Coccidioidomycosis and Valley Fever

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Background

Coccidioidomycosis is caused by Coccidioides immitis, a soil fungus native to the San Joaquin Valley of California (see the image below), and by C posadasii, which is endemic to certain arid-to-semiarid areas of the southwestern United States, northern portions of Mexico, and scattered areas in Central America and South America. Although genetically distinct, the 2 species are morphologically identical.



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A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.

Few immunologic differences are noted between the 2 species of Coccidioides, and the manifestations of infection with either organism are assumed to be identical; however, this hypothesis has not been formally tested. For all intents and purposes, all subsequent references to C immitis in this article also apply to C posadasii.

See A Chronic, Scaly Rash Mistaken for MRSA: Case Presentation, a Critical Images slideshow, to review additional images and details of a case of Coccidioidomycosis.

Clinical aspects

Coccidioidomycosis is typically transmitted by inhalation of airborne spores of C immitis or C posadasii (see Etiology). Infection occurs in endemic areas and is most commonly acquired in the summer or the late fall during outdoor activities.

Travelers to endemic areas are at risk for contracting the disease, which may not become clinically evident until after they have returned home.[1] In addition, infection may be acquired outside of endemic areas via transport of contaminated material. Diagnosis often is delayed in nonendemic areas because coccidioidal infection initially is not considered in the differential.[2, 3, 4, 5]

In most patients with coccidioidal infection, the primary infection is in the lungs. In 60-65% of cases, this infection is asymptomatic.

In other cases, a mild influenzalike illness develops 1-4 weeks after exposure. The symptoms are indistinguishable from other respiratory illnesses, with fever, sore throat, cough, headache, fatigue, and pleuritic chest pain. Resolution typically occurs over several weeks (although fatigue may persist for months), and 95% or more of patients recover without any further sequelae.

A more involved presentation, with the constellation of fever, arthralgias, erythema nodosum or erythema multiforme, and chest pain is commonly referred to as San Joaquin Valley fever (or simply Valley fever) or desert rheumatism (see Workup).

Coccidioidomycosis spreads beyond the lungs in approximately 0.6% of the infections in the general population. Most extrapulmonary disseminated infections are a result of hematogenous spread. Dissemination can be rapid and fatal. Virtually any organ of the body can be involved (eg, endocrine glands, eye, liver, kidney, prostate, peritoneal cavity), but Coccidioides species has a predilection for the lungs, skin, soft tissue, joints, and CNS, especially the meninges. Meningitis is a grave complication.

Disseminated disease may occur in an otherwise healthy individual, but the risk is significantly higher in individuals with altered cellular immunity due to disease (eg, HIV infection, lymphoma), medical treatment (eg, corticosteroid therapy), or pregnancy. In addition, risk of dissemination or progressive pulmonary disease is higher in certain racial groups (eg, Filipinos, blacks). (See Epidemiology and Clinical.)

Extrapulmonary primary infections can occur with trauma causing a puncture wound from a contaminated object. Laboratory workers and children are especially at risk for cutaneous or soft tissue lesions, including chancres, with regional lymphadenitis.[6, 2, 3, 7, 4, 8, 9]

Diagnosis requires isolation of the organism in culture, identification on histologic specimens, or serologic testing (see Workup). Most patients infected with Coccidioides are asymptomatic or have self-limited symptoms and require only supportive care. Symptomatic patients usually come to medical attention because of respiratory tract or systemic manifestations. Management in symptomatic patients varies with the clinical syndrome (see Treatment).

Amphotericin and oral azoles are the mainstays of antifungal therapy for coccidioidomycosis. Duration of therapy for the infection is often prolonged and may last several months to years, with lifelong suppression needed in certain patients.[6, 2, 3, 7]

Historical background

Wernicke and Posadas first described a case of coccidioidomycosis in 1892 in South America, in an Argentinean soldier with predominantly cutaneous manifestations. Two years later in the United States, a patient with disseminated coccidioidomycosis was first reported in California in 1894.

In 1896, Rixford and Gilchrist reported a few cases in which they identified the infecting agent as a protozoanlike organism and named it Coccidioides immitis. Ophuls further described the fungal life cycle and pathology of C immitis in 1905.

The disease was considered rare and uniformly fatal until 1929, when a Stanford University medical student, Harold Chope, accidentally inhaled a culture of Coccidioides and developed a nonfatal pulmonary illness accompanied by erythema nodosum. This case sparked interest that resulted in researchers uncovering the association between C immitis and the clinical condition known as San Joaquin Valley fever. Charles E. Smith and colleagues subsequently developed coccidioidin skin test and serologic testing for coccidioidomycosis.

The importance of the illness increased during the 1930s and 1940s, starting with the influx of immigrants from the Midwest who arrived in the San Joaquin Valley of California to escape drought and to seek agricultural employment. The thousands of military personnel building airstrips and participating in desert combat training during World War II led to many important studies on the pathogenic organisms and the epidemiology, clinical features, and diagnosis of coccidioidomycosis by the military health services.

Interest in coccidioidomycosis has been renewed because of massive migration to the Sunbelt states. Areas that were once sparsely populated are now major cities, which increases the population at risk for the disease. Phoenix and Tucson, Arizona; Bakersfield and Fresno, California; and El Paso, Texas, are prime examples.

These locales also have a growing population of individuals who are unusually susceptible to the most serious consequences of infection, due to advanced age or immunocompromise. Interest also has increased because of an explosion in the number of cases that occurred during the great coccidioidomycosis outbreak in California in 1991-1994.

The first effective therapy for coccidioidomycosis, intravenous amphotericin B, was first used in 1957. Since the 1980s, various oral antifungal agents, including ketoconazole, itraconazole, and fluconazole, have led to further advances in the treatment of coccidioidomycosis. The roles of newer agents (eg, voriconazole, posaconazole, caspofungin) are still being explored.

Pathophysiology

The vast majority of coccidioidal infections result from airborne transmission. Pulmonary infection can result from inhalation of a single spore in humans, but high inoculum exposures are more likely to result in symptomatic disease. Inhaled C immitis or C posadasii arthroconidia (ie, spores; see the image below) are deposited into the terminal bronchiole.



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Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules conta....

In the bronchioles, the arthroconidia enlarge to form spherules, which are round double-walled structures measuring approximately 20-100 μm in diameter. The spherules undergo internal division within 48-72 hours and become filled with hundreds to thousands of offspring (ie, endospores). Rupture of the spherules leads to the release of endospores, which mature to form more spherules.[4]  

As an arthroconidium transforms into a spherule, the resulting inflammation results in a local pulmonary lesion. Extracts of C immitis organisms react with complement, leading to the release of mediators of chemotaxis for neutrophils.

Some of the endospores are engulfed by macrophages, initiating the acute inflammation phase. If the infection is not cleared during this process, a new set of lymphocytes and histiocytes descend on the infection site, leading to granuloma formation with the presence of giant cells. This is the chronic inflammation phase. People with severe disease may have both acute and chronic forms of inflammation.

Numerous studies have established that immunity mediated by T cells is critical to controlling the infection.[10] The innate cellular response (neutrophils, macrophages mononuclear cells, NK cells) also contributes to host defense. T-cell activation and cytokine formation stimulate inflammatory cells and facilitate killing of the organism. T-helper type 1 (Th-1) cytokines, particularly interferon-gamma, promote macrophage killing of endospores.

A failure of the host to respond appropriately indicates either a specific or a generalized deficiency in cell-mediated immunity. This is clinically overt in patients who have conditions that impair cell-mediated immunity and in those who are using agents that interfere with T-cell function. Other factors, such as immune-complex formation and antigen overload, can also cause failure of host response.

Some of the phagocytized arthroconidia are theorized to be transported back to draining lymph nodes by macrophages and can cause lymphangitis. The inoculating dose responsible for infection is small and may be 10 or fewer arthroconidia.

The presence of spherules triggers an acute inflammatory reaction. Spherules react with complement and promote chemotaxis of neutrophils and eosinophils. A mononuclear infiltrate may develop followed by subsequent conversion to polymorphonuclear predominance.

Pathogenicity of the organism is largely related to the resistance of the spherule to eradication by host defenses. Spherules and endospores produce no known toxins, and as new spherules are propagated in infected tissue, progressive suppuration and tissue necrosis occur. Neutrophils and mononuclear cells attempt phagocytosis of the organism, and giant cells are formed to attack larger fungal structures.

The body responds to the presence of the endospores with activation of complement and release of chemotactic factors. An intense, primarily neutrophilic, inflammatory reaction follows; however, the recruited neutrophils and macrophages are unable to kill the organisms because the spherules are resistant to phagocytosis. T-cell mediated immunity is important for killing and clearing of the organism; therefore, deficiencies in this arm of the immune system render the host of the fungus extremely vulnerable to disease and dissemination.[4]

Nonrespiratory transmission

In rare occurrences, direct inoculation of Coccidioides (eg, from contaminated penetrating objects).causes primary cutaneous coccidioidomycosis with lymphatic extension to the regional lymph nodes; these cases resolve without treatment. In 2009, a report alleged transmission of coccidioidomycosis to a human by a cat bite.[11] This occurred in a veterinary assistant who had been bitten on the hand by a cat that was later diagnosed with disseminated disease.

Case reports have documented rare instances of coccidioidomycosis transmitted through other modes. These include transplantation of organs from infected donors and sexually transmitted cases.

Dissemination

In some individuals, Coccidioides leaves the lungs to establish disseminated lesions in distant parts of the body. To establish extrapulmonary sites of infection, the fungal elements must move from the bronchiole into the lung parenchyma and enter and leave the vascular space.

Initially, the organism may spread via lymphatic drainage of infected macrophages from the initial terminal bronchiole lesion, as demonstrated by sequential involvement of the hilar nodes, followed by the paratracheal and then supraclavicular nodes, and finally reaching the common lymphatic duct.

From the thoracic duct, spread of the infection becomes hematogenous. Certain host factors, clinical findings, and laboratory findings suggest dissemination including advanced age, immunocompromised state, late stages of pregnancy, and ethnic or racial factors (see Epidemiology).

With dissemination, cell-mediated immunity can become impaired further, often reflected by anergy to coccidioidal skin tests. The mechanism for this effect on cell-mediated immunity is unclear, although many theories have been postulated. Antigen overload, suppressor cells, formation of immune complexes, and elaboration of immunosuppressive substances by the fungi may contribute to the impairment in cell-mediated immunity.[4] Eventually, immunity may recover with treatment and control of the coccidioidomycosis.

Etiology

Coccidioidomycosis is caused by C immitis and C posadasii, 2 genetically distinct but morphologically identical species of a soil fungus endemic to certain arid-to-semiarid regions of the Western Hemisphere. The ecologic niche of Coccidioides is in the desert Southwest. This zone is characterized by low elevations (below 3700 ft), scant rainfall (5-20 in/y), mild winters (40-54°F) and hot summers, and sandy alkaline soil with increased salinity.[6, 12, 13]

Desert Southwest zones are found in areas of the Western Hemisphere from latitudes 40° north to 40° south.[2, 14, 15] The endemic areas for Coccidioides in the United States include Arizona, south central California (San Joaquin Valley), Nevada, New Mexico, certain parts of Utah, and the western half of Texas.

