Definitions of the levels of evidence (I-III) and grades of recommendation (A-E) are provided at the end of the "Major Recommendations" field.
Primary Respiratory Infection
Primary infections due to Coccidioides species most frequently manifest as community-acquired pneumonia 1 to 3 weeks after exposure. Distinguishing coccidioidomycosis from other etiologies is usually difficult without specific laboratory confirmation, such as detection of anticoccidioidal antibodies in serum samples or identification of Coccidioides species in sputum samples or another respiratory specimen. Therefore, residents of and recent travelers to regions where community-acquired pneumonia is endemic should be evaluated for Coccidioides species as a possible etiologic agent. Coccidioides species are listed by the Centers for Disease Control and Prevention (CDC) as Select Agents, and their growth in culture requires handling in a secure and contained fashion.
Uncomplicated Acute Coccidioidal Pneumonia
How best to manage primary respiratory coccidioidal infections is an unsettled issue because of the lack of prospective controlled trials. For many (if not most) patients, management may rely on periodic reassessment of symptoms and radiographic findings to assure resolution without antifungal treatment. On the other hand, some authorities propose treatment of all symptomatic patients to decrease the intensity or duration of symptoms. Although physicians speculate that early treatment may decrease the frequency or severity of dissemination, there are no data to support this speculation (C-III). Several special circumstances are usually considered to warrant initiation of therapy. Chief among these is concurrent immunosuppression, such as that which accompanies acquired immune deficiency syndrome (AIDS), receipt of an organ transplant, therapy with high-dose corticosteroids, or receipt of inhibitors of tumor necrosis factor (TNF) (such as etanercept or infliximab). Also, other patients who are likely to handle pulmonary coccidioidal infection less well include those with diabetes mellitus or preexisting cardiopulmonary disease (A-II). The diagnosis of primary infection during pregnancy, especially in the third trimester or immediately postpartum frequently prompts the initiation of treatment (A-III). During pregnancy, amphotericin B is the treatment of choice because fluconazole (and likely other azole antifungals) are teratogenic (A-III). Persons of Filipino or African descent have a higher risk for dissemination, and this may also be taken into consideration (B-III). Finally, patients who are judged to have exceptionally severe primary infections may be more likely to benefit from treatment than those patients with a more mild illness. Although opinion varies as to the most-relevant factors for judging severity of illness, commonly used indicators include weight loss of >10%, intense night sweats persisting longer than 3 weeks, infiltrates involving more than one-half of one lung or portions of both lungs, prominent or persistent hilar adenopathy, anticoccidiodial complement-fixing antibody concentrations in excess of 1:16 (as determined by a reference method or equivalent titer), inability to work, symptoms that persist for >2 months, or age >55 years. Commonly prescribed therapies include currently available oral azole antifungal agents at dosages of 200 to 400 mg per day. Courses of typically recommended treatment range from 3 to 6 months.
As the patient's illness improves, either with or without antifungal therapy, continued monitoring at 1 to 3-month intervals for 1 year or longer is advised to assess the resolution of pulmonary infiltrates and to identify, as early as possible, those patients who develop infection outside of the chest. Monitoring usually should include patient interviews, physical examinations (as appropriate), serologic tests, and radiographic examinations. Determining pulmonary lesions that evolve into residual nodules is useful because it obviates the need for establishing the nodule's etiology at a future time. Identifying dissemination is accomplished with histologic examination and culture of suspicious skin lesions, analysis of aspirates of joint effusions, and lumbar puncture of patients who develop progressively severe or persistent headaches, mental status changes, or other meningeal signs. Although extrapulmonary dissemination is infrequent, early detection of patients in whom dissemination does occur would afford benefit by earlier initiation of treatment and a resulting reduction in tissue destruction.
Diffuse Pneumonia
Bilateral reticulonodular or military infiltrates produced by Coccidioides species suggest either an underlying immunodeficiency state with concurrent fungemia or an exposure to a high inoculum of fungal spores, as may occur as a result of laboratory accidents or at archeology sites. In such patients, therapy is usually begun either with amphotericin B or high-dose fluconazole. Amphotericin B is more frequently used as initial therapy if significant hypoxia is present or if deterioration is rapid (A-III). Several weeks of therapy are often required to produce clear evidence of improvement. After this time, during convalescence, amphotericin B therapy may be discontinued and replaced with treatment with an oral azole antifungal (B-III). In combination, the total length of therapy should be at least 1 year, and for patients with severe immunodeficiency, oral azole therapy should be continued as secondary prophylaxis (A-III). Because diffuse pneumonia due to Coccidioides species is usually a manifestation of fungemia, patients should be evaluated for the possibility of other extrapulmonary lesions that may also require attention.
