Coccidioides species are dimorphic fungi endemic to parts of the American West. Acute primary infection with C immitis is most often asymptomatic, but it can manifest as a complex of symptoms called “Valley Fever” by residents of the endemic areas. Valley Fever includes fever, malaise, dry cough, joint pains, and sometimes a rash. There are few diagnostic physical or radiologic findings, but the illness persists for weeks. Disseminated forms of the disease can involve lesions in the bones, joints, skin, and a progressive chronic meningitis.
COCCIDIOIDES IMMITIS AND COCCIDIOIDES POSADASII
Coccidioides species are dimorphic fungi commonly encountered within North America in the desert regions of the southwestern United States and northern Mexico. In contrast to Blastomyces and Histoplasma species that grow in the body as budding yeast-like cells, the tissue form of Coccidioides species is a large (12-100 μm), round-walled spherule (Figure 47–7A). This structure is quite distinctive and unique among the pathogenic fungi. Its formation takes place in a process illustrated in Figure 47–8. Spherule development requires simultaneous invagination of the fungal membrane (plasmalemma) and production of new cell wall to form the large multicompartmental structure. The compartments differentiate into uninucleate structures called endospores, each with a thin wall layer. Multiple endospores develop within each spherule and the entire structure is surrounded by an extracellular matrix. The spherule eventually ruptures, releasing 200 to 300 endospores (Figure 47–9), each of which can differentiate into another spherule.
Coccidioides immitis. A. Lung tissue with a large thick-walled spherule containing multiple endospores. The smaller spherule to its left has ruptured releasing endospores. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange, 1997.) B. Mold phase in which alternate cells have differentiated to form barrel-shaped arthroconidia. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
Life cycle of Coccidioides immitis. The nature cycle takes place in desert climates with modest rainfall. Hyphae differentiate into arthroconidia, which break loose and may be suspended in the air. Soil disruptions and wind facilitate spread and the probability of inhalation into human lungs. In the human host environment, in vivo differentiation produces cleavage planes and eventually huge spherules. The spherules rupture releasing endospores, which can then repeat the in vivo cycle.
Coccidioides immitis. This electron micrograph of infected mouse lung shows a spherule filled with endospores (E) and one that has discharged its endospores into the surrounding tissue. Note the thickness of the spherule wall (SW). (Reprinted with permission from Drutz DJ, Huppert M. J Infect Dis. 1983;147:379, Figure 7. Copyright University of Chicago Publisher.)
✺ Spherules differentiate to form and release endospores
Dimorphism involves unique spherule
In the environment, Coccidioides grows as a mold under harsh conditions in sandy alkaline soil with high salinity, such as those in arid, desert regions. In the laboratory, Coccidioides growth becomes visible in 2 to 5 days. The hyphae are septate and produce thick-walled, barrel-shaped arthroconidia (Figure 47–7B) in about 1 week. Mature arthroconidia readily separate from the hyphae and survive for long periods in the environment. When airborne, they are the infectious particles in nature. Arthroconidia can be converted to spherules in the laboratory, but only under very specialized conditions.
As with other fungi, the application of modern genotyping methods has led to name splitting within the Coccidioides genus. The original C immitis isolated in California’s San Joaquin Valley appears to be a distinct clone, and most strains from elsewhere in the Americas belong to another species (C posadasii). Because there are no differences in disease between the two species, and since clinical laboratories cannot easily distinguish between them, the more clinically familiar name C immitis will be used to refer to both species here.
Barrel-shaped arthroconidia form in hyphae
Conidia are readily airborne
Coccidioidomycosis is the most geographically restricted of the systemic mycoses because C immitis grows only in the alkaline soil of semiarid climates known as the Lower Sonoran life zone (Figure 47–4). These areas are characterized by hot, dry summers, mild winters with few freezes, and annual rainfall of about 10 inches during brief rainy seasons. Ecologic “islands” with these conditions are found scattered throughout Central and South America. The primary endemic zones in the United States are in Arizona, Nevada, New Mexico, western Texas, and the arid parts of central and southern California. Three unrelated cases in the eastern half of Washington State could give this zone its most northern extension. The area between the Cascade and Rocky Mountains is also dry and arid, but prolonged winter freezes make it less hospitable for Coccidioides species. Persons living in the endemic areas are at high risk of infection, and positive skin test rates of 50% to 90% occur in long-time residents of highly endemic areas. Coccidioidomycosis is not transmissible from person to person.
