eMedicine Specialties > Infectious Diseases > Fungal Infections

Coccidioidomycosis (Infectious Diseases)

Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center
Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences; Ana Paula Oppenheimer, MD, MPH,, Staff Physician, Department of Medicine, Richmond University Medical Center

Updated: Jun 25, 2008

Introduction

Background

Coccidioides immitis and Coccidioides posadasii are dimorphic fungi that are endemic to the Western Hemisphere, to certain arid regions in the southwestern United States, and to Mexico, Central America, and South America. The 2 species are morphologically identical but genetically and epidemiologically distinct. C immitis is geographically limited to California's San Joaquin valley region, whereas C posadasii is found in the desert of the southwest United States, Mexico, and South America. The manifestations of exposure to either organism are assumed to be identical; however, this hypothesis has not been formally tested.

The disease has numerous designations related to the location it is acquired (eg, valley fever, San Joaquin fever, desert fever, California fever) or its clinical manifestations (eg, desert rheumatism, coccidioidal granuloma). Most simply and commonly, the symptomatic infection is referred to as cocci.

Coccidioidomycosis was first recognized as a distinct disease entity in 1892. In 1900, coccidioidomycosis was identified as a fungal infection. The first documented case of coccidioidomycosis was diagnosed in an Argentinean soldier with predominantly cutaneous manifestations. The actuality that coccidioidomycosis is not a rare, uniformly fatal infection was not appreciated until a medical student accidentally inhaled the Coccidioides organism and developed a nonfatal pulmonary illness accompanied by erythema nodosum. Researchers then noted the association between this presentation and the clinical condition known as San Joaquin Valley fever.

The importance of the illness increased during the 1930s and 1940s, 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 entry of thousands of military personnel building airstrips and participating in desert combat training during World War II also influenced the importance of the illness. The importance of coccidioidomycosis to the military led to many important studies on the pathogenic organisms and the epidemiology, clinical features, and diagnosis of coccidioidomycosis.

Interest in coccidioidomycosis has been renewed because of massive migration to the Sunbelt states. Areas of the country that were sparsely populated are now major population centers filled with individuals who are now susceptible to coccidioidomycosis. Phoenix and Tucson, Arizona; Bakersfield and Fresno, California; and El Paso, Texas, are prime examples. These locales also have a growing segment of individuals who are unusually susceptible to the most serious consequences of infection, particularly older and immunocompromised populations. 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 ecologic niche of the fungus is the lower Sonoran life zone. This zone is characterized by low elevations, scant rainfall (5-15 in/y), mild winters (40-54°F) and hot summers, and sandy alkaline soil with increased salinity. The Coccidioides organism is chiefly restricted to areas of the Western Hemisphere from latitudes 40° north to 40° south. Areas of highest endemicity include the southern-central portions of California (San Joaquin Valley), Arizona, southern New Mexico, western Texas, and northern Mexico. In addition, certain regions of Central America and South America have appropriate climatic conditions for the organism.

Infection is acquired via the respiratory tract. The number of cases of coccidioidomycosis in endemic regions rises sharply in the late summer and early fall. In the fall (ie, dry season), soil disturbances, either natural (wind) or man-made (agricultural endeavors, construction, archeological excavations) are likely to send the fungus airborne, enhancing the likelihood of its inhalation.

Coccidioidomycosis is considered to be an occupational hazard in endemic regions, and it is a compensable illness. Given the mode of transmission, outdoor activities are the primary risk factor. Infection may be acquired outside of endemic areas via transport of contaminated material. Alternatively, the infection may be acquired in endemic areas, but the initial symptom complex occurs after the patient has left the area.

Pathophysiology

Inhaled airborne arthroconidia are deposited into the terminal bronchiole and transform into spherules, causing an inflammatory reaction. Spherules react with complement and promote chemotaxis of neutrophils and eosinophils. The spherules reproduce by a process known as endosporulation, rupture, and liberate viable endospores. 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 forms of inflammation.

The following unproven possibilities for dissemination have been proposed:

• Hematogenous dissemination: Spherules or endospores gain access to alveoli and pulmonary parenchyma and then to the bloodstream.
• Lymphatic spread followed by hematogenous spread: Infected macrophages from the initial terminal bronchiole lesion travel through the lymphatic channels to the thoracic duct and then gain access to the bloodstream.

Numerous studies have established that immunity mediated by T cells is critical to controlling the infection.¹ 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.

Frequency

United States

An estimated 100,000 infections occur annually in the United States, and approximately one third to two thirds of these cases are subclinical. An occasional case transmitted via fomites is reported outside of endemic areas.

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.

The great 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-naïve 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% of the population within the endemic regions of California and Arizona.¹ 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.

