Mark R. Schleiss
Coccidioidomycosis is the infection caused by the dimorphic fungus Coccidioides immitis. The history of the identification of this organism and the clinical study of the infections caused by this agent have been the subject of a number of comprehensive reviews.1-2 Although it was initially believed that coccidioidomycosis was an invariably lethal infection, by the mid- 1930s, it was recognized that the organism was in fact responsible for a very common, acute, and generally self-limited disease that was known as the San Joaquin Valley fever. In regions where coccidioidomycosis is endemic, Valley fever continues to be an important public health problem. In addition, coccidioidomycosis has emerged in recent years as an important cause of disease in immunocompromised patients, particularly those with human immunodeficiency virus (HIV) infection.
The life cycle of C immitis is complex (reviewed in Parish and Blair4) and demonstrates 2 distinct phases: a saprophytic (vegetative) phase and a parasitic phase. In soil, the organism grows as a mycelium, with branching septated hyphae. As they mature, the mycelia develop rectangular spores (arthroconidia); at this stage, the hyphae become very fragile, and arthroconidia easily become airborne. When inhaled, the arthroconidia begin the parasitic phase, and spherules form. Spherules are round, double-walled structures that reproduce by formation of spherical internal spores, termed endospores. A single spherule may produce thousands of endospores, and as the spherule ruptures, each endospore may in turn develop into a new spherule, perpetuating the parasitic phase.
In general, C immitis appears to be confined to the Western hemisphere. The endemic areas lie in the southwestern United States, encompassing west Texas, New Mexico, Arizona, and California. The organism can also be found in northwestern Mexico and a few small areas of Central and South America. These endemic areas have arid climates, hot summers, few winter freezes, low altitude, and alkaline soil—ecological conditions that favor C immitis. The organism is drought resistant, and periodic increases in cases are observed when prolonged drought is followed by periods of heavy rain. Arthroconidia may become airborne after windstorms or disruption of soil by farming or construction work. Since infection requires that arthroconidia be inhaled, person-to-person transmission does not play a role in acquisition of coccidioidomycosis.
Hospitalizations for coccidioidomycosis are common, particularly in endemic areas. County of residence, older age, black race, male sex, intercurrent HIV infection, and pregnancy are all risk factors strongly associated with an increased risk for hospitalization.5
The primary portal of entry in most patients is the lung, although the organism may enter through the skin. Accordingly, signs and symptoms of respiratory tract infection represent the major clinical manifestations of acute coccidioidomycosis in most patients.6 Pulmonary coccidioidomycosis occurs in 95% of all cases. The majority of individuals with acute coccidioidomycosis will have either asymptomatic infection or mild upper respiratory tract symptoms. Approximately 40% of patients with primary infection will develop a more severe systemic illness 1 to 3 weeks after exposure, characterized by cough, malaise, fever, chills, night sweats, anorexia, and weakness. Lower respiratory tract illness may include pneumonia and parapneumonic effusion. Chest pain may be quite severe in some patients, and hemoptysis is commonly encountered in adult patients, although it is rare in children. The radiographic appearance of acute coccidioidomycosis is nonspecific. Bronchopneumonic infiltrate associated with hilar adenopathy is the most common presentation, although an interstitial pattern may be encountered. Widespread intrathoracic disease (“miliary pattern”) may be encountered with disseminated infection.
Pulmonary infection can be divided into 3 main categories: primary, complicated, and residual pulmonary coccidioidomycosis.6 Primary infection occurs with inhalation of airborne arthroconidia: Remarkably, as few as 10 arthroconidia are capable of producing infection. Symptomatic disease manifests with predominantly an influenzalike syndrome, with accompanying pneumonia or pleural effusion. Complicated pulmonary coccidioidomycosis includes severe and persistent pneumonia, progressive primary coccidioidomycosis, fibrocavitary coccidioidomycosis, empyema, and, rarely, acute respiratory distress syndrome (ARDS). Residual disease comprises 2 entities: pulmonary nodule and fibrosis.