Other endemic areas are the regions of Mexico that border the western United States. The fungi also are endemic to some Central American countries, including Guatemala, Honduras, and Nicaragua. Certain desert regions of South America (Brazil, Argentina, Paraguay, Venezuela) also are endemic.

C immitis is largely limited to the San Joaquin Valley. C posadasii is found in the other areas of Coccidioides endemicity. The manifestations of infection with either organism are assumed to be identical.

Coccidioides life cycle

Coccidioides is a dimorphic fungus, meaning that it assumes 2 different forms, yeast or mold, depending on the environment. In soil, Coccidioides grows as a mold (mycelium) with branching septate hyphae. During the rainy season, the mycelia grow rapidly, but they are also the least infectious form of the organism.[6]

As the soil becomes drier, in late summer and early fall, the hyphae develop into arthrospores. Arthrospores measure 3-5 µm and are extremely hardy, withstanding extreme heat, desiccation, and changes in soil salinity and remaining viable in the soil for months to years. When the soil is disturbed by wind or excavation, arthrospores readily disarticulate into single arthroconidia (rectangular spores measuring 8-30 μm in diameter) and become airborne.[7] (See the image below.) The arthroconidia are the infectious particles of coccidioidomycosis.



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Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules conta....

Coccidioides arthroconidia are extremely infectious; a single C immitis arthroconidium may be sufficient to produce a respiratory infection. However, exposure to high spore burdens increases the likelihood of more severe disease in otherwise healthy persons.

If inhaled by animals or humans, the arthroconidia can reach the pulmonary alveoli. The size of the arthroconidium allows it to be deposited in the terminal bronchiole but probably does not allow it to reach the alveolar space by means of direct inhalation.

Once in the alveoli, Coccidioides enters the yeast stage of its life cycle. The arthroconidium sheds its outer coating, swells, and becomes a spherule—a round, thick-walled multinucleate structure that contains hundreds to thousands of uninucleate endospores. Rupture of the spherule leads to release of the contained endospores, each of which matures into spherules, repeating the cycle.

Rarely, direct inoculation of C immitis (eg, from contaminated penetrating objects) causes primary cutaneous coccidioidomycosis with lymphatic extension to the regional lymph nodes; these cases resolve without treatment.

Domesticated, zoo, and wild animals can also be infected with Coccidioides species. In 2009, a report alleged transmission of coccidioidomycosis to a human by a cat bite.[11] This occurred in a veterinary assistant who had been bitten on the hand by a cat that was later diagnosed with disseminated disease.

Case reports have documented rare instances of coccidioidomycosis transmitted through other modes. These have included donated organs and sexual transmission.

Epidemiology

Coccidioides (C immitis and C posadasii) is endemic in the soil in certain regions of the Western Hemisphere, almost all of which are located between latitudes 40° north and 40° south.[2, 14, 15] These areas are characterized by semiarid climates with hot summers and alkaline soil.

Although residents of endemic areas are at highest risk for acquiring infection, coccidioidomycosis is being recognized increasingly outside of these areas due to travel, population mobility, immunosuppression, and reactivation. Diagnosis often is delayed in nonendemic areas because coccidioidal infection initially is not considered in the differential diagnosis.[2, 3, 4, 5]

United States statistics

In the United States, C immitis is endemic in California's San Joaquin Valley, while C posadasii is endemic in areas of the desert Southwest, including southern parts of Arizona as well as certain parts of Utah, Nevada, New Mexico, and Texas. Coccidioidomycosis occurs both among residents of these endemic areas as well as travelers who visit there. An occasional case transmitted via fomites is reported outside of endemic areas.

Historically, people at greatest risk for contact include farmers, construction workers, and archaeologists.[16, 17] Thus, otherwise healthy persons exposed to high spore burdens have a higher likelihood of more severe disease.

The exact incidence of coccidioidal infections can only be inferred because approximately 60% of those infected are asymptomatic or have subclinical disease and never come to medical attention. An estimated 150,000 infections occur annually in the United States. This estimate is higher than the 100,000 cases per year previously cited in the literature and reflects population increases in southern Arizona and central California, where the organism is endemic.[12, 7] From 1988-2011, the incidence of coccidioidal infections in Arizona, California, Nevada, New Mexico, and Utah increased from 5.3 per 100,000 to 42.6 per 100,000.[18]

Approximately 25,000 new, clinically evident cases of coccidioidomycosis are reported annually in the United States. As many as 75 deaths per year result from the infection.

Based on skin test data, 80% or more of residents living in endemic areas for 5 years or longer will have a positive coccidioidin skin test result. The prevalence of positive skin test results ranges from 50-70% in the southwestern United States and increases with age.

Several sharp upsurges in the incidence have occurred. The western migration of the 1930s and the influx of military personnel in the 1940s triggered notable increases. In 1978, the first true epidemic occurred after an unprecedented dust storm that originated in the lower end of the San Joaquin Valley, quadrupling the incidence of disease.

A coccidioidal epidemic occurred in California in 1991-1994. In 1992, this outbreak produced a peak of approximately 4200 cases, an increase of more than 14-fold from baseline. One explanation for the epidemic is that it occurred after a 5-year drought that was terminated by above-average rainfall. This rainfall allowed dormant arthrospores to germinate and to be carried aloft by summer winds. At the same time, a marked influx of disease-naive individuals into the area further set the stage for the epidemic.

In areas of highest endemicity, the infection rate is approximately 2-4% per year. The prevalence in endemic areas has varied over time; the disease affects 30-40% of the population within the endemic regions of California and Arizona.[10] This figure is lower than findings from epidemiologic studies performed 50 years ago, when 68% of the population was found to have skin tests positive for coccidioidal antigens. Positive skin test results are related to the duration of residence in endemic areas and to occupational and recreational exposure to dust.

The number of cases of coccidioidomycosis in endemic regions rises sharply in the late summer and early fall, after the soil dries. At that time, soil disturbances, either natural (wind) or man-made (agricultural endeavors, construction, archaeological excavations), are likely to send Coccidioides spores airborne, enhancing the likelihood of its inhalation. In particular, outbreaks have been documented after earthquakes (eg, the 1994 Northridge earthquake in California) and wind storms.

Arizona, where coccidioidomycosis is a reportable condition, has the greatest number of cases. This likely represents symptomatic cases only. More than 5,000 cases are reported annually in Arizona, and the state has noted a steady increase in cases, with 7 cases per 100,000 persons in 1990, increasing to 15 cases per 100,000 persons in 1995[19] and an estimated 75 cases per 100,000 persons in 2007.

In California, the number of annually reported coccidioidomycosis cases more than tripled from 2000-2006, rising from 2.4 to 8 cases per 100,000 population.[20] The annual incidence was highest in Kern County (150 cases per 100,000 population), with the hospitalization rate highest among non-Hispanic blacks, increasing from 3 cases to 7.5 cases per 100,000 population.

Coccidioidal disease has a significant socioeconomic impact in the United States. An otherwise healthy individual diagnosed with symptomatic coccidioidomycosis may miss more than one month of school or work. Recent estimates of antifungal medication costs range from $5000 to $20,000 per person per year of therapy for the disease.[3, 21]

Scholarship athletes represent a precisely defined group to calculate endemic risk for infection within a young adult population.[22] Case rates were higher for scholarship athletes in Tucson, Arizona, than for other students, highlighting the need to routinely test students for coccidioidomycosis in endemic areas.

International statistics

Coccidioidomycosis is a disease of the American continents. It was first described in Argentina in the late 1800s, and most of what is known today was due to investigations made in the United States in the early 1900s. Currently, all countries in between have described cases of coccidioidomycosis, and most have recognized endemic areas.

The incidence of coccidioidal infections in other endemic areas of North and South America outside of the United States is unknown. The infection risk remains highest in the endemic areas of northern Mexico and Central and South America. However, the incidence over time may not mirror the increase seen in the southwestern United States, because the latter increase has been driven by construction and immigration of uninfected individuals into the area.

The prevalence of coccidioidomycosis in the Americas is as follows[23] : 56% in Mexico, 42% in Guatemala, very low prevalence in Venezuela and Colombia, 26% in Brazil, 44% in Paraguay, and 40% in Argentina. In an endemic area of Brazil, coccidioidomycosis has been linked to hunting of armadillos.[15]

The incidence of coccidioidomycosis outside of the Western Hemisphere is extremely low, but cases (primarily imported from California, Arizona, and Mexico) have been reported in the following countries:

Racial differences in incidence

No race predilection for primary infection with Coccidioides species has been observed. However, the risk of dissemination or progressive pulmonary disease is higher in Filipinos and blacks, and possibly in other Asians, Hispanics, and Native Americans.[30] The risk of dissemination is 175 times greater in Filipinos and 10 times greater in blacks than in non-Hispanic whites.[7] Hispanics with A or B type blood groups also have a slightly higher risk for advanced and/or disseminated disease compared with the population as a whole.[31]

This risk persists when analyses are controlled for age, sex, additional demographic features, concurrent medical problems, duration of exposure, and occupation.[32] When these populations are infected with the Coccidioides organism, their rate of skin test positivity decreases, and their complement-fixation titer increases compared with findings in the non-Hispanic white population.

One large study of 536 individuals demonstrated that 2.6% of non-Hispanic whites had dissemination, compared with 3.4% of Hispanic individuals, 7.3% of Filipinos, 22% of African Americans, and 20% of Asians.[33]

Sexual and age-related differences in incidence

An increased incidence of primary coccidioidal infection may be apparent in older boys and men because of occupational exposure. Women who are pregnant, especially during the third trimester and in the immediate postpartum period, are at higher risk for dissemination than the general population.[7, 34, 35]

All age groups can be affected. Primary infection of the newborn rarely occurs.[35] Infection of the genital tract of the mother can result in placental involvement, coccidioidal endometritis, and aspiration of infected amniotic fluid by the fetus. Both congenital and perinatal transmission of Coccidioides species have been reported. However, infants can experience severe disease within the first few months of life, especially if exposed to a large respiratory inoculum.

Prognosis

Most patients with coccidioidomycosis have an excellent prognosis; most infections are self-limited and resolve within a few months without the need for medical intervention. In more than 90% of symptomatic individuals, no further sequelae develop. Treatment with antifungal therapy is effective in most of the defined clinical syndromes, however, and therefore the prognosis for recovery in these patients is also excellent.

Chronic coccidioidomycosis develops in 5-8% of patients following primary pulmonary disease. This is characterized by pulmonary disease, with or without extrapulmonary spread, or by extrapulmonary disease alone. Chronic pulmonary disease generally represents failure of local defenses and is commonly associated with advanced age and/or diabetes. The most common forms are cavity or nodule formation, which frequently represent a transition from acute disease to resolution.

Fewer than 1% of patients progress to disseminated disease. Patients with suppressed immune systems or those taking immunosuppressant medications are especially at risk for progressive or disseminated disease, and their coccidioidal infections may be difficult to eradicate.

