DEFINITION AND ETIOLOGY
Coccidioidomycosis, commonly known as valley fever, is caused by the dimorphic soil-dwelling fungus Coccidioides. Genetic analysis has demonstrated the existence of two species, C. immitis and C. posadasii.These species are indistinguishable with regard to the clinical disease they cause as well as in routine laboratory tests. Thus, the organism will be referred to simply as Coccidioides for the remainder of this chapter.
Coccidioidomycosis is confined to the Western Hemisphere between the latitudes of 40°N and 40°S. In the United States, areas of high endemicity include the southern portion of the San Joaquin Valley of California, the south-central region of Arizona, and the southwestern Rio Grande Valley. However, infection may be acquired in other areas of the southwestern United States, including the southern coastal counties in California, southern Nevada, and southwestern Utah. Outside the United States, coccidioidomycosis is endemic to northern Mexico as well as to localized regions of Central America. In South America, there are endemic foci in Colombia, Venezuela, northeastern Brazil, Paraguay, Bolivia, and north-central Argentina. The risk of infection is increased by direct exposure to soil harboring Coccidioides. Because of difficulty in isolating Coccidioides from the soil, the precise characteristics of potentially infectious soil are not known. In general, Coccidioides appears to be supported in previously uncultivated desert soil, such as that found in the Lower Sonoran Life Zone.
However, several outbreaks have been associated with soil from archaeologic excavations of Amerindian sites both within and outside of the recognized endemic region. In endemic areas, many cases of Coccidioides infection occur without obvious soil or dust exposure. Climatic factors appear to increase the infection rate in these regions. In particular, periods of dryness after rainy seasons have been associated with marked increases in the number of cases. Recently, the number of cases of symptomatic coccidioidomycosis has increased dramatically in south-central Arizona, where most of the state’s population resides.The factors causing this increase have not been fully elucidated; however, an influx of older, susceptible individuals into the region as well as increased construction in previously undeveloped desert appear to be involved.
PATHOGENESIS, PATHOLOGY, AND IMMUNE RESPONSE
On agar media and in the soil, Coccidioides exists as a filamentous mold.Within this mycelial structure, individual filaments (hyphae) elongate and branch, some growing upward. Cells within the hyphae degenerate, leaving alternating barrel-shaped viable cells called arthroconidia. Measuring only ∼2 × 5 ìm, arthroconidia may become airborne for extended periods. The small size of the arthroconidia also allows them to evade initial mechanical mucosal defenses and reach the alveolus, where infection is initiated in the nonimmune host. Once in a susceptible host, the arthroconidia enlarge, become rounded, and develop internal septations. The resulting structures, called spherules (Fig. 104-1), may attain sizes of 80 ìm and are unique to Coccidioides. The septations encompass uninuclear elements called endospores. Spherules may rupture and release packets of endospores that can themselves develop into spherules, thus propagating infection locally. If returned to artificial media or the soil, the fungus reverts to its mycelial stage. Clinical observations and data from studies of animals strongly support the critical role of a robust cellular immune response in the host’s control of coccidioidomycosis. Necrotizing granulomas containing spherules are typically identified in patients with resolved pulmonary infection. In disseminated disease, granulomas are generally poorly formed or do not develop at all, and a polymorphonuclear leukocyte response occurs frequently. In patients who are asymptomatic or in whom the initial pulmonary infection resolves, delayed-type hypersensitivity to coccidioidal antigens is routinely documented.
CLINICAL AND LABORATORY MANIFESTATIONS
Coccidioidomycosis is protean in its manifestations. Of infected individuals, 60% are completely asymptomatic, and the remaining 40% have symptoms that are related principally to pulmonary infection, including fever, cough, and pleuritic chest pain.The risk of symptomatic illness increases with age. Coccidioidomycosis is commonly misdiagnosed as community-acquired bacterial pneumonia. There are several cutaneous manifestations of primary pulmonary coccidioidomycosis.Toxic erythema consisting of a maculopapular rash has been noted in some cases. Erythema nodosum (typically over the lower extremities) or erythema multiforme (usually in a necklace distribution) may occur; these manifestations are seen particularly often in women. Arthralgias and arthritis may develop. The diagnosis of primary pulmonary coccidioidomycosis is suggested by a history of night sweats or profound fatigue as well as by peripheral-blood eosinophilia or hilar or mediastinal lymphadenopathy on chest radiography. While pleuritic chest pain is common, pleural effusion is less so, occurring in fewer than 10% of cases. Such effusions are invariably associated with a pulmonary infiltrate on the same side.The cellular content of these effusions is mononuclear in nature; Coccidioides is rarely grown from effusions. Although primary pulmonary coccidioidomycosis usually resolves without sequelae, several complications may ensue. Pulmonary nodules are residua of primary pneumonia.