An important diagnostic clue in patients with primary coccidioidomycosis is the presence of cutaneous manifestations. The most common skin manifestation of acute coccidioidomycosis is erythema nodosum. The appearance of these lesions, known in California as the “valley bumps,” correlates with the development of cell-mediated immunity and is associated with a lower risk of dissemination. These painful, tender lesions are distributed on the anterior tibial surface. Although not specific for coccidioidomycosis, the finding of erythema nodosum in a child residing in an endemic area strongly suggests recent acute coccidioidomycosis. Less commonly, erythema multiforme may be present, and, like erythema nodosum, this rash is also assumed to be immunologically mediated. Interstitial granulomatous dermatitis and Sweet syndrome have recently been recognized as additional reactive signs of the infection.7Primary cutaneous infection with C immitis is rare, with most cases being attributed to laboratory accidents. The skin may also be a target organ in the setting of disseminated infection (see next section).
Other Coccidioidomycosis Disease Categories
Approximately 0.5% of patients with acute coccidioidomycosis will develop disseminated infection. Dissemination is more common in men, pregnant women (discussed in this section), and in certain ethnic groups (individuals of African, Mexican, or Filipino ancestry). Major disseminated disease sites include bones, joints, visceral organs, and the central nervous system.
Local pain is the usual hallmark of musculo-skeletal coccidioidomycosis, with warmth and swelling accompanying the systemic symptoms of infection. Over one third of cases of disseminated coccidioidomycosis are complicated by osteomyelitis, which is unifocal in most cases. Any bone can become infected, but the most commonly involved sites are skull, metacarpals, metatarsals, spine, and tibia. Bone scans are more sensitive than plain radiographs in making the diagnosis. When present, vertebral lesions tend to be multiple and pose a high risk for central nervous system spread. Tendinitis, synovitis, or frank arthritis may result from bloodstream dissemination. Swelling and tenderness are present, most commonly involving the ankle and knee. Fungus can usually be cultured from the affected synovial fluid, and synovial biopsy is indicated in suspect cases.
Coccidioidomycosis meningitis is an important and serious complication of disseminated infection.8 It typically presents within the first 6 months following primary infection. Importantly, the signs of meningeal irritation common in bacterial meningitis are generally absent. Headache is the most common symptom. Fever, weakness, vomiting, focal neurologic deficits, and meningismus may occur, but many patients are asymptomatic; therefore, any patient with disseminated coccidioidomycosis should probably undergo lumbar puncture regardless of symptoms. Cerebrospinal fluid analysis typically shows a mononuclear pleocytosis, with decreased glucose and elevated protein levels. Meningitis may be associated with parenchymal involvement evident on magnetic resonance imaging. The course of coccidioidomycosis meningitis is often chronic. Hydrocephalus is a common complication. C immitis is rarely recovered from cerebrospinal fluid, but complement-fixing antibodies for coccidioidin are present in almost all cases.
Other manifestations of disseminated coccidioidomycosis may include seeding of visceral organs, genitourinary tract infection, ophthalmic complications (chorioretinitis), and cutaneous infection. Muscle involvement may occur in disseminated cases, with occasional development of abscesses or draining sinus tracts. Of particular interest to pediatricians is the issue of coccidioidomycosis in pregnancy. Pregnant women are at high risk of dissemination of coccidioidomycosis, presumably due to the physiological reduction in type 1 T-helper-cell cytokine responses that occurs during pregnancy.9,10Historically, untreated disseminated coccidioidomycosis during pregnancy was thought to be associated with extensive maternal and fetal mortality and was a leading cause of maternal death in endemic areas of endemicity, demonstrating a dramatically increased risk of dissemination in African American women.11 As recently as 1995, therapeutic abortions and early deliveries were advocated in certain contexts, although more recent reports suggest that the risk of transplacental infection and fetal complications may have been overstated.12Infection in the newborn may also be acquired via the birth canal. The mortality of disseminated disease is higher in neonates than in older children or adults.
Coccidioidomycosis in Immunocompromised Patients
In recent years C immitis has emerged as a major pathogen in immunocompromised patients, particularly those with HIV infection.13C immitis also has an enhanced pathogenic potential in other immunosuppressed patients, such as organ transplant recipients, children with congenital immunodeficiencies, and patients on immunosuppressive therapies, including tumor necrosis factor antagonists such as infliximab.14-16 Coccidioidomycosis in immunocompromised patients represents a mix of new and reactivated infections. Diffuse pulmonary disease is common, and lung biopsy is often required to make the diagnosis. Extrapulmonary disease may be difficult to eradicate, necessitating chronic suppressive therapy (see section “Therapy”). Even a remote history of residence or travel to an endemic area should be sought, since the major problem in making the diagnosis is a lack of suspicion of the possibility of coccidioidomycosis.