Factors associated with increased risk of more severe disease include the following:

Disseminated disease may require months to years of antifungal therapy, and high-risk patients are at significant risk for relapse when treatment is stopped, even after extended courses (years) of treatment.

Coccidioidal IgG titers may be useful to assess risk for dissemination (titers >1:16) and monitor response to therapy (fourfold or greater decline in titer).

Although morbidity is substantial in coccidioidomycosis, mortality is very low; the mortality rate is approximately 0.07%. Death occurs most commonly in patients with disseminated disease, underlying risk factors, or immunosuppression. In immunocompromised patients, mortality can be as high as 70% even with appropriate therapy.[2, 3, 4] Few patients with advanced HIV infection who develop Coccidioides infection have survived longer than a few months.

In disseminated disease, the mortality rates in neonates and infants are much higher than those seen in children, adolescents, and adults. Septic shock may develop, especially in older or immunocompromised patients, and unfortunately, the outcome in these patients is uniformly poor.

Of the clinical syndromes, mortality is highest in coccidioidal meningitis. If left untreated, meningitis is fatal in 90% of patients within 1 year and is universally fatal within 2 years. Mortality rates can be 20-40%, even with treatment.

Mortality is significantly increased in coccidioidal meningitis patients with complications such as hydrocephalus or infectious arteritis. Hydrocephalus is the most common complication (30%) and carries a mortality rate of 40%. Occlusion of the cranial vessels by inflammatory exudates may lead to stroke. Occlusion occurs in 10% of patients and increases the likelihood of mortality.[37]

Patient Education

Residents of and travelers to endemic areas should be aware of the risk of coccidioidal infection. Education about the possibility of acquiring infection through exposure to dust or soil and the avoidance of avoiding activities that increase the likelihood of dust inhalation (eg, recreational activities, construction, archaeological digs) is particularly important for patients at high risk (eg, immunocompromised patients, pregnant women, African Americans, Filipinos, those with diabetes).

For patient education information, see the Procedures Center, as well as Bronchoscopy.

History

The incubation period of coccidioidomycosis averages 10-16 days, with a range of less than 7 days to 30 days.[2] The natural history of Coccidioides infection is usually one of a self-limited respiratory tract infection. In most cases, symptoms do not occur or are so mild that the infected individual does not seek medical attention.[10, 38] Approximately 30-40% of patients develop symptomatic disease, ranging from a mild influenzalike illness, to subacute pneumonia, to, rarely, respiratory failure.

Common symptoms of primary infection are nonspecific and include fever, cough, chest pain, fatigue, dyspnea, headache, arthralgias, and/or myalgias. Skin manifestations are also seen in a small percentage of cases. In addition to the above symptoms, infection can progress to various presentations. The constellation of fever, arthralgias, erythema nodosum or erythema multiforme, and chest pain is commonly referred to as San Joaquin Valley fever (or simply Valley fever) or desert rheumatism.

A study by Johnson and colleagues reported the following frequency of symptoms[39] :

Other symptoms included the following:

Primary pulmonary infection may progress to overt pneumonia and chronic lung infections; hematogenous spread may occur, leading to disseminated disease, with focal involvement such as arthritis, osteomyelitis, and meningitis. Patients who have disseminated disease present with dramatic sweats, dyspnea at rest, fever, and weight loss.

Exposure history

In patients with suspected coccidioidomycosis, a history of travel to, or residence in, an endemic area is very important in establishing the risk of exposure. The exposure may be as limited as driving through an endemic area.[6, 2, 3, 7, 4, 8, 9] The clinician should inquire about activities that involve increased exposure to dust or soil (eg, farming, construction work, archaeological digs). Rare cases of infection from contaminated fomites (eg, contaminated plaster cast, dusty clothing) have been reported.[4]

Coccidioidomycosis is considered to be an occupational hazard in endemic regions, and it is a compensable illness in such cases.

Severe disease

Dissemination usually occurs weeks to months after the initial infection but may occur after 1 year in a host who is immunocompromised. In addition, reactivation of treated primary disease may occur at any time in a host who is immunosuppressed. Some patients may have no radiographic evidence of previous pulmonary disease, as well as no history of a preceding respiratory illness.

Factors associated with increased risk of more severe coccidioidal disease include the following:

The male-to-female ratio in disseminated disease is 5:1, but this disparity reverses in pregnant women.

Physical Examination

No physical findings are pathognomonic for coccidioidal infection. However, in endemic areas, coccidioidal infection should be a strong consideration for patients who present with an influenzalike illness and a lower-extremity rash. Suggestive signs of disseminated disease include dramatic sweats, dyspnea at rest, fever, and weight loss.

In addition to nonspecific systemic signs (eg, fever), findings on physical examination reflect the organ system or systems involved.

Respiratory manifestations

Pulmonary coccidioidomycosis may be difficult to differentiate from other acute or subacute respiratory infections with fever. Most symptomatic primary infections are not easily diagnosed as coccidioidomycosis unless classic findings (eg, erythema nodosum) are present in an endemic area.

Respiratory symptoms are related to the severity of lung involvement and destruction, and they range from cough, to mild respiratory distress, to respiratory failure and acute respiratory distress syndrome.

Pulmonary involvement may manifest as the following:

Less commonly, diffuse coccidioidal pneumonia in immunocompetent hosts manifests as respiratory failure. This is due to either inoculation with a large number of spores or to hematogenous seeding of the lung at several sites.

Approximately 5% of pulmonary infections result in the formation of nodules. These typically cause no symptoms but may be indistinguishable from a neoplasm on radiologic studies without histologic examination.

Approximately half of these nodules resolve spontaneously. However, persistent nodules can eventually degenerate into thin-walled cavitations, which may erode into adjacent small airways or the pleural space, resulting in hemoptysis or pneumothorax. Rupture of a peripheral coccidioidal cavity into the pleural space is a complication that is most common in young male patients.

Patients with diabetes mellitus or preexisting pulmonary fibrosis (eg, from cigarette smoking) may develop a chronic fibrotic pneumonia process. These patients may present with chronic cough and systemic symptoms such as fever, night sweats, and weight loss, as well as local symptoms.

Skin manifestations

Cutaneous hypersensitivity reactions are common in primary coccidioidomycosis. More than 50% of affected children, and 25% of infected individuals overall, develop diffuse, evanescent, maculopapular rashes or urticaria that may progress to erythema nodosum or erythema multiforme after 3-21 days. Erythema multiforme is more common in children, but erythema nodosum is the classic presentation in an endemic area.

Erythema nodosum presents as tender, erythematous nodules, 1-2 cm in diameter, on the anterior lower extremities (see the image below), although they may develop virtually anywhere. Erythema multiforme consists of relatively symmetric erythematous, expanding macules or papules that evolve into classic iris or target lesions with bright-red borders. Central vesicle formation is common.



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Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.

Ocular hypersensitivity reactions frequently accompany erythema nodosum. These include phlyctenular conjunctivitis, episcleritis, scleritis, and keratoconjunctivitis.

These cutaneous hypersensitivity reactions are a favorable prognostic sign; they suggest a low risk of dissemination because they correlate with development of cell-mediated immunity. Erythema nodosum occurs less often in persons outside of endemic areas and occurs infrequently in blacks, Hispanics, and Filipinos. Among adults, women experience erythema nodosum much more frequently than men.

Cutaneous hypersensitivity reactions must be distinguished from cutaneous Coccidioides infection, in which the organism is present in the lesion. The skin eventually is involved in most types of disseminated disease. Cutaneous infection usually results from hematogenous seeding, but direct inoculation may occur, evidenced by lymphangitis.

Cutaneous coccidioidal infection has a variable appearance; papules, plaques, and verrucous lesions are the most common. The classic skin manifestation of coccidioidomycosis is a verrucous granuloma at the nasolabial fold. Other typical lesions include granulomatous papules, nodules, and plaques, especially on the head. These lesions can progress to subcutaneous involvement, sinus tracts, abscesses, and chronic ulcers (see the image below).

Abscess formation may be associated with underlying bone or organ involvement. Facial involvement is associated with a 10-fold increase in the probability of coccidioidal meningitis.

Disseminated infection can also result in ulceration and fistulas from underlying infection.



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Soft tissue abscess due to cocci.

Musculoskeletal manifestations

Musculoskeletal involvement occurs in one third of patients with dissemination and include the following:

Although arthritis is usually monoarticular, it can be migratory in nature. Knees are the most common joints involved, followed by ankles and wrists. Physical findings are not helpful in differentiating coccidioidomycosis from other causes of monoarthritis or oligoarthritis.

Arthrocentesis samples typically reveal an exudative effusion. The presence of organisms varies, and reports suggest that direct visualization of organisms is rare but can occur in up to half of cases.

Coccidioidomycosis also affects joints, causing synovitis. Infection of the bone typically causes a chronic osteomyelitis, often draining to soft tissue and creating fistulae. Long bones, as well as bones of the hands, feet, pelvis, and skull, may be involved. Approximately 60% of incidents of coccidioidomycosis are limited to a single bone, with 20% involving 2 bones and 10% involving 3 bones. Vertebral osteomyelitis can affect any part of the vertebra, sparing the disc, but putting the patient at risk of meningitis.[40]

Although osteomyelitis can occur from direct inoculation of bone from contaminated penetrating objects, it is more commonly due to hematogenous spread and disproportionately affects the vertebra; paraspinal abscesses are a possible complication. Local pain and tenderness may be evident with vertebral osteomyelitis or paraspinous abscesses. Progressive bony destruction in the vertebrae can lead to spinal cord compression that may require urgent surgical intervention.

Other common sites of involvement include the tibia, femur, skull, and bones of the hands and feet. Other complications of osteomyelitis include contiguous joint arthritis, draining sinus formation, and subcutaneous abscess formation in adjacent soft tissue.

Other organ involvement

Coccidioides infection can involve virtually any organ system. At autopsy, involvement of the liver, spleen, kidney, adrenal glands, psoas muscle, heart, thyroid, and prostate has been noted. These infected sites rarely are responsible for the presenting signs or symptoms. Infection of the thyroid gland has been reported to result in a thyroid abscess and thyrotoxicosis.

Lymph node involvement can be prominent; occasionally, such cases lead to a mistaken diagnosis of lymphatic malignancy. Supraclavicular and cervical lymphadenopathy are common and probably result from lymphatic drainage from the pulmonary infection site. Lymphadenopathy may be generalized, and associated drainage from contiguous lesions is not unusual.

In a minority of patients, splenic enlargement is clinically apparent. Hepatic involvement with prominently elevated alkaline phosphatase levels is common in the context of widespread disease. Hepatic infection is usually asymptomatic but can be part of a hepatic-pulmonary syndrome with a brief hepatitis-like illness, hepatic granulomas, and eosinophilia.

Coccidioidal infection of the biliary tree is uncommon but has been reported to present as abdominal pain and obstructive jaundice. Intestinal obstruction and peritonitis have also been reported to be secondary to coccidioidal infection.[41]

Cardiovascular complications account for an extremely small percentage of clinical presentations. In the rare cases in which they do occur, however, they can be devastating. Pericardial effusions and can produce cardiovascular compromise and tamponade in extreme cases.[42] Myocardial involvement is most often discovered at autopsy.

