition to triazole monotherapy. (See 'Mild to moderate disease' above.)

There are no trials comparing amphotericin B with triazole antifungal therapy. The use of amphotericin B in combination with a triazole for more severe disease is based upon expert opinion that amphotericin B may exert an antifungal effect more quickly. 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 [40] and evidence of increased efficacy in other fungal infections [41,42]. Trials in patients with HIV-1 infection and cryptococcosis [43] and histoplasmosis [44] have suggested that a single dose of 10 mg/kg liposomal amphotericin B is not inferior to standard courses of liposomal amphotericin B. There are no data regarding this in coccidioidomycosis and it is not currently recommended.

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 gamma, alone or in combination with other immunomodulatory agents, may lead to clinical improvement [45-47], the efficacy of this approach has not been generally established.

Management aspects specific to immunocompromised and/or pregnant individuals are discussed separately. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Management considerations for special populations'.)

Issues related to certain clinical manifestations — Because of the diversity of possible locations and severity of coccidioidal lesions, guidelines cannot address all 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.

Soft tissue infection without bone involvement — An oral triazole antifungal (fluconazole 400 mg once daily or itraconazole 200 mg twice daily with food) is appropriate for most patients with skin and soft tissue infection. The duration of treatment is generally 6 to 12 months but may be longer, especially in immunocompromised individuals. Relapses after therapy can occur. (See 'Risk of relapse after treatment' below.)

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.

●Mild to moderate bone and/or joint disease – For patients with nonsevere bone and/or joint disease, an oral triazole antifungal (preferably itraconazole) is appropriate. Data suggest that itraconazole (200 mg twice daily with food) may be superior to fluconazole in this setting. In a study of 50 patients with coccidioidal bone and/or joint infection, 52 percent of patients receiving itraconazole had clinical response to therapy compared with 26 percent of patients receiving fluconazole, although the difference was not statistically significant [32]. Moreover, relapse rates after discontinuation were lower for itraconazole. If fluconazole is used, some experts recommend doses higher than 400 mg daily (eg, 800 mg once daily), although data are lacking to support this recommendation.

●Severe bone and/or joint disease – 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 plus a triazole antifungal (eg, itraconazole 200 mg orally twice daily). We prefer a lipid formulation, such as liposomal amphotericin B at 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.

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 months to 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.)

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.

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 orthopedic or neurosurgical 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 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.

Supraclavicular lymphadenopathy — We treat supraclavicular adenopathy with an oral triazole antifungal (fluconazole 400 mg once daily or itraconazole 200 mg twice daily with food) for 6 to 12 months. Although lymphadenopathy usually resolves with antifungal therapy, surgical resection may be required in some cases. Relapses after therapy can occur.

Prostatic infection — For patients with prostatic infection, the approach to treatment depends upon how the infection is identified.

For asymptomatic 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. Generally, these prostatic lesions do not become symptomatic, and the patients do not go on to develop new lesions elsewhere.

If coccidioidal involvement of the prostate is discovered as the result of a transurethral or radical prostatectomy, the greater anatomic disruption by 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) is appropriate [48]. Duration of therapy should be at least 6 months in immunocompetent patients and at least 12 months in immunocompromised patients. Decision to stop treatment should be directed by change in serologic titer.

In contrast to the above, patients presenting with clinical symptoms of genital tract involvement (eg, prostatitis, testicular or epididymal swelling) require prolonged courses of triazole antifungal therapy [49].

Monitoring — We monitor patients every 12 weeks with clinical evaluation, appropriate imaging, and the complement-fixation titer for the duration of therapy and for at least one to two years after treatment has completed [50]. The complement-fixation titer is an important tool in assessing response to treatment; 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, voriconazole, and posaconazole should have therapeutic drug monitoring. (See "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

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 [32]. However, these relapse rates are likely underestimates, because many treating providers were unwilling to stop treatment at the end of the study.

Almost all 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 with nonmeningeal coccidioidomycosis, some clinicians elect to continue treatment indefinitely if the site of the initial lesion is particularly critical, because a repeat 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 "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Secondary prevention'.)

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".)

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SUMMARY AND RECOMMENDATIONS

●Definition and incidence of disseminated infections – Extrathoracic coccidioidomycosis is coccidioidal infection that is clinically apparent outside the thoracic cavity. The risk of dissemination is low, but certain groups are at increased risk (eg, immunocompromised individuals, pregnant individuals in their second or third trimester, and those of African or Filipino descent). (See 'Introduction' above and 'Definition and incidence of disseminated infections' above.)

●Pathogenesis – Infection is usually acquired by inhalation, causing primary pulmonary infection. Dissemination of infection beyond the thoracic cavity may occur. Extrathoracic dissemination is usually the result of hematogenous spread. (See 'Pathogenesis' above.)

●Clinical manifestations – Disseminated infection frequently becomes evident within weeks and usually within six months after the initial exposure if antifungal therapy has not been given. The most common sites of disseminated lesions are skin, subcutaneous soft tissue, meninges, and skeleton. (See 'Clinical manifestations' above.)

●Diagnosis – 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 spp outside the chest. (See 'Diagnosis' above.)

●Antifungal therapy

•Mild to moderate disease – For nonpregnant patients who present with extrathoracic nonmeningeal coccidioidomycosis and are without lesions that pose an emergency, we suggest initial therapy with fluconazole or itraconazole rather than amphotericin B (Grade 2C). 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 'Mild to moderate disease' above.)

•Severe disease – For nonpregnant patients who present with rapidly progressive disease or lesions that could cause significant organ compromise, we suggest combination therapy with amphotericin B plus a triazole (Grade 2C). Once the patient is clinically stable, amphotericin B can be stopped and triazole monotherapy continued for the rest of the treatment duration. (See 'Severe or refractory disease' above.)

●Adjunctive surgical intervention – 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 'Determining the need for surgery' above.)

●Duration of therapy – 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 'Management' above.)

●Monitoring and risk of relapse – 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 'Monitoring' above and '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.