Demonstration of the organism by examination and culture of clinical specimens, with confirmation of positive cultures utilizing nucleic acid hybridization methods, remain the definitive diagnostic approaches to establishing the diagnosis of coccidioidomycosis.17 Sputum, joint fluid, bronchoalveolar lavage fluid, soft tissue aspirates, and deep tissue surgical specimens offer the best yield by culture. Spinal fluid culture is positive by culture only about one third of the time, and when the diagnosis of meningitis is being considered, multiple lumbar punctures may increase the diagnostic yield. It is important to remember that cultures of C immitis represent a potentially severe biologic hazard, and laboratory personnel should be alerted to the possibility of the diagnosis prior to processing of specimens. Microscopic examination of clinical specimens may be useful, to search for the presence of endospore-containing spherules. Fine-needle aspiration of suspect lesions in soft tissue or bone, synovial biopsies, and skin biopsies all provide suitable specimens for histopathological evaluation.
Nonculture techniques, such as fungal DNA detection by polymerase chain reaction, colorimetric and antibody-based assays to detect cell wall or capsular polysaccharides, and serology, are also helpful in making the diagnosis of coccidioidomycosis.18 The mycelial phase antigen, coccidioidin, is the most important target of antibody response. Serum IgM antibodies, called precipitins, can be detected 1 to 3 weeks after onset of symptoms in most cases and are readily identifiable by a variety of immunodiffusion, latex agglutination, or enzyme immunoassay methods. Complement-fixing serum IgG antibodies (CFA) appear later in the course of infection, and usually decline 6 to 8 months following primary infection, although antibody may continue to be detectable for years. The CFA titer is a useful marker of disease activity. Sera should be run in paired fashion (acute and convalescent) for titer comparison. Rising titers are a bad prognostic sign, whereas falling titers suggest improvement. In the majority of patients with meningitis, CFA is present in cerebrospinal fluid, and titers parallel the course of meningeal disease.
Skin tests may also be used in the diagnostic approach to coccidioidomycosis, although interpretations of these tests can be problematic. Most patients with symptomatic primary infections will have a positive test (> 5 mm induration) within 1 month of disease onset. Patients with erythema nodosum may have a severe response to skin tests because of their particularly intense delayed-type hypersensitivity response to coccidioidin antigen. Cutaneous anergy is common in individuals with disseminated coccidioidomycosis, and a negative skin test in such patients does not exclude the diagnosis.
The decision to initiate antifungal therapy in the setting of coccidioidomycosis depends on the extent of disease and the risk factors a patient may have for complicated or disseminated disease. Although most patients with symptomatic primary infection recover spontaneously, treatment is mandated in several clinical settings. Once disease has spread outside the lung (bone, joint, and soft tissue infections, genitourinary tract infections, and central nervous system involvement), antifungal therapy is almost always warranted. In certain circumstances, individuals with symptomatic primary infection should also be treated, even if disease appears to be limited to the lungs, since the risk of dissemination is high. These patients include pregnant women, young infants, the immunocompromised, and individuals with chronic or debilitating illnesses. The magnitude of the CFA titer at time of diagnosis is also of value in making decisions regarding therapy. Disseminated disease is virtually never seen if the CFA titer is 1:32 or less. Therefore, titers of more than 1:32 may represent an indication for therapy in symptomatic primary infection, irrespective of other clinical findings.
Historically, amphotericin B and its lipid congeners have been regarded as the gold standards of therapy for severe pulmonary and disseminated coccidioidomycosis. The availability of azoles and, more recently, triazoles have relegated the amphotericins to use only in severe or widely disseminated disease, azole intolerance, or when contraindications to azoles exist, such as during pregnancy. The extended-spectrum azoles, such as posaconazole and voriconazole, may prove to be more efficacious in the treatment of coccidioidomycosis than prior azoles, including fluconazole and itraconazole.
C immitis meningitis represents a special circumstance regarding treatment. In meningitis, the intrathecal use of amphotericin B is still frequently recommended, alone or in combination with a triazole. Because of the extremely high risk of relapse, therapy, typically a triazole, appears to need to be given for life.19