Urinary tract involvement is rare (with the exception of asymptomatic coccidiuria) and is usually found in the setting of widely disseminated disease. The prostate may serve as a nidus of infection and has been implicated as a source of urinary cultures that are positive for the Coccidioides organism. Involvement of the ovaries and testicles is very uncommon.

Ocular coccidioidomycosis is rare but is probably underappreciated. Ocular involvement usually occurs in the context of disseminated disease. Ocular coccidioidomycosis can present as a lacrimal gland fossa mass or with eye pain, photophobia, and other symptoms of chorioretinitis or iridocyclitis. Anterior uveitis and posterior uveitis (choroiditis and chorioretinitis) are uncommon, and endophthalmitis is rare and can occur without systemic involvement.[43]

Meningitis

Approximately 50% of patients with disseminated coccidioidomycosis acquire CNS disease. It can occur acutely with primary infection or later with dissemination. The meninges can be the only site of dissemination, in which case the patients is at increased risk of complications and death.[44]

Coccidioidal meningitis can present as an acute process but it is usually chronic with insidious onset, in contrast to meningitis from bacterial causes. Persistent headaches should be evaluated thoroughly upon worsening, especially in cases of unusual severity, associated nausea and vomiting, blurry vision, or a change in mental status (eg, drowsiness and confusion). Other common manifestations include nuchal rigidity and photophobia.

Symptoms related to increased intracranial pressure (eg, nausea, vomiting, altered mental status) are relatively common. Less-common presentations include focal neurologic deficits, cranial nerve palsies, tremulousness, intention tremor, papilledema, gait abnormalities, seizure, and coma.[45]

Typically a granulomatous and suppurative basilar process, coccidioidal meningitis can also involve the brain parenchyma and spinal cord with granulomas and abscesses. Hydrocephalus is a common sequela and is often present at initial diagnosis in children.

Septic shock

Septic shock generally develops in older individuals or immune-compromised patients. For example, patients with advanced HIV disease may present with a fulminant picture of respiratory failure, diffuse pneumonia, fungemia, and septic shock that resembles a gram-negative infection.

This condition is diagnosed on the basis of established criteria and hemodynamic monitoring. Cytokine assays reveal elevated levels of tumor necrosis factor (TNF) and interleukin-6, as in bacterial sepsis.

Coccidioidal fungemia

This is a very rare, fulminant complication of disseminated coccidioidomycosis. Coccidioidal fungemia seems to be more common in patients with comorbidities and immunosuppressive states. The literature notes 113 cases, with about 38% associated with HIV; 18% with corticosteroids; 10% with solid organ transplants; and 4% with pregnancy. Dissemination occurred to the liver, spleen, and meninges/CNS, but endocarditis was not found. Serologic tests were positive in 87% patients. Overall mortality at 30 days was 62%, with a mean survival of 11.4 days. Survival is poorest in immunocompromised patients or those not receiving antifungal therapy.[46]

Approach Considerations

Because most patients recover spontaneously, pursuing documentation of coccidioidal infection is not imperative unless the patient is immunocompromised or has signs of severe progressive disease or dissemination. Diagnosis requires isolation of the organism in culture, identification on histologic specimens, or serologic testing.

The diagnostic evaluation is guided by the patient's clinical presentation and the clinician’s index of suspicion. General laboratory tests include a complete blood count (CBC) and erythrocyte sedimentation rate (ESR). Typical results are a normal white blood cell count or mild lymphocytosis, monocytosis, and/or eosinophilia (>5%) and an elevated ESR.

The specific laboratory tests include the following:

Observation of Coccidioides in a clinical specimen establishes the diagnosis. Specimens may include any of the following:

Coccidioides urinary antigenemia has been found positive in more than 70% of immunocompromised patients with HIV/AIDS or solid organ transplant; no reports on its sensitivity in less compromised or immunocompetent patients are available.[48] One study has suggested an association between low serum mannose-binding lectin (MBL) levels and symptomatic coccidioidomycosis.[49]

Chest radiography is indicated, with further imaging studies as appropriate. Lumbar puncture is mandatory in patients with suspected meningitis.

Serologic Studies

For more than half a century, detection of antibodies to coccidioidal antigens has been used to establish the diagnosis of coccidioidomycosis and to monitor patients undergoing therapy.[6, 2, 3, 7, 4, 50, 51] As false positives are rare, a positive serologic result is very likely to be clinically relevant in the appropriate clinical setting; however, a negative result does not exclude the diagnosis. Repeat testing following a negative result improves sensitivity.

Serologic tests for coccidioidomycosis measure titers of immunoglobulin M (IgM) or immunoglobulin G (IgG). These tests can also be performed on cerebrospinal fluid (CSF) upon suspicion of coccidioidal meningitis.

Immunoglobulin M

The appearance of immunoglobulin M (IgM) or precipitin antibody against Coccidioides is the most sensitive serologic indication of early infection. IgM is detected in approximately half of all coccidioidal infections within the first week and in approximately 90% by 3 weeks.

The IgM antibody fades over several weeks. In most patients, these antibodies dissipate within 6 months. However, IgM may persist and/or reappear under certain circumstances (eg, chronic cavitary coccidioidomycosis or systemic reinfection associated with ventriculoperitoneal shunt placement).

Methods of IgM detection are as follows:

IgM has only qualitative significance, as the magnitude does not correlate with dissemination or extent of disease. Also, a high rate of false-positives is noted, especially in conditions that stimulate humoral immunity.

Immunoglobulin G

Immunodiffusion and complement fixation (CF) methods can detect coccidioidal immunoglobulin G (IgG). IgG antibodies detected via CF become positive in 85-90% of patients by 3 months after infection onset, persist 6-8 months, and disappear as infection resolves. However, in some cases IgG can persist for years.

In contrast to IgM, for which quantification is uninformative, the CF titer is useful as a quantitative measure of the extent and progression of disease. The CF IgG titer may be low or absent in mild or asymptomatic disease or in immunosuppressed patients. Approximately 95-100% of patients with titers of 1:16 or less do not have disseminated disease. High titers (ie, 1:32 or higher) persist in severe, untreated extrapulmonary or disseminated disease.

Coccidioidal CF titers in the serum and cerebrospinal fluid can be followed to monitor the effect of treatment on disease and predict relapses.

Cultures

The most definitive method for diagnosis is isolation of the organism from clinical specimens. The fungus grows well on most common laboratory media within 3-5 days of inoculation on laboratory media, even when spherules are not present on direct examination. However, the morphology of the colonies (white and cottony mold) is not adequate for identification because other organisms have similar mycelial forms.

Observation of typical arthroconidia may be used to identify the Coccidioides organism.

Identification can be confirmed with a commercially available nucleic acid (gene) probe. Confirmation with exoantigen testing may also be performed, although this test has been replaced by nucleic acid probes. Culture of the organism and definitive identification takes up to 3 weeks.

In culture, Coccidioides spherules can convert to arthroconidia, which are highly contagious. For that reason, cultures should be performed only in Biosafety level 3 laboratories.

Polymerase Chain Reaction Testing

PCR assays are used to detect a target gene after DNA extraction from biopsy specimens.[52] In the clinical setting, Coccidioides PCR serum testing was found to have very high specificity and negative predictive value.[53] PCR testing is a safer and faster alternative to handling highly virulent cultures of Coccidioides.

PCR amplification has been used successfully to identify the highly specific Ag2/PRA antigen gene of C posadasii in appropriate samples of sputum.[54] This technique can be applied to both clinical specimens and cultures.[55, 56] The MBP-1 gene for both Coccidioides species and the SOW-gp82 gene for C posadasii have also been identified with high sensitivity and high specificity via PCR.[57]

Skin Testing

Skin testing for diagnosis of coccidioidomycosis involves the intradermal injection of a coccidioidal antigen preparation (eg, coccidioidin, spherulin). The induration of the skin is measured at 24 hours and 48 hours after the injection. An induration greater than 5 mm is considered reactive. Erythema at the injection site does not aid in the diagnosis of coccidioidomycosis. The skin test becomes positive 10-45 days after infection or 2-21 days after symptom onset, preceding the appearance of serologic markers.

Coccidioidin and spherulin are no longer available in the United States. However, Ampel et al found that archived coccidioidin from the 1970s retains its potency and specificity.[58]

The assessment of cutaneous reactivity to coccidioidal antigens has limited diagnostic utility due to low sensitivity and specificity in endemic areas.[4] A dermal delayed-type hypersensitivity reaction to coccidioidin is highly specific for coccidioidal infection. However, a positive result may not be related to current disease because, in most persons, this skin test result remains positive for life after infection. In addition, a low level of cross-reactivity with blastomycosis and histoplasmosis occurs.

Results in infected individuals may be falsely negative because of a lack of immune response. Anergy is common in patients with disseminated disease, even without underlying immunosuppression.

Although skin testing has important limitations when it is used as a screening procedure for recent infections with C immitis, cutaneous reactivity to coccidioidal antigens has epidemiologic and prognostic implications. In patients in whom coccidioidomycosis is diagnosed with the help of other tests, the results on skin testing of a lack of delayed-type hypersensitivity is a negative prognostic factor.

Radiography and Other Imaging Studies

Obtain chest radiography in all patients with suspected or confirmed coccidioidomycosis, to check for signs of pulmonary infection. Radiographs may be normal or may show a variety of nonspecific changes[6, 2, 3, 7, 4, 8, 5, 59, 60, 40] :

Computed tomography or magnetic resonance imaging scanning, and possibly positron-emission tomography (PET) scanning may also be valuable. For discussion of imaging studies in coccidioidomycosis, see Imaging Studies in Coccidioidomycosis.

Lumbar Puncture

Perform lumbar puncture in patients with fever, headache, nuchal rigidity, meningismus, mental status changes, or ataxia.[9, 59] Many physicians perform lumbar puncture in all patients with extrapulmonary disease or significantly elevated CF IgG titers.

CSF analysis typically reveals a lymphocytic pleocytosis with elevated protein levels and hypoglycorrhachia. In as many as 70% of patients, coccidioidal meningitis is associated with eosinophils in the CSF. Coccidioidomycosis is the most common cause of eosinophilic pleocytosis in the United States.

The diagnosis is aided by the detection of complement-fixating antibodies in the CSF. Coccidioidal meningitis preferentially involves the basilar meninges.

Demonstration of elevated CF titers in CSF establishes the diagnosis of coccidioidal meningitis. CF IgG is present in 90% of patients with coccidioidal meningitis. Elevated CSF CF titers can also be seen with isolated epidural coccidioidal involvement, but only the CSF total protein value is elevated in that situation.

False-positive CSF CF titers are rare but can occur in patients with very high serum CF titers and no meningeal involvement. Rarely, patients with meningitis as their only site of coccidioidal infection have positive CSF CF titers with negative serum CF titers.