International

The frequency of infection in endemic areas of Central America, Mexico, and South America, is unknown.

Mortality/Morbidity

Potential complications of coccidioidomycosis are numerous (see Complications).

Race

Although no specific immunologic defect has been detected, African American, Hispanic, Filipino, and Asian individuals with Coccidioides infection are at higher risk of serious coccidioidomycosis, with both pulmonary and disseminated disease. This risk persists when analyses are controlled for age, sex, additional demographic features, concurrent medical problems, duration of exposure, and occupation.² 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.³
• The elevated incidence of disease in these individuals does affect clinical decision-making, particularly regarding the interpretation of symptoms and options for treatment.
• Patients treated with tumor necrosis factor (TNF) antagonists are at an increased risk for coccidioidomycosis, adding this population to other immunosuppressed individuals (eg, those with HIV infection or organ transplants). Substantial resources are being directed toward vaccine development.

Clinical

History

As in much of clinical medicine, interpretation of the patient's history, physical findings, and clinical data, as directed by previous experience and knowledge, is crucial for focusing the diagnostic possibilities. More than in many other illnesses, the patient's travel history is of considerable importance, and even transient exposure to endemic areas greatly increases the likelihood of infection in a patient presenting with a compatible illness.

Presentation

Coccidioidomycosis can manifest in various forms. Symptoms depend on the location and number of individual lesions, reflecting the site of infection. More than 60% of patients remain asymptomatic, while others develop mild illness 1-4 weeks following the initial infection.

• Primary pulmonary coccidioidomycosis
  • After exposure to the organism, a 2- to 3-week incubation generally occurs. In 50-75% of immunocompetent individuals who inhale arthrospores (infectious particles derived from breakdown of hyphae), symptoms do not occur or are so mild that the infected individual does not seek medical attention.^1,4  The only evidence of infection is a skin test that is positive for coccidioidal antigens.
  • The natural history is a gradual resolution of symptoms, even without antifungal treatment, over 2-6 weeks.
  • In symptomatic patients, the most common initial presentation is pulmonary infection. Symptoms in these individuals include the following:
    • Fever
    • Cough
    • Chest pain
    • Fatigue
    • Shortness of breath
    • Chills
    • Sputum production
    • Night sweats
    • Headache (common, even in the absence of meningitis)
    • Weight loss
    • Arthralgias, myalgias
  • These symptoms are nonspecific, but diagnosis may be aided by observing for erythema nodosum or erythema multiforme, skin manifestations that develop during the primary infection and that affect 25% of infected individuals, mostly women. These symptoms tend to resolve after several weeks.
• Chronic coccidioidomycosis
  • Five to 8% of patients with primary pulmonary disease develop chronic coccidioidomycosis. 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 (see also Complications).
    • Coccidioidal nodules represent inflammatory debris-filled cavities that may persist or, more commonly, may become thin-walled cavities or resolve. Symptoms are rare, and diagnostic confusion can occur because only 12% of these lesions become calcified.
    • Cavities are frequently solitary, thin-walled, apical, and peripheral. They are usually asymptomatic, and 50% completely disappear within 2 years.
    • Diagnostic difficulties are more likely to occur when an air-fluid level is present or when an infiltrate surrounds the cavity.
• Progressive pulmonary disease: Diffuse progressive pulmonary disease involves increasing portions of the lungs, with symptoms persisting from months to years. Chest radiographs show progressive interstitial changes, with fibrosis, volume loss, and inflammation. Cavitary disease may be noted. Although treatment may be effective in patients with progressive pulmonary disease, the prognosis is poor in those with advanced age and/or diabetes.
• Disseminated disease
  • Extrapulmonary disease represents a progression from the initial pulmonary presentation, occurring within weeks or up to more than 2 years. Less than 1% of affected individuals develop disseminated disease, which can be rapid and fatal. The male-to-female ratio is 5:1, but this disparity reverses in pregnant women.
  • Patients present with dramatic sweats, dyspnea at rest, fever, and weight loss.
  • Disseminated disease suggests hematogenous spread of the Coccidioides infection beyond the pulmonary parenchyma. Virtually any organ of the body can be involved (endocrine glands, eye, liver, kidney, prostate and peritoneal cavity), but organs of predilection reportedly include skin, bone, joints, and the CNS. Rare infection sites include the subserosal intestines, heart, and urinary bladder. The disease usually spreads via lymphatic drainage 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 there, spread of the coccidioides becomes hematogenous.
  • The most common sites of disseminated disease include the skin, meninges, and skeleton.
  • Certain host factors, clinical findings, and laboratory findings suggest dissemination. Established risk factors include advanced age, an immunocompromised state, late stages of pregnancy, and ethnic or racial factors (see Race). Diffuse spread revealed on chest radiographs indicates a high risk of extrapulmonary dissemination. Patients who do not develop a cutaneous response to coccidioidal antigens and those with a pronounced serologic response are also at an increased risk.
  • Involvement of the skin and subcutaneous tissues is characterized by the following:
    • Skin manifestations are part of the primary illness. A transient, fine, nonpruritic papular rash appears early in the disease process but is often missed.
    • Erythema nodosum appears as tender lesions, generally on the anterior surface of the lower extremities, although the lesions may develop virtually anywhere. The lesions are tender to palpation, erythematous, and 1-2 cm in diameter.
    • Erythema multiforme manifests as relatively symmetric erythematous, expanding macules, or papules that evolve into classic iris or target lesions with bright-red borders. Central vesicle formation is common.
  • Involvement of the brain meninges and spinal cord is characterized by the following (see also Complications):
    • Coccidioidal meningitis can be part of disseminated disease but can also occur without involvement of other sites; the latter is associated with an increased risk of complications and death.
    • Meningitis manifests as a persistent headache, which should be evaluated thoroughly upon worsening, 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.
    • CSF usually contains increased protein levels and decreased levels of glucose and lymphocytic pleocytosis. Eosinophils in the CSF in the appropriate clinical situation support the diagnosis.
    • MRI shows ventricular enlargement and hydrocephalus.
    • Nonspecific laboratory abnormalities may include hyponatremia in association with syndrome of inappropriate antidiuretic hormone (SIADH).
  • Bone and joint manifestations are characterized by the following (see also Complications):
    • Migratory arthralgias, especially of the knees and ankles, are common. The triad of arthralgias, fever, and erythema nodosum is termed desert rheumatism.
    • Patients report dull, persistent bone pain and localized percussion tenderness.
    • Osteomyelitis presents in 40% of disseminated disease cases. The spine, ribs, cranial bones, and distal ends of long bones are commonly involved.
    • If the vertebral column is involved, careful neurologic examination is warranted to evaluate for cord impingement. Joint involvement is usually monoarticular or oligoarticular. Physical findings are not helpful in differentiating coccidioidomycosis from other causes of monoarthritis or oligoarthritis.
    • All patients with disseminated disease should undergo CT scanning to evaluate for asymptomatic bone disease.
  • Presentation in special hosts: Several conditions predispose to dissemination of the disease. These include conditions that create a T-cell disturbance, such as immunotherapy administered for transplants, HIV infection, high-dose steroid therapy, and anti-TNF therapy. Third-trimester pregnancy and the peripartum period also predispose to disseminated infection.
  • Immunosuppressed patients display unremitting symptoms (ie, fever, chest pain, weight loss) for months. Chest radiographic findings are similar to those of pulmonary tuberculosis.
  • Patients infected with HIV may present with a fulminant picture of respiratory failure, diffuse pneumonia, fungemia, and septic shock that resembles a gram-negative infection. The mortality rate is very high in such cases. The CD4 count is usually below 100 cells/μL, and the viral load is usually high. Few patients with HIV infection who develop Coccidioides infection have survived longer than a few months.