Pulmonary Nodule, Asymptomatic
If a stable solitary nodule is determined to be due to Coccidioides species by noninvasive means or by fine-needle aspiration, specific antifungal therapy, or resection is unnecessary (E-II). Similarly, in the absence of significant immunosuppression, antifungal therapy is not recommended if the lesion is completely resected and the diagnosis is determined from the excised tissue. Stability can be determined by repeated radiographic examination of the chest for 2 years demonstrating no change in the size of the nodule. Should enlargement of the nodule occur, reevaluation with sputum cultures and measurement of coccidioidal serum antibodies may help to determine whether the patient's infection is active and warrants therapy. Consideration also should be given to the possibility of cancer coexistent with the coccidioidal infection, in which case resection of the nodule would usually be necessary.
Pulmonary Cavity
Asymptomatic
Many cavities caused by Coccidioides species are benign in their course and do not require intervention. Such cavities harbor viable fungus, and cultures of samples of sputum or other respiratory secretions commonly yield colonies of Coccidioides species. Most authorities do not consider these characteristics of asymptomatic cavities sufficient reason to initiate treatment. Moreover, in the absence of controlled clinical trials, evidence is lacking that antifungal therapy has a salutary effect on the course of asymptomatic coccidioidal cavities (B-III). With the passage of time, some cavities disappear, obviating the need for intervention. Although an indefinite follow-up period without intervention is appropriate for many patients, eventual resection from 1 to several years after the cavity is identified may be recommended to avoid future complications, especially if the cavity is still detectable after 2 years, if it demonstrates progressive enlargement, or if it is immediately adjacent to the pleura (B-III).
Symptomatic
Complications of coccidioidal cavities include local discomfort, superinfection with other fungi or possibly bacteria, or hemoptysis. Should these complications occur, oral therapy with azole antifungals may result in improvement, although recurrence of symptoms, (at least in some patients), may occur on cessation of therapy. If a bacterial superinfection is present, treatment for several weeks with an oral antibacterial may also reduce symptoms. However, such therapies usually do not result in the closure of the cavity. In cases in which the surgical risks are not unusually high, resection of localized cavities is likely to resolve the problem and may be recommended as an alternative approach to chronic or intermittent therapy.
Ruptured
Rupture of a coccidioidal cavity into the pleural space, resulting in a pyopneumothorax, is an infrequent but serious complication of a necrotizing coccidioidal pneumonia. In young, otherwise-healthy patients, surgical closure by lobectomy with decortication is the preferred management (A-II). Antifungal therapy is recommended for treatment, particularly in cases with delay of diagnosis and coexistent diseases (C-III). For patients for whom the diagnosis was delayed a week or more or for patients in whom there are coexistent diseases, management approaches are less uniform and may include courses of therapy with amphotericin B or oral azole antifungal drugs prior to surgery, or chest tube drainage without surgery (C-III).
Chronic Progressive Fibrocavitary Pneumonia
Initial treatment with oral azole antifungal agents is recommended (A-II). If the patient improves sufficiently, therapy should be continued for at least 1 year. If therapy is not satisfactory, switching to an alternative azole antifungal, raising the dosage of the azole, or therapy with amphotericin B are alternative strategies (B-III). Surgical resection may be a useful option for refractory lesions that are well localized or in cases in which significant hemoptysis has occurred.
Disseminated Infection (Extrapulmonary)
Nonmeningeal
Initial therapy is usually initiated with oral azole antifungal agents, most commonly fluconazole or itraconazole (A-II). Clinical trials have used 400 mg per day of ketoconazole, itraconazole, or fluconazole. Some experts recommend higher dosages (up to 2000 mg per day of fluconazole; up to 800 mg per day of itraconazole, administered in 200-mg doses) (B-III). Amphotericin B is recommended for alternative therapy, especially if lesions are appearing to worsen rapidly and are in particularly critical locations, such as the vertebral column (B-III). Amphotericin B dosage is similar to that for diffuse coccidioidal pneumonia, although the duration of therapy may be longer. In patients experiencing failure of conventional deoxycholate amphotericin B therapy or experiencing intolerable drug-related toxicities, lipid amphotericin B formulations have been demonstrated to be safe and to cause less nephrotoxicity and may be considered. Animal model studies have indicated that the higher amphotericin B dosages that can be given via lipid formulations produce results superior to those seen with the maximally tolerated deoxycholate amphotericin B. However, there have been no clinical trials assessing the efficacy of lipid formulations of amphotericin B.