Bronchoscopy

Bronchoscopy is a useful diagnostic procedure in suspected coccidioidal infection if results from other studies (eg, sputum, serologies) are not diagnostic. Successful identification of C immitis (and Mycobacterium tuberculosis) using endoscopic ultrasonography has been reported.[61]

Bronchoscopy may be able to double the yield (compared with sputum) in patients with parenchymal infiltrates and cavitary lesions. In one small series, bronchoscopy established a diagnosis of coccidioidal infection in almost 70% of such cases.[62]

Bronchoscopy is especially useful in patients with tracheal or endobronchial coccidioidal infection, in whom the appearance of lesions can range from erythematous plaques to submucosal nodules to endobronchial masses, and diagnosis is established histologically or from culture.

Bronchoscopy with bronchoalveolar lavage, needle aspiration, and/or lung biopsy may be indicated with persistent or progressive infections, especially in hosts who are immunocompromised.

Bronchoscopy has a very low yield in solitary pulmonary nodules secondary to coccidioidomycosis and is not recommended in these patients.

Biopsy

Peripheral solitary pulmonary nodules secondary to coccidiomycosis are especially amenable to diagnosis by percutaneous transthoracic needle biopsy. Most percutaneous transthoracic needle biopsies are CT guided, which allows direct visualization of the needle into the lesion. Specimen fungal stains demonstrating spherules or culture growing C immitis are diagnostic. Cytology of the specimen should be obtained to rule out malignancy.

Closed pleural biopsy may be diagnostic in patients with coccidioidal pleural effusions. Identification of spherules infiltrating the pleural is diagnostic. Culture of pleural biopsy specimens has the highest yield, with isolation of C immitis of in all cases in one small series. The typical pleural effusion is exudative and lymphocytic with modest eosinophilia. Pleural fluid cultures have a low yield, with isolation of C immitis in less than 20% of patients.

Surgical biopsy may be required if the diagnosis cannot be established using the aforementioned approaches. Surgical biopsy is best suited for sampling lymph nodes or parenchymal lung disease. Cervical mediastinoscopy can access most mediastinal lymph nodes and video-assisted thoracoscopy can be used to obtain parenchymal lung tissue.

In extrapulmonary coccidiomycosis, fine-needle aspiration provides a quick and less invasive diagnosis if easily accessible subcutaneous lymph nodes are noted on examination.[63]

Synovial biopsy may be needed to document coccidioidal dissemination to a joint.

Histologic Findings

The diagnosis of coccidioidomycosis can be made by observing spherules (≤70 μm in diameter) that contain endospores in specimens of any body fluid, including sputum or lesion smears and biopsy material. (See the images below.) Direct examination of sputum is less sensitive than cultures for the identification of spherules.

Sputum smears can be stained with potassium hydroxide [KOH]. Spherules are also identified on smears by using calcofluor white or cytologic stains. Spherules are identified in biopsy specimens using standard stains such as hematoxylin and eosin or Papanicolaou stains. Other useful stains for tissue specimens include periodic acid-Schiff stain (PAS) or Gomori methenamine silver stain.



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Pulmonary cocci spherule (Hematoxylin-eosin stain).



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Pulmonary cocci spherule, periodic acid-Schiff stain.

The predominant tissue reaction is granulomatous. In acute lesions, macrophages and polymorphonuclear neutrophils may be numerous. As lesions become chronic, fibrosis ensues. Caseation and, rarely, calcification may occur.



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Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.



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A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).



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A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).



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Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).



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Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).

Approach Considerations

Most patients infected with Coccidioides are asymptomatic or have self-limited symptoms and require only supportive care. Symptomatic patients usually come to medical attention because of respiratory tract or systemic manifestations. Management in symptomatic patients varies with the clinical syndrome.

Because most Coccidioides infections resolve without specific therapy, few clinical trials have assessed outcomes in less-severe disease. Most treatment recommendations represent consensus guidelines based on the Mycosis Study Group trials and the experience of many investigators.

Even physicians in endemic regions disagree on who should be treated, the length of treatment, and what agent should be used.[64, 3] However, the Infectious Diseases Society of America has published Practice Guidelines for the Treatment of Coccidioidomycosis.[65]

Three questions should be asked before a case of coccidioidomycosis is treated.

  1. Is intervention necessary?
  2. If antifungal therapy would be beneficial, which agents are appropriate?
  3. Is a surgical procedure necessary for debridement and reconstruction of destructive lesions?

In the decision-making process, significant weight is given to the severity of infection, risk factors for dissemination (eg, race and ethnicity, extremes of age, immunologic status), any severe comorbidity (eg, diabetes, pregnancy, significant preexisting vital organ dysfunction, negative skin test results), and a serum complement-fixation IgG titer of at least 1:32.[14, 6, 2, 3, 7, 4, 8, 9, 59, 66, 60, 40, 45]

Commonly used indicators to judge the severity of illness include the following:

Risk factors for dissemination for which treatment should be initiated include the following:

The objectives of treatment are resolution of infection, decrease of antibody titers, return of function of involved organs, and prevention of relapse.

Antifungal Medications

If the option to treat is chosen, several medications are available for management. Amphotericin B, introduced in 1957, remains the treatment of choice for severe infections. It is usually reserved for worsening disease or lesions located in vital organs such as the spine. It can be administered either in the classic amphotericin B deoxycholate formulation or as a lipid formulation.

Azoles

The introduction of azoles revolutionized therapy for coccidioidomycosis, and these agents are usually the first line of therapy. However, none of the azoles is safe to use in pregnancy and lactation because they have shown teratogenicity in animal studies.

Of the azoles, ketoconazole is the only one that is approved by the US Food and Drug Administration (FDA) for treatment of coccidioidomycosis. Nevertheless, although it was initially used in the long-term treatment of nonmeningeal extrapulmonary disease, more-potent, less-toxic triazoles (fluconazole and itraconazole) have replaced it.

Itraconazole (400 mg/day) appears to have efficacy equal to that of fluconazole in the treatment of nonmeningeal infection and have the same relapse rate after therapy is discontinued. However, itraconazole seems to perform better in skeletal lesions,[67] whereas fluconazole performs better in pulmonary and soft tissue infection. Serum levels of itraconazole are commonly obtained at the onset of long-term therapy because its absorption is sometimes erratic and unpredictable.

Dosages vary but usually are as follows:

For patients who are unresponsive to fluconazole, options are limited. Several case reports have studied the efficacy of 3 newer antifungal agents in the treatment of disease that is refractory to first-line therapy: posaconazole and voriconazole (triazole compounds similar in structure to fluconazole) and caspofungin (glucan synthesis inhibitor of the echinocandin structural class).[68, 69, 70] However, these drugs have not been FDA approved, and clinical trials are lacking. Susceptibility testing of Coccidioides species in one report revealed uniform susceptibility to most antifungal agents, including these newer drugs.[71]

In very severe cases, combination therapy with amphotericin and an azole have been postulated, although no trials have been conducted. Caspofungin in combination with fluconazole has been cited as beneficial in a case report of a 31-year-old Korean man with coccidioidal pneumonia.[72] In a case report of a 23-year-old black male with HIV and coccidioidal meningitis, combination therapy of amphotericin B and posaconazole led to clinical improvement.[73]

Posaconazole has been approved by the European Commission as salvage therapy for refractory coccidioidomycosis.[74] Clinical trials are now ongoing for further evaluation.[75, 76, 68]

Anecdotal reports show that 800 mg/day of posaconazole (a derivative of itraconazole) in divided doses was successful and caused relatively few side effects in patients in whom conventional therapy had failed. Long-term therapy (1-2 years) was well-tolerated. In one case series, 2 patients treated with posaconazole experienced symptomatic and laboratory improvement.[73] In another study, 17 of 20 patients with pulmonary and nondisseminated disease responded well to posaconazole 400 mg/day, and no adverse events were noted.[77]

Voriconazole is also being studied in salvage therapy for refractory cases. A case report indicated that voriconazole in combination with amphotericin B as salvage therapy for disseminated coccidioidomycosis was successful.[78]

Several case reports have studied caspofungin, with differing results. Caspofungin 50 mg/day following administration of amphotericin B in a patient with acute pulmonary coccidioidomycosis who had undergone transplantation showed promising results.[79, 80] In a patient with disseminated coccidioidomycosis, first-line therapy with amphotericin B and caspofungin alone failed to elicit a response, but the patient was then given caspofungin combined with fluconazole, with good results.[72]

A third published report described a patient with disseminated and meningeal coccidioidomycosis in whom conventional therapy with fluconazole, voriconazole, and amphotericin B failed; caspofungin 50 mg/day after a loading dose of 70 mg IV was also unsuccessful.[81]

No studies have directly compared amphotericin B with azole therapy.

Duration of therapy and complications

The duration of therapy is dictated by the clinical course of the illness, but it should be at least 6 months in all patients and often a year or longer in others. Therapy is tailored based on a combination of resolution of symptoms, regression of radiographic abnormalities, and changes in CF IgG titers. Immunocompromised patients and patients with a history of meningeal involvement require lifelong treatment.

Complications related to antifungal medication are as follows:

The cost of antifungal therapy is high, from $5,000 to $20,000 per year. These costs increase for critical patients in need of intensive care. Arizona spent an average of $33,762 per patient with coccidioidomycosis between 1998 and 2001.[82]

Investigational Agents

Suggestions have been made for the use of interferon-gamma in the treatment of fungal infections, given their association with cell-mediated immunity, although coccidioidomycosis was not specifically mentioned among them.[76]  The description of a case of disseminated severe coccidioidomycosis in a patient with autosomal dominant interferon-gamma receptor 1 deficiency certainly suggests more research in the area.[83] Clinical trials are necessary to evaluate promising in vitro findings against Coccidioides and other dimorphic fungal infections.

Treatment of Coccidioidomycosis by Disease Stage

Treatment of coccidioidomycosis can be divided as follows:

Uncomplicated acute pneumonia

Antifungal therapy is not usually necessary for uncomplicated acute primary coccidioidal pneumonia. Because coccidioidal pneumonia resolves spontaneously in 95% of cases without any treatment, most uncomplicated cases can be managed with follow-up visits every 3-6 months for as long as 2 years to confirm resolution of symptoms and radiographic abnormalities.

Although no studies demonstrate that therapy hastens resolution or stops dissemination, some experts propose treatment of all symptomatic patients, especially if risk factors are present. Patients with a higher clinical severity score and symptom score are more likely to be treated. Outcomes are not significantly different, although more complications have been seen in those with cessation of treatment.[9, 84]

Treatment should definitely be offered to patients with the following risk factors:

Elevated CF IgG titers and higher-risk ethnicity (eg, Filipino, black, Hispanic) may sway the decision to treat patients.

Typical antifungal therapy of acute primary pulmonary coccidioidomycosis in these high-risk groups consists mainly of oral azoles at the recommended adult doses (see Medication). During pregnancy, amphotericin B is the treatment of choice because the azoles may be teratogenic.

No consensus has been reached on the duration of therapy, but 6 months of treatment is most common, and CF IgG titers are used to monitor response to therapy. Periodic follow-up is recommended for up to 1 year or longer.