✺ Geographically restricted to Sonoran Desert
High proportion of locals have been infected
Infection cannot typically be acquired without at least visiting an endemic area, although some interesting examples have been recorded in which the endemic zone itself “paid a visit” and resulted in infections. In 1978, a storm originating in Bakersfield, California (endemic zone), carried a thick cloud of dust all the way to San Francisco. This weather event was followed by cases of coccidioidomycosis in persons who had never left the Bay Area. Similarly, infection in a patient who had never left the southeastern United States was epidemiologically associated with exposure to pre-processed cotton grown in Arizona. In 1992, a tenfold increase in disease in California followed an unusually wet winter in which the storms created a drought–rain–drought pattern just right for growth of the mold (and wildflowers). When the Sonoran Desert blooms, a Coccidioides arthroconidium “crop” is not far behind. The incidence of coccidioidomycosis is increasing in the United States primarily because of the influx of populations into the sunbelt states where C immitis is endemic. Ninety percent of new cases of coccidioidomycosis occur in California or Arizona.
Arthroconidial wall resists phagocytosis
Rainfall pattern influences attack rate
Coccidioides immitis is also a notorious cause of infection in laboratory workers. The high infectivity of cultured arthroconidia has caused it to be classified as a significant biohazard and potential bioweapon.
✺ Considered a potential bioweapon
Inhaled arthroconidia are small enough (2-6 μm) to bypass the defenses of the upper tracheobronchial tree and lodge in the terminal bronchioles and alveoli. After infection, the typical incubation period before the onset of symptoms is 1 to 3 weeks. Human monocytes can ingest and kill some arthroconidia on initial exposure, although the outer portion of the wall of the arthroconidium has antiphagocytic properties, allowing them to persist into the early stages of spherule development. Surviving arthroconidia convert to the spherule stage, which begins its slow growth to a size that makes effective phagocytosis difficult. Although polymorphonuclear neutrophils are able to digest the spherule wall, their access appears to be restricted by the extracellular matrix surrounding it. The young endospores are released in packets that include the extracellular matrix derived from the parent spherule, which may protect them until they develop into new spherules.
Arthroconidial wall resists phagocytosis
Spherules produce endospores with extracellular matrix
Several proteases found in the conidial cell wall or in spherules have been proposed as C immitis virulence factors. In addition to their role in the fungal life cycle, some of these enzymes attack host substrates, such as collagen, elastin, and immunoglobulins, but no direct specific contribution to disease has been defined. Components of the spherule outer wall and a metalloproteinase found there have been linked to virulence in animals and to survival of developing endospores.
Proteases and spherule outer wall may be linked to virulence
Lifelong immunity to coccidioidomycosis clearly develops in most of those who become infected. This immunity is associated with strong polymorphonuclear leukocyte and TH1-mediated responses to coccidioidal antigens. In most cases, a mixed inflammatory response is associated with early resolution of the infection and development of a positive delayed-type hypersensitivity skin test. Progressive disease is associated with weak or absent cellular immunity and loss of delayed-type hypersensitivity to coccidioidal antigens. In most infected persons, the infection is controlled after mild or unapparent illness. The disease progresses when cell-mediated immunity and consequent macrophage activation do not develop. Such immune deficits may be a result of disease (AIDS) or immunosuppressive therapy, but progressive coccidioidomycosis may infrequently occur in persons with no known immune defects.
Cell-mediated immunity is of prime importance
✺ Progressive disease develops in patients with AIDS or defects in cell-mediated immunity
The central event in the host–pathogen interaction in coccidioidomycosis appears to be the reaction to arthroconidia or to endospores released from ruptured spherules. Arthroconidia can be phagocytosed and killed by polymorphonuclear leukocytes even before an adaptive immune response is mounted. The handling of endospores requires the additional participation of macrophages that do not become maximally effective until activated by cytokines produced by the TH1 subsets. Prior to this, C immitis endospores may be able to impair phagosome–lysosome fusion in the phagocyte.
Endospores must be destroyed by cytokine-activated macrophages
Humoral mechanisms are not known to play a major role in immunity to coccidioidomycosis. In fact, C immitis is resistant to complement-mediated killing, and levels of complement-fixing antibody are inversely related to the process of disease resolution. Persons with minimal objective indications of tissue involvement (eg, lesions and radiographs) have strong T-lymphocyte responses to C immitis antigens and little if any detectable anti-Coccidioides antibody. Those with disseminated disease and absent cellular immunity have high titers of antibody. Thus, the levels of antibody seem to indicate the degree of antigenic stimulation rather than any known contribution to resolution of the infection.