Generally single, located in the upper lobes, and ≤ 4 cm in diameter, nodules are often discovered on a routine chest radiograph in an asymptomatic patient. Calcification is uncommon. Pulmonary cavities occur when a nodule extrudes its contents into the bronchus, resulting in a thin-walled shell. These cavities can be associated with persistent cough, hemoptysis, and pleuritic chest pain. Rarely, a cavity may rupture into the pleural space, causing pyopneumothorax. In such cases, patients present with acute dyspnea, and the chest radiograph reveals a collapsed lung with a pleural airfluid level. Chronic or persistent pulmonary coccidioidomycosis manifests with prolonged symptoms of fever, cough, and weight loss and is radiographically associated with pulmonary scarring, fibrosis, and cavities. It occurs in fewer than 1% of patients, many of whom already have chronic lung disease of other etiologies. In some cases, primary pneumonia presents as a diffuse reticulonodular pulmonary process (detected by plain chest radiography) in association with dyspnea and fever. Primary diffuse coccidioidal pneumonia may occur in settings of intense environmental exposure or profoundly suppressed cellular immunity, with unrestrained fungal growth that is frequently associated with fungemia. Dissemination outside the thoracic cavity occurs in fewer than 1% of infected individuals.
Dissemination is more likely to occur in males, particularly those of African-American or Filipino ancestry, and in persons with depressed cellular immunity, including patients with HIV infection and peripheral-blood CD4+ T-cell counts of <250/ìL; those receiving chronic glucocorticoid therapy; those with allogeneic solid-organ transplants; and those being treated with tumor necrosis factor á antagonists.Women who acquire infection during the second or third trimester of pregnancy are also at risk for disseminated disease. Common sites for dissemination include the skin, bone, joints, soft tissues, and meninges. Dissemination may follow symptomatic or asymptomatic pulmonary infection and may involve only one site or multiple anatomic foci.When it occurs, clinical dissemination is usually evident within the first few months after primary pulmonary infection. Meningitis, if untreated, is uniformly fatal. Patients usually present with a persistent headache, which is occasionally accompanied by lethargy and confusion. Nuchal rigidity, if present, is not severe. Examination of cerebrospinal fluid (CSF) demonstrates lymphocytic pleocytosis with profound hypoglycorrhachia and elevated protein levels. CSF eosinophilia is occasionally documented.With or without appropriate therapy, patients may develop hydrocephalus, which presents clinically as a marked decline in mental status, often with gait disturbances.
As mentioned above, coccidioidomycosis is often misdiagnosed as community-acquired bacterial pneumonia. Serology plays an important role in establishing the diagnosis of coccidioidomycosis. Several techniques are available, including the traditional tube-precipitin (TP) and complement-fixation (CF) assays, immunodiffusion (IDTP and IDCF), and enzyme immunoassay (EIA) to detect IgM and IgG antibodies. TP antibody is found in serum soon after infection and persists for weeks.TP titers are not useful for gauging disease progression, and this antibody is not found in the CSF.Titers of CF antibody generally rise later than do those of TP antibody, and CF antibody usually persists longer. Rising CF titers are associated with clinical progression, and the presence of CF antibody in CSF is an indicator for coccidioidal meningitis. Because of its commercial availability, the coccidioidal EIA is frequently used as a screening tool for coccidioidal serology. However, the frequent false-positive results obtained with the IgM EIA make this test unreliable. Instead, the traditional TP or IDTP should be used. In addition, while the sensitivity and specificity of the IgG EIA appear to be high when compared with those of the CF and IDCF assays, the optical density obtained in the EIA does not correlate with the serologic titer of either of the latter tests. Coccidioides grows within 3–7 days at 37°C on a variety of artificial media, including blood agar.Therefore, it is always useful to obtain samples of sputum or other respiratory fluids and tissues for culture in suspected cases of coccidioidomycosis. The clinical laboratory should be alerted to the possibility of this diagnosis, since Coccidioides can pose a significant hazard to laboratory workers if it is inadvertently inhaled.