Asymptomatic pulmonary nodule

Antifungal therapy for asymptomatic pulmonary nodules is not typically recommended in immunocompetent patients. Most lesions do not require any further investigation, especially if they are unchanged on serial imaging for 2 or more years. If the nodule starts enlarging, measure coccidial serum antibodies to determine whether disease has become active, which warrants therapy. Resection is indicated if no diagnosis is established and malignancy is a concern.

Diffuse pneumonia

Initially, treat patients with diffuse pulmonary disease (ie, miliary or reticulonodular infiltrates) with amphotericin B or high-dose fluconazole for several weeks until definite signs of improvement are observed. If there is rapid deterioration or significant hypoxia, amphotericin B is used more frequently.

After clear evidence of improvement emerges, therapy may be changed to an oral azole to complete a prolonged course of antifungal therapy. Because these patients are often immunocompromised, the total duration of therapy should be at least 1 year, with secondary prophylaxis continuing indefinitely for subgroups of patients who are severely immunodeficient.

In a retrospective study of oral azole therapy in 224 patients with moderately severe pulmonary disease who received treatment within 30 days of onset of symptoms versus 30 days after the onset of symptoms, the incidence of dissemination and the need for antifungal therapy longer than 1 year were significantly reduced in the group who received early treatment with azoles, but the mortality reduction was insignificant.[37]

In the same study, only 27% of patients developed a complement-fixation titer greater than 1:32 (vs 45% in the group who received late treatment with azoles). These results suggest that in patients with moderately severe pulmonary disease, institution of early or azole therapy should be considered. Further study is needed to confirm this finding.[37]

Pulmonary cavity

Asymptomatic cavities should be monitored because many resolve on their own. Serial imaging can be performed to confirm stability. Cavities should be resected if they are still detectable within 2 years, if they enlarge, or if they are adjacent to the pleura.

Individuals with symptomatic (eg, hemoptysis, or pain) or enlarging cavities may respond to oral azole therapy or to oral antibacterial therapy if bacterial superinfection of the cavity is present. However, symptoms may recur upon cessation of therapy, and the cavities usually do not resolve with antifungal therapy.

Resection should be considered, depending on the risks. Large (>5 cm) or enlarging cavities were previously treated with surgical resection after amphotericin treatment, but in current practice a trial of oral azole therapy is warranted. Surgical resection is reserved for cavities refractory to therapy or for patients with persistent complications such as hemoptysis.

Ruptured cavities (a complication of necrotizing coccidioidal pneumonia) often present as a hydropneumothorax or empyema. Chest tube drainage (if indicated) and antifungal therapy (azoles or amphotericin) are recommended in anticipation of eventual surgical resection. Surgical reduction of cavities is usually performed after 4 weeks of amphotericin treatment. Ruptured nodules may require lobectomy with decortication.

Chronic progressive pneumonia

Individuals with chronic progressive fibrocavitary pneumonia should immediately start antifungal treatment with an oral azole and continue therapy for at least 1 year. Fluconazole at 400 mg/day and itraconazole at 200 mg twice daily appear to be equivalent in efficacy, but more patients demonstrate a response with itraconazole, which becomes evident at 12 months of therapy.

Doses should be increased or a different azole tried, if necessary, to obtain maximal responses. Amphotericin B is an alternative treatment if there is no response. Surgical resection is an option reserved for patients with refractory disease. Surgery in patients with chronic pulmonary coccidioidal infection is not uniformly curative and may result in serious complications. The potential complications of surgery include the development of postoperative bronchopleural fistula and postoperative cavity formation.

Surgical indications include the following:

Limitations to surgical treatment include the following:

Disseminated extrapulmonary infection other than meningitis

All patients with disseminated coccidioidomycosis warrant prolonged antifungal treatment. Therapy for nonmeningeal extrapulmonary disease can be initiated with oral azoles unless the disease is rapidly progressive or in a critical location (such as the vertebral column); in such situations, the alternative therapy is amphotericin B.

Some authors suggest initial therapy with amphotericin B until significant clinical, radiographic, and laboratory test (in particular, CF IgG titers) improvements are documented, followed by completion of the antifungal regimen with an oral azole. Fluconazole and itraconazole are the most commonly used azoles, at doses from 400-2000 mg/day for fluconazole and up to 800 mg/day for itraconazole.

In patients who warrant amphotericin B therapy but have drug-related toxicities, lipid amphotericin B formulations can be considered and have been effective in animal models, although no human clinical trials have assessed their efficacy. Combination therapy with amphotericin B and an azole has been reported, but no clinical trials have demonstrated its superiority to single-agent treatment, and antagonism with combination therapy has been reported for other fungal infections.

Bone and joint involvement

Vertebral involvement may also require surgical debridement and stabilization. Surgical intervention may also be indicated for debridement or draining of effusions or abscesses.

Bone and joint disease is treated as disseminated coccidioidomycosis, although itraconazole is thought to perform better than fluconazole in bone disease. In patients with chronic osteomyelitis, drainage of sequestrum in bones and debridement of adjacent purulent soft tissues often is necessary. Joint involvement can be managed by incision and drainage, although occasionally synovectomy and arthrodesis are needed. Immobilization of limbs affected by the disease may be necessary.

The benefit of irrigation and local instillation of amphotericin B to joints, cavities, or abscesses affected by coccidioidomycosis is controversial, and no clear data supporting this practice are available.

Septic shock

The treatment of septic shock associated with coccidioidomycosis relies on the use of antifungal therapy and appropriate resuscitative and supportive measures. However, this entity carries a poor prognosis.

Two patients with coccidioidomycosis and septic shock treated with drotrecogin alfa (activated protein C) were the first survivors reported. Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

Coccidioidal meningitis

While patients with suspected coccidioidal meningitis can be treated adequately in an outpatient setting, hospitalization helps facilitate confirmation of diagnosis and initiation of therapy.

Fluconazole can be used in the treatment of mild to moderate meningitis and, occasionally, life-threatening meningitis in patients who opt against amphotericin B or who have contraindications to its use. Because of its excellent penetration into the cerebrospinal fluid (CSF), fluconazole has become the drug of choice for long-term therapy of meningeal infection. The 2016 guidelines of the Infectious Diseases Society of America recommend fluconazole as initial therapy.[65]

The usual dosage of fluconazole is 400 mg/day, but many physicians start with 800 or 1000 mg/day. Itraconazole 400-600 mg/day offers comparable efficacy. If the azole therapy elicits a response, treatment is continued indefinitely, because treatment is suppressive rather than curative and relapse rates are high.[45]

Some physicians initiate intrathecal amphotericin B along with the azole, whereas others reserve amphotericin B for cases in which azoles fail.[45, 85] The optimal dose and duration of intrathecal amphotericin is unknown. The IV dose ranges from 0.5-1.5 mg/kg/day, given in 5% glucose over 2-6 hours; the intrathecal dose, administered via cisternal injection, is 0.01-1.5 mg/dose administered at intervals that range from daily to every 48 hours to once per week. Headache, nausea, and fever begin about 30 minutes following the injection and may last for hours.

These injections continue until signs of intolerance appear, including vomiting, prostration, and dose-related mental-status changes. Corticosteroids (eg, 25 mg cortisone succinate) are added to the amphotericin injection to reduce these drug-related inflammation symptoms.

An alternative is continuous infusion of amphotericin B given via a programmable pump implanted into the abdominal wall and connected to the cisternal subarachnoid space. Liposomal amphotericin is lipid-based and has less nephrotoxicity than the deoxycholate formulation

Ventricular peritoneal shunts may be required to treat complications of meningitis (eg, hydrocephalus). In the absence of a CSF block, lumbar peritoneal shunting may be required.

CNS vasculitis is a life-threatening complication of coccidioidal meningitis. Short-term treatment with high-dose IV corticosteroids has been reported with varying results in regards to benefit; however, this information is anecdotal.

Coccidioidomycosis in High-Risk Patients

Coccidioidal infection in immunocompromised individuals and specific groups of immunocompetent individuals follows a more aggressive course than in other groups. These include pregnant women, organ transplant recipients, and patients with HIV disease. Patients receiving immunosuppressive agents for cancer chemotherapy or autoimmune diseases or patients taking long-term corticosteroids are also at increased risk.[86] Progressive pulmonary disease occurs in 40% of immunocompromised individuals.

Although skin reactivity to coccidioidal antigens may be impaired, serologic response in all patients, except those with the most profound immunocompromise, remains intact.

Pregnant women

Pregnancy can pose a clinical challenge. Pregnancy is a risk factor for disseminated coccidioidomycosis because of shifts in T-cell immunity, cytokine production, and hormone changes. Rates of dissemination and mortality are increased late in pregnancy, particularly in the third trimester.

Pregnant women who develop coccidioidomycosis and present with erythema nodosum are extremely unlikely to have a negative outcome, however. In addition, women who have a history of resolved infection prior to pregnancy do not have a significant rate of recrudescence.

Some of the older literature recommended that abortion be considered in pregnant women because of the virulent nature of coccidioidomycosis in these patients. More recent reviews of coccidioidomycosis in pregnancy, however, concluded that although the disease can complicate pregnancy, appropriate management has led to satisfactory outcomes for the mother and child, suggesting that abortion need not be recommended.[87, 88]

Transplant recipients

The immunosuppressive regimen that transplant recipients require places them at increased risk for coccidioidomycosis. A review of coccidioidomycosis in solid organ transplant recipients in an endemic area showed an incidence of 5.7%.

Patients with a history of the disease may experience reactivation or contract primary infection from the donated organ or the environment.[89] Clinical manifestations are similar to those in normal hosts, but dissemination is more frequent (25%) and more rapid. Previously resolved infections reactivate at a rate of approximately 10% per year. Prior coccidioidomycosis does not contraindicate transplantation.

No clear consensus on prophylaxis has been reached. Many programs advocate lifelong prophylaxis, in which case the risks of emergence of resistance and side effects of azole therapy should be considered. The Mayo Clinic Hospital in Arizona advocates a targeted approach to prophylaxis and treatment.[89, 90] Fluconazole is the most commonly used azole.

Pretransplant period

Special attention should be given to patients with end-stage liver disease or alcoholic liver disease and patients on prednisone therapy, because their risk is higher and diagnosis is difficult, as it mimics the underlying disease. All patients should provide a detailed history (including residence in and travel to endemic areas) and undergo serologic testing, immunodiffusion, complement fixation, and chest radiography. These tests should be repeated the day of the transplant and should be repeated annually. All patients should be cleared by an infectious disease specialist.

If the diagnosis of coccidioidomycosis is made during the pre-evaluation testing, treatment is recommended for a year or more, and transplant surgery should be postponed until coccidioidomycosis is cleared. Follow with lifelong antifungal therapy thereafter.

Posttransplant period

Most commonly, coccidioidomycosis is due to reactivation of previous disease. Primary disease can also occur, however, usually within 6-12 months after transplantation, which is the period of more intense rejection therapy. Treat for 1 year or more, and continue for the duration of immunosuppression.