Antibody production is inversely related to disease progression
COCCIDIOIDOMYCOSIS: CLINICAL ASPECTS
More than 50% of those infected with C immitis experience no symptoms, or the disease is so mild that it cannot be recalled when evidence of infection (serology, skin test) is discovered. Others develop malaise, cough, chest pain, fever, and arthralgia 1 to 3 weeks after infection. This illness, dubbed Valley Fever by the local San Joaquin Valley residents, lasts 2 to 6 weeks with few distinctive findings. The chest X-ray is usually clear or shows only hilar adenopathy. Red, inflamed skin nodules, known as erythema nodosum, may occur during the course of initial Coccidioides infection, particularly on the extremities. Occurring most frequently in women, these nodules may provide a clinical clue to the cause of infectious symptoms. In most cases, all clinical symptoms of Valley Fever resolve spontaneously, but often only after considerable discomfort and loss of productivity. In more than 90% of cases, there are no pulmonary residua. A small number of cases progress to a chronic pulmonary infection characterized by cavity formation and a slowly relapsing course that extends over years. Less than 1% of all primary infections and 5% of symptomatic cases disseminate to foci outside the lung.
✺ Valley fever usually self-limiting
✺ Erythema nodosum common in women
Chronic and disseminated disease less than 1%
There is a well-recognized but poorly understood predisposition to chronic infections among distinct patient populations. Disseminated disease is more common in men, as well as people from sub-Saharan Africa and southeast Asia, particularly the Philippines. Given the importance of CD4-mediated immunity in controlling coccidioidomycosis, patients with AIDS or transplants are also at particular risk for disseminated infection. Evidence of extrapulmonary infection almost always appears in the first year after infection. The most commonly involved sites are bones, joints, skin, and the central nervous system. Coccidioidal meningitis develops slowly with gradually increasing headache, fever, neck stiffness, and other signs of meningeal irritation. The CSF findings are similar to those in tuberculosis and other fungal causes of meningitis, such as C neoformans. Mononuclear cells predominate in the cell count, but substantial numbers of neutrophils and eosinophils are often present. If untreated, the disease is slowly progressive and fatal.
✺ Genetic factors and immune status are predictors for dissemination
✺ Meningitis is chronic
With enough persistence, direct examination of infected tissue can reveal diagnostic forms of C immitis. The thick-walled spherules are so large and characteristic (Figure 47–7A) that they are difficult to miss in wet mounts (KOH, calcofluor) or biopsy sections. Skin and visceral lesions are most likely to demonstrate spherules; however, these fungal forms are rarely seen in the CSF. Spherules released into expectorated sputum are often small (10-15 mm) and immature without well-developed endospores, thus difficult to visualize. In contrast, spherules stain well in histologic sections of infected tissue using either H&E or special fungal stains.
Direct examination for spherules can be diagnostic
Culture of C immitis from sputum, visceral lesions, or skin lesions is not difficult, but must be undertaken only by those with experience and proper biohazard protection. Cultures of CSF are positive in less than half the cases of meningitis. Laboratories must be warned of the possibility of coccidioidomycosis to ensure diagnosis and prevent inadvertent laboratory infection. The latter is particularly significant outside the endemic areas, where routine precautions may not be in place. Identification requires observation of typical arthroconidia and confirmation using a DNA probe. Nucleic acid amplification procedures for direct detection are in development.
Culture from CSF may be difficult
Substantial risk of laboratory infection with arthroconidia
Serologic tests are particularly useful in the diagnosis and management of coccidioidomycosis (Figure 47–10). One half to three-quarters of patients with primary infection develop anti-Coccidioides IgM antibody during the first 3 weeks of illness. IgG antibodies (measured by complement fixation) appear in the third week or later, and their titer and duration depend on the extent of disease. IgG disappears with resolution or successful treatment, and it persists with continuing infection. In an appropriate clinical setting, the detection of specific antibodies can confirm the diagnosis of coccidioidomycosis, but their absence does not exclude it. In managing disseminated disease, the magnitude of the IgG titer is a measure of the extent of disease, and the direction of any change is often an indication of prognosis. For example, a high (>1:32) and rising titer indicates a poor prognosis. The presence of IgG in the CSF is also important in the diagnosis of coccidioidal meningitis because cultures are frequently negative. The coccidioidin skin test was also a useful tool to indicate prior exposure, but it is no longer routinely available.
Serologic tests in coccidioidomycosis.
Coccidioidin skin test remains positive for life
Precipitating IgM indicates acute infection
✺ IgG detected by complement fixation quantitates disease
Primary coccidioidomycosis is self-limited, and no antifungal therapy is indicated except to reduce the risk of dissemination in patients with risk factors, such as immunocompromise and pregnancy. Itraconazole is preferred for acute or progressive pulmonary disease, with fluconazole as an alternative agent. Disseminated, extrapulmonary infection may require amphotericin B. Fluconazole is often favored as treatment for meningitis because of its enhanced CSF penetration. In cases of refractory meningitis, amphotericin B may be infused directly into the CSF. Unlike other forms of the disease that can be treated for cure, coccidioidomycosis involving the CNS often requires lifelong therapy.
Primary disease treated only with risk factors
Amphotericin B and azoles in progressive disease