Coccidioides can also be identified directly.While treatment of samples with potassium hydroxide is rarely fruitful in establishing the diagnosis, examination of sputum or other respiratory fluids after Papanicolaou or Gomori methenamine silver staining reveals spherules in a significant proportion of patients with pulmonary coccidioidomycosis. For fixed tissues (e.g., those obtained from biopsy specimens), spherules with surrounding inflammation can be demonstrated with hematoxylin-eosin or Gomori methenamine silver staining. Currently, there are two main classes of antifungals useful for the treatment of coccidioidomycosis. While once routinely prescribed, amphotericin B in all its formulations is now reserved for only the most severe cases of dissemination and for intrathecal or intraventricular administration to patients with coccidioidal meningitis in whom triazole therapy has failed. The original formulation of amphotericin B, which is dispersed with deoxycholate, is usually administered intravenously in doses of 0.7–1.0 mg/kg either daily or three times per week. The newer lipid-based formulations— amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and amphotericin B liposomal complex—appear to offer no therapeutic advantage over the deoxycholate formulation but are associated with less renal toxicity.
The lipid dispersions are administered intravenously at doses of 5 mg/kg daily or three times per week. Triazole antifungals are the principal drugs now used to treat most cases of coccidioidomycosis. Clinical trials have demonstrated the usefulness of both fluconazole and itraconazole, and evidence indicates that itraconazole may be more efficacious against bone and joint disease. Because of its demonstrated penetration into CSF, fluconazole is the azole of choice for the treatment of coccidioidal meningitis. For both drugs, a minimal oral adult dosage of 400 mg/d should be used. The maximal dose of itraconazole is 200 mg three times daily, but higher doses of fluconazole may be given.Two newer triazole antifungals, posaconazole and voriconazole, are now available.However, given the paucity of clinical data, the high cost, and (particularly for voriconazole) the potential toxicity, these agents should be reserved for cases that remain recalcitrant when treated with fluconazole or itraconazole. High-dose triazole therapy may be teratogenic; thus, amphotericin B should be considered as therapy for coccidioidomycosis in pregnant women. Most patients with focal primary pulmonary coccidioidomycosis require no therapy.
Patients for whom antifungal therapy should be considered include those with underlying cellular immunodeficiencies and those with prolonged symptoms and signs of extensive disease. Specific criteria include symptoms persisting for ≥2 months, night sweats occurring for >3 weeks,weight loss of >10%, a serum CF antibody titer of >1:16, and extensive pulmonary involvement apparent on chest radiograph. Diffuse pulmonary coccidioidomycosis represents a special situation. Because most patients with this form of disease are profoundly hypoxemic and critically ill, many clinicians favor beginning therapy with amphotericin B and switching to an oral triazole once clinical improvement occurs. The nodules that may follow primary pulmonary coccidioidomycosis do not require treatment. However, nodules are not easily distinguished from pulmonary malignancies by means of radiographic imaging (including positron emission tomography scans). Close clinical follow-up and biopsy may be required to distinguish these two entities. Most pulmonary cavities do not require therapy.
Antifungal treatment should be considered in patients with persistent cough, pleuritic chest pain, and hemoptysis. Occasionally, pulmonary coccidioidal cavities become secondarily infected.This development is usually manifested by an air-fluid level within the cavity. Bacterial flora or Aspergillus species are commonly involved, and therapy directed at these organisms should be considered. Surgery is rarely required except in cases of persistent hemoptysis or pyopneumothorax. For chronic pulmonary coccidioidomycosis, prolonged antifungal therapy—lasting for at least 1 year—is usually required, with monitoring of symptoms, radiographic changes, sputum cultures, and serologic titers. Most cases of disseminated coccidioidomycosis require prolonged antifungal therapy. Duration of treatment is based on resolution of the signs and symptoms of the lesion in conjunction with a significant decline in serum CF antibody titer. Such therapy routinely is continued for at least several years. Relapse occurs in 15–30% of individuals once therapy is discontinued. Coccidioidal meningitis poses a special challenge. While most patients with this form of disease respond to treatment with oral triazoles, 80% experience relapse when therapy is stopped. Thus, life-long therapy is recommended. In cases of triazole failure, intrathecal or intraventricular amphotericin B may be used. Installation requires considerable expertise and should be performed only by an experienced health care provider. Shunting of CSF in addition to appropriate antifungal therapy is required in cases of meningitis complicated by hydrocephalus. It is prudent to obtain expert consultation in all cases of coccidioidal meningitis.
There are no proven methods to reduce the risk of acquiring coccidioidomycosis among residents of an endemic region.Avoidance of direct contact with uncultivated soil or with visible dust containing soil presumably reduces the risk. Prophylactic antifungal therapy may be useful in patients who have evidence of active or recent coccidioidomycosis and are about to undergo allogeneic solidorgan transplantation. Data on the use of antifungal agents for prophylaxis in other situations are scanty and do not suggest efficacy.