Infections from the donor organ

The history of the donor is as important as that of the recipient, but is not always available. Several case reports have highlighted the possibility of coccidioidomycosis transmitted from donated kidneys, livers, and especially lungs. Receiving an organ from a previously infected donor does not always result in active infection, however.[91] Nevertheless, coccidioidemia has occurred, and autopsy findings revealed microabscesses in several organs. Lifelong prophylaxis is recommended.

HIV-infected patients

In the appropriate geographical setting, coccidioidomycosis is the most common opportunistic infection in patients with HIV. Presentation with coccidioidomycosis may lead to the diagnosis of HIV, or the disease can manifest if CD4+ counts fall to low levels.[92] Co-infection with coccidioidomycosis and tuberculosis have been described.

The introduction of antiretroviral (ARV) therapy has led to a decline in the rates of coccidioidomycosis morbidity. Patients on ARV therapy who have higher CD4+ counts and undetectable HIV RNA levels tend to have less severe disease.

Primary prophylaxis for patients with HIV in endemic areas is not recommended routinely. Treatment of active disease is the same as in other patients; however, if the CD4+ cell count is less than 250/μL, antifungal therapy should continue until the count recovers to above 250 cells/μL. Indefinitely continue suppressive therapy after active disease (ie, secondary prophylaxis) with oral itraconazole (200 mg twice a day) or fluconazole (400 mg each day), regardless of the CD4+ cell count.

Patients on antitumor necrosis factor therapy

Although biologic agents used to treat rheumatoid arthritis and other autoimmune diseases are usually linked to reactivation of tuberculosis and histoplasmosis, a study found that out of 13 patients with rheumatologic disease in an endemic area, all 12 treated with infliximab developed coccidioidomycosis while on therapy. Of these, one third developed disseminated disease. Given the high risk of developing coccidioidomycosis, empiric therapy should be considered before starting infliximab therapy, if serology findings for Coccidioides are positive.[36]

Elderly patients

Older patients are at an increased risk for disseminated disease and diffuse progressive pulmonary disease, but not because of age itself. The mortality rate in patients older than 65 years is increased, with one report describing a mortality rate of 15%. However, more than age, the state of the immune system seems to be the most important factor for dissemination of coccidioidomycosis.

Hospital Admission

The need for hospitalization in patients with coccidioidomycosis is dictated by symptoms and the severity of disease and does not differ from patients with any other respiratory condition. Oral azole therapy is effective; therefore, most coccidioidal infections can be managed in an outpatient setting.

Indications for admission include the following:

Sepsis syndrome, respiratory distress, severe hypoxemia, or severe or unresolving pneumonia as manifestations of acute or disseminated coccidioidal infection are indications for inpatient management. Coccidioidal disease that requires surgical intervention is best managed in an inpatient setting. Refractory cases requiring intravenous amphotericin also require hospitalization; however, once the patient is stable, he or she can be treated in an infusion center environment.

While patients with suspected coccidioidal meningitis can be treated adequately in an outpatient setting, hospitalization helps facilitate confirmation of diagnosis and initiation of therapy.

In a retrospective assessment 158 of 536 patients identified during the first 4 months of a coccidioidal epidemic required hospitalization.[33] The most important factors associated with hospitalization was shortness of breath, followed by age greater than 50 years; African descent; chills, fever, and cough; a negative skin test result; and an initial complement-fixation titer greater than 1:32. Patients who developed erythema nodosum were approximately one third as likely as the others to require hospitalization.

Isolation precautions are not necessary with hospitalized patients because person-to-person transmission of the disease does not occur; however, draining wounds may pose an infectious risk from aerosolization of organisms growing in the dressing or cast material. Enforce proper disposal of contaminated materials.[2]

Deterrence and Prevention

Individuals who live or travel to endemic areas should be aware that the risk of infection is related to exposure to disrupted soil and dust, as may occur around construction sites or during dust storms. Occupational risk and exposure are highest among persons in close proximity to soil and dust, such as gardeners, farm workers, construction workers, and persons involved in archaeological digs.

Laboratory personnel in microbiology laboratories should take proper precautions when handling cultures with possible growth of Coccidioides immitis.

Some protection may be afforded with a well-fitted dust face mask, but these are not always practical or available.

For patients with organ transplants and a history of coccidioidomycosis, antifungal treatment at the time of engraftment has been proposed, although no formal recommendations exist.

Vaccines

No vaccines to prevent coccidioidomycosis currently are used in humans.[93] A killed spherule-derived vaccine was found to be efficacious in animals but not protective in humans.

Multiple Coccidioides species cell-surface antigens have been investigated for their ability to stimulate protective T-cell-mediated immune responses.[82] Currently, recombinant DNA techniques to develop vaccines using the proline-rich[94] and other antigens from the Coccidioides spherule appear promising.

Consultations

Consultation with infectious disease and pulmonary specialists should be requested. Consultation with a neurosurgeon, neurologist, orthopedic surgeon, and/or wound surgeon may be needed to manage complications.

Report cases to the infectious disease and local health departments. Coccidioidomycosis is a reportable disease in states where the disease is endemic, such as California, New Mexico, Arizona, and Nevada.

Long-Term Monitoring

Regular follow-up visits with a primary physician are necessary to document resolution or development of complications. Monitoring visits should be scheduled every 1-3 months and should include a patient interview, physical examination, serologic testing, radiographic examinations, and procedures, as necessary. Patients receiving antifungal therapy require continued monitoring for adverse effects of these agents by history and laboratory testing.

Expert consultations should be considered if needed. Continue follow-up care for at least 1-2 years or until resolution of all coccidioidal disease occurs.

Patients with complications such as chronic pulmonary and all extrapulmonary infections should receive routine follow-up for several years after diagnosis. Follow-up care of patients with disseminated coccidioidomycosis includes periodic monitoring of the complement fixation (CF) titer. Initially, monitor CF titers monthly until a consistent decrease has been documented; continue to measure titers periodically until the level is less than 1:8. Also monitor other abnormal laboratory or radiographic studies at regular intervals.

Relapses of coccidioidomycosis can be predicted by recurrence of symptoms, physical findings, and increases in the CF titer. Development of hydrocephalus in a patient with coccidioidal meningitis who is otherwise stable and improving does not imply failure of antifungal therapy.

Monitor routine health maintenance as well as reviews of all medications for potential drug interactions with the prescribed antifungal therapy.

IDSA Guidelines on the Treatment of Coccidioidomycosis

Guidelines on coccidioidomycosis by the Infectious Diseases Society of America include the following:[65]

Medication Summary

In general, the severity and tempo of coccidioidomycosis dictates the approach to treatment. In patients with suspected or documented uncomplicated primary infection, treatment varies from careful observation to long-term azole therapy.

Some authors have suggested that empiric treatment may decrease the rate of disseminated infection, but this has not been proven in any controlled studies and no conclusive guidelines specify which uncomplicated infections need treatment. However, groups who are at risk for dissemination (eg, blacks, Filipinos, individuals with HIV or AIDS, individuals with diabetes mellitus, women in the third trimester of pregnancy) warrant more aggressive treatment.

Historically, amphotericin B has been the drug of choice to treat disseminated coccidioidomycosis. Oral azoles have provided a desirable alternative for both initial therapy and completion of courses after amphotericin therapy. The benefits of azoles include oral formulations and fewer adverse effects.

Azole antifungals are not used in pregnant women because these agents are teratogenic. Pregnant women may be treated with amphotericin B.

Patients with more advanced disease require more aggressive treatment. In particular, patients who exhibit signs of meningitis need either intravenous antibiotic therapy with amphotericin unless otherwise contraindicated or high-dose azole therapy with or without intrathecal amphotericin. Steroids may be somewhat beneficial in patients with vasculitis.

Effective antifungal therapy can be given in an outpatient or inpatient setting. The initial use of amphotericin may require an inpatient stay, and long-term amphotericin therapy requires placement of an indwelling intravenous catheter, such as a peripherally inserted central catheter (PICC) line.

Amphotericin B

Clinical Context:  Amphotericin B is the drug of choice for rapidly progressing coccidioidal infection and disease nonresponsive to oral azole therapy. It is administered IV or intrathecally. Intrathecal amphotericin B has been used for coccidioidal meningitis.

Amphotericin B is a polyene antifungal agent produced by a strain of Streptomyces nodosus. Depending on the concentration attained in body fluids and on fungal susceptibility, this agent can be fungistatic or fungicidal. It binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent cell death. Metabolic clearance is prolonged and not affected by renal or hepatic insufficiency.

Three lipid formulations (Ambisome, Abelcet, Amphotec) promising for reducing toxicity are currently licensed for use when amphotericin B fails or is unacceptably toxic. There is a significant reduction in nephrotoxicity and infusion-related reactions with continuous 24-h infusion vs conventional 2-h to 6-h infusion.

Fluconazole (Diflucan)

Clinical Context:  Fluconazole is a synthetic triazole antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol. It is used to treat mild-to-moderate infections or severe or life-threatening infections in patients intolerant of amphotericin B. It may be used for maintenance after course of amphotericin B in coccidioidal meningitis. It penetrates CSF well. Metabolic clearance is prolonged in renal dysfunction.

Fluconazole is preferred over ketoconazole because of better response rates and less GI and endocrine adverse effects. It is available as an oral suspension.

Ketoconazole

Clinical Context:  Ketoconazole is an imidazole broad-spectrum antifungal agent that inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death.

This agent has been used in treatment of coccidioidomycosis, although fluconazole and itraconazole are preferred because of low response rates (< 40%) with ketoconazole. In addition, it may have greater GI and endocrine adverse effects at high doses.

Administer ketoconazole orally for mild-to-moderate infections that warrant treatment. It penetrates CSF poorly, but in unusual cases is used to treat coccidioidal meningitis.

Itraconazole (Sporanox)

Clinical Context:  A triazole analogue of ketoconazole, itraconazole is preferred to its parent compound because of enhanced safety and efficacy. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. It is used for mild-to-moderate infections that warrant treatment. Despite poor CSF penetration, it is successfully used to treat coccidioidal meningitis.

An IV form is available, but long-term usage is not established. Itraconazole is also available in an oral solution, which provides better, more consistent absorption than the capsule. Take capsules with full meal to improve absorption, but take oral solution on empty stomach, if possible.

Voriconazole (Vfend)

Clinical Context:  Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Case reports describe efficacy in disseminated disease or meningitis refractory to first-line agents.

Posaconazole (Noxafil)

Clinical Context:  Posaconazole is a triazole antifungal agent that possesses structural similarities to itraconazole. It blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption.

Posaconazole is available as an oral suspension (200 mg/5 mL). It is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Caspofungin (Cancidas)

Clinical Context:  Caspofungin is the first of a new class of antifungal drugs (glucan synthesis inhibitors). It inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall. It is used to treat refractory invasive aspergillosis.

Class Summary

Antifungal agents preferentially bind to the primary fungal cell membrane sterol (ergosterol). Amphotericin B increases the permeability of the cell membrane, which in turn causes intracellular components to leak. Azoles interfere with an enzyme in the sterol biosynthesis pathway production of cell membrane ergosterol. Echinocandins block fungal cell wall synthesis by inhibiting 1,3-beta glucan synthase.