Physical

Findings on physical examination reflect the organ system or systems involved.

• Pulmonary involvement may reveal evidence of consolidation with bronchial breath sounds, rales, rhonchi, dullness to percussion, and increased tactile and vocal fremitus.
  • Chest radiographic findings are abnormal in most cases, revealing infiltrates, hilar adenopathy, and even pleural effusion and pneumothorax. The presence of peritracheal adenopathy indicates spread of the infection. Nodules and cavities occur usually in association with enlarged lymph nodes.
  • Less commonly, diffuse coccidioidal pneumonia in immunocompetent hosts manifests as respiratory failure due to either high inoculum or fungemia seeding the lung at several sites. 
  • Apical fibronodular lesions with small cavities that are similar to findings in pulmonary tuberculosis are common in chronic progressive pneumonia.
  • A chest radiograph that reveals a miliary pattern is less common. This is an ominous sign that represents the development of small millet seed granulomas throughout the lung and other organs. It can occur in immunocompromised or immunocompetent hosts.
• Extrapulmonary physical findings depend on the involved organ.
  • Skin - Erythema nodosum, erythema multiform, verrucae (especially around the nasolabial area), ulcerations, abscesses
  • Bones - Osteomyelitis, septic arthritis, synovitis
  • Meninges - Tremulousness, gait abnormalities (especially in children), papilledema

Causes

• The Coccidioides organism is dimorphic, meaning that it assumes 2 different forms, depending on the environment. It grows in the mycelial form in the soil of endemic areas.
  • As the mycelial structure matures, alternating hyphal cells either expand into barrel-shaped structures or shrink and die, producing the characteristic arthroconidia.
  • The arthroconidia are