Combination therapy with amphotericin B and an azole has been administered to some patients, especially when infection is widespread or in cases in which there has been disease progression during treatment with a single agent. Although combination therapy may improve responses, there is no evidence that such an approach is superior to treatment with a single agent, and for other fungal infections, there are examples of antagonism with combination therapy, as has been demonstrated in vitro with Coccidioides species.
Surgical debridement or stabilization is an occasionally important, if not critical, adjunctive measure. Factors that favor a recommendation for surgical intervention are large size of abscesses, progressive enlargement of abscesses or destructive lesions, presence of bony sequestrations, instability of the spine, or impingement on critical organs (such as a pericardial effusion on the heart) or tissues (such as an epidural abscess on the spinal cord).
Meningitis
Therapy with oral fluconazole is currently preferred by most clinicians. The dosage used in reported clinical trials was 400 mg per day (A-II). Some physicians begin therapy with 800 or 1000 mg per day of fluconazole (B-III). Itraconazole, administered in dosages of 400 to 600 mg per day has also been reported to be comparably effective (B-II). Some physicians also initiate therapy with intrathecal amphotericin B in addition to an azole on the basis of their belief that responses are more prompt with this approach. The dose and duration of intrathecal amphotericin B in this circumstance ranges between 0.1 mg and 1.5 mg per dose (C-III). Patients who respond to azole therapy should continue this treatment indefinitely (A-III). Hydrocephalus nearly always requires a shunt for decompression (A-III). Hydrocephalus may develop regardless of the therapy being used and need not require switching to alternative therapy (B-III). Patients who do not respond to fluconazole or itraconazole would be candidates for intrathecal amphotericin B therapy with or without continuation of azole treatment. The intrathecal dosage of amphotericin B normally ranges between 0.1 and 1.5 mg per dose, administered at intervals ranging from daily to weekly, beginning at a low dosage and increasing the size of the dosage until the appearance of patient intolerance (indicated by severe vomiting, prostration, or transient dose-related mental status).
The most common life-threatening complication of coccidioidal meningitis in the modern era is central nervous system (CNS) vasculitis leading to cerebral ischemia, infarction, and hemorrhage. Some physicians have personal experience demonstrating the efficacy of administering high-dose, intravenous, short-term corticosteroids for this condition, whereas other physicians have not noted similar benefit.
Prophylaxis for Coccidioidomycosis in Solid-Organ Transplant Recipients
The risk of coccidioidomycosis among solid-organ transplant recipients in an area of endemicity was 4% to 9%, with the majority of infections occurring within 1 year after transplantation. Because infection in such patients frequently disseminates and carries a high risk of mortality, there is interest in reducing the number of these complications in patients from or within the regions of endemicity by use of preemptive prophylactic antifungal therapy. One transplantation program in the area of endemicity has employed a strategy of targeted prophylaxis, whereby patients with certain risk factors for coccidioidomycosis (a positive serological test result prior to receipt of a transplant or a history of coccidioidomycosis) receive prophylactic fluconazole at the time of transplantation, and thus far, the results are encouraging.
Management of Patients Infected with HIV-1
Before the introduction of highly active antiretroviral therapy (HAART), coccidioidomycosis was a major opportunistic infection in the area of endemicity among individuals infected with human immunodeficiency virus (HIV)-1. The incidence of clinically apparent coccidioidal infection has since decreased. Prevention of coccidioidomycosis among HIV-1-infected patients living in the area of coccidioidal endemicity by prophylactic use of an antifungal is not effective for most patients. Treatment is recommended for all patients with HIV-1 infection and peripheral blood CD4+ lymphocyte counts <250 cells/microL who have clinically active coccidioidomycosis. Therapy should be continued as long as the CD4+ cell count is <250 cells/microL. However, it may be reasonable to stop therapy in those patients with higher CD4+ cell counts if there is clinical evidence of control of the coccidioidal infection (except for patients with meningitis, for whom therapy should be life-long).
Definitions:
Quality of Evidence
- Evidence from >1 properly randomized, controlled trial
- Evidence from >1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time-series; or from dramatic results of uncontrolled experiments
- Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees
Strength of Recommendation
- Good evidence to support a recommendation for use; should always be offered
- Moderate evidence to support a recommendation for use; should generally be offered
- Poor evidence to support a recommendation; optional
- Moderate evidence to support a recommendation against use; should generally not be offered
- Good evidence to support a recommendation against use; should never be offered