What is coccidioidomycosis?How is coccidioidomycosis transmitted?What are the signs and symptoms of coccidioidomycosis?What is disseminated coccidioidomycosis?What is required for the diagnosis of coccidioidomycosis?What is the role of antifungal therapy in the treatment of coccidioidomycosis?When was coccidioidomycosis first identified?What is the pathophysiology of coccidioidomycosis?What is the role of cell-mediated immunity in the pathogenesis of coccidioidomycosis?What causes lymphangitis in the pathophysiology of coccidioidomycosis?What is the role of spherules in the pathophysiology of coccidioidal infections?What is the pathophysiology of nonrespiratory transmission of coccidioidomycosis?What is the pathophysiology of disseminated coccidioidomycosis?What causes coccidioidomycosis?What is the life cycle of Coccidioides?Where is Coccidioides (C immitis and C posadasii) endemic?In which areas of the US is Coccidioides (C immitis and C posadasii) endemic?Which occupations pose the greatest risk for developing coccidioidomycosis?What is the incidence of coccidioidomycosis in the US?What are the coccidioidal infection rates in endemic areas of the US?What is the socioeconomic impact of coccidioidomycosis in the US?When is routine testing of students for coccidioidomycosis indicated in endemic areas?What is the global prevalence of coccidioidomycosis?What is the incidence of coccidioidomycosis outside of the Western Hemisphere?What are the racial predilections for coccidioidomycosis?How does the incidence of coccidioidomycosis vary by sex?How does the incidence of coccidioidomycosis vary by age?What is the prognosis of coccidioidomycosis?Which factors increase the risk for severe coccidioidomycosis?What is the prognosis of disseminated coccidioidomycosis?What is the morbidity and mortality associated with coccidioidomycosis?What should be included in patient education for coccidioidomycosis?What is the clinical progression of coccidioidomycosis?What are the symptoms of coccidioidomycosis?What is the clinical progression of primary pulmonary coccidioidomycosis?Which history is characteristic of coccidioidomycosis?Which factors increase the risk for disseminated coccidioidomycosis?Which physical findings are characteristic of coccidioidomycosis?What are symptoms of respiratory (pulmonary) coccidioidomycosis?What is the common manifestation of pulmonary involvement in coccidioidomycosis?What are less common pulmonary manifestations of coccidioidomycosis?What are dermatologic findings characteristic of coccidioidomycosis?What is the musculoskeletal findings characteristic of coccidioidomycosis?How is coccidioidomycosis manifested in the joints?What are less common physical findings of coccidioidomycosis?Which physical findings suggest meningitis in disseminated coccidioidomycosis?What are physical findings suggestive of septic shock in coccidioidomycosis?What is coccidioidal fungemia in coccidioidomycosis?Which factors are used to narrow the differential diagnoses of coccidioidomycosis?Which conditions should be included in the differential diagnoses of coccidioidomycosis?Which conditions should be included in the differential diagnoses of coccidioidomycosis with cystic lesions seen on chest imaging studies?Which conditions should be included in the differential diagnoses of coccidioidomycosis with focal or multifocal cavitary lesions seen on chest imaging studies?Which conditions should be included in the differential diagnoses of coccidioidomycosis with cystic or cavitary lesions seen on chest imaging studies?What are the differential diagnoses for Coccidioidomycosis and Valley Fever?Which general lab studies are included in the workup of coccidioidomycosis?Which specific lab tests are included in the workup of coccidioidomycosis?How is coccidioidomycosis diagnosed?What is the role of imaging studies in the workup of coccidioidomycosis?What is the role of serologic studies in the workup of coccidioidomycosis?What is the role of immunoglobulin M (IgM) detection in the workup of coccidioidomycosis?Which methods of immunoglobulin M (IgM) detection are used in the workup of coccidioidomycosis?What is the significance of the appearance of immunoglobulin M (IgM) in the workup of coccidioidomycosis?What is the role of immunoglobulin G (IgG) detection in the workup of coccidioidomycosis?What is the role of cultures in the workup of coccidioidomycosis?What is the role of polymerase chain reaction (PCR) assays in the workup of coccidioidomycosis?What is the role of skin testing in the workup of coccidioidomycosis?Which skin testing finding is a negative prognostic factor for coccidioidomycosis?What is the role of imaging studies in the workup of coccidioidomycosis?What is the role of lumbar puncture in the workup of coccidioidomycosis?What is the role of bronchoscopy in the workup of coccidioidomycosis?What is the role of biopsy in the workup of coccidioidomycosis?Which histologic findings are diagnostic of coccidioidomycosis?Which factors determine treatment options for coccidioidomycosis?What is the decision-making process for treatment selection in coccidioidomycosis?How is the severity of coccidioidomycosis determined?What are risk factors for dissemination of coccidioidomycosis?What are the goals of treatment for coccidioidomycosis?What is the role of amphotericin B in the treatment of coccidioidomycosis?What is the first line of therapy for coccidioidomycosis?What is the role of azoles in the treatment of coccidioidomycosis?What is the role of combination therapies in the treatment of coccidioidomycosis?What is the role of posaconazole for the treatment of coccidioidomycosis?What is the role of caspofungin for the treatment of coccidioidomycosis?What is the duration of antifungal therapy for coccidioidomycosis?What are possible complications of antifungal medication for the treatment of coccidioidomycosis?What are the costs of antifungal therapy for coccidioidomycosis?What is the role of interferon-gamma in the treatment of coccidioidomycosis?What are the disease stages of coccidioidomycosis?How frequently does uncomplicated acute pneumonia in coccidioidomycosis resolve spontaneously?What are the indications for treatment of uncomplicated acute pneumonia in coccidioidomycosis?What are the treatment options for uncomplicated acute pneumonia in coccidioidomycosis?What is the treatment for an asymptomatic pulmonary nodule in coccidioidomycosis?What is the treatment for diffuse pneumonia in coccidioidomycosis?What is the treatment for a pulmonary cavity in coccidioidomycosis?What is the treatment for chronic progressive pneumonia in coccidioidomycosis?What is the role of surgery in the treatment of chronic progressive pneumonia in coccidioidomycosis?What is the treatment for disseminated coccidioidomycosis?What is the treatment for disseminated coccidioidomycosis with bone and joint involvement?What is the treatment for septic shock in coccidioidomycosis?What is the treatment for coccidioidal meningitis?What must be considered when treating coccidioidomycosis in high-risk patients?How is coccidioidomycosis treated during pregnancy?What is the incidence of coccidioidomycosis in transplant recipients?What is the treatment of coccidioidomycosis during the pretransplant period?What is the treatment of coccidioidomycosis during the posttransplant period?How is the risk of coccidioidomycosis transmitted by donor organ managed?What is the treatment for coccidioidomycosis in HIV-infected patients?What is the treatment for coccidioidomycosis in patients on antitumor necrosis factor therapy?What is the treatment for coccidioidomycosis in elderly patients?When is inpatient treatment indicated for coccidioidomycosis?What is included in inpatient treatment of coccidioidomycosis?How is coccidioidomycosis prevented?What is the role of vaccines in the prevention of coccidioidomycosis?Which specialist consultations are needed for the treatment of coccidioidomycosis?What is including in long-term monitoring of coccidioidomycosis?What are the Infectious Diseases Society of America (IDSA) treatment guidelines for coccidioidomycosis?What is the role of drug treatment for coccidioidomycosis?Which medications in the drug class Antifungals are used in the treatment of Coccidioidomycosis and Valley Fever?

Author

Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH, Physician, San Antonio Infectious Diseases Consultants; Adjunct Professor of Medicine, Department of Medicine, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

Coauthor(s)

Ana Paula Oppenheimer, MD, MPH, Fellow, Section of Infectious Diseases, Wake Forest University Baptist Medical Center

Disclosure: Nothing to disclose.

Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center

Disclosure: Nothing to disclose.

George R Thompson III, MD, FIDSA, Associate Professor of Medicine, Assistant Director, Coccidioidomycosis Serology Laboratory, Department of Medical Microbiology and Immunology, Department of Medicine, Division of Infectious Diseases, University of California, Davis, School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Acknowledgements

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases,Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Ear, Nose and Throat Advances in Children, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, and Surgical Infection Society

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Archana Chatterjee, MD, PhD Professor of Pediatrics, Medical Microbiology and Immunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologist and Medical Director of Infection Control, Children's Hospital

Archana Chatterjee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, International Society for Infectious Diseases, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Michele M Cheung, MD Consulting Staff, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of California, San Francisco, School of Medicine

Michele M Cheung, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

John E Cho, MD Staff Physician, Providence Tarzana Medical Center

John E Cho, MD is a member of the following medical societies: American College of Chest Physicians, California Medical Association, and Phi Beta Kappa

Disclosure: Nothing to disclose.

James de la Torre, MD Resident Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, and Infectious Diseases Society of Ohio

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Joseph Kim, MD Chairman, Department of Emergency Medicine, Western Medical Center; Clinical Instructor, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Catherine O'Keefe, DNP, APRN Assistant Professor of Nursing and Pediatric Nurse Practitioner, Pediatric Infectious Diseases, Creighton University Medical Center

Catherine O'Keefe, DNP, APRN is a member of the following medical societies: American Academy of Nurse Practitioners, National Association of Pediatric Nurse Practitioners, and Nebraska Nurse Practitioners

Disclosure: Nothing to disclose.

Michael Peterson, MD Chief of Medicine, Vice-Chair of Medicine, University of California, San Francisco, School of Medicine; Endowed Professor of Medicine, University of California, San Francisco-Fresno, School of Medicine

Michael Peterson, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Allison J Richard, MD Assistant Professor of Emergency Medicine, Keck School of Medicine of the University of Southern California; Associate Director, Division of International Medicine, Attending Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Barry J Sheridan, DO Chief Warrior in Transition Services, Brooke Army Medical Center

Barry J Sheridan, DO is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Guy W Soo Hoo, MD, MPH Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Medical Intensive Care Unit, Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, Veteran Affairs Greater Los Angeles Healthcare System

Guy W Soo Hoo, MD, MPH is a member of the following medical societies: American Association for Respiratory Care, American College of Chest Physicians, American College of Physicians, American Thoracic Society, California Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Kelley Struble, DO Fellow, Department of Infectious Diseases, University of Oklahoma College of Medicine

Kelley Struble, DO is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Peggy Weintrub, MD Chief, Division of Pediatric Infectious Diseases, Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine

Peggy Weintrub, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

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A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.

Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.

Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.

Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.

Soft tissue abscess due to cocci.

Pulmonary cocci spherule (Hematoxylin-eosin stain).

Pulmonary cocci spherule, periodic acid-Schiff stain.

Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.

A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).

A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).

Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).

Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).

Soft tissue abscess due to cocci.

Pulmonary cocci spherule (Hematoxylin-eosin stain).

Pulmonary cocci spherule, periodic acid-Schiff stain.

Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.

A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.

Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.

A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).

A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).

Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).

Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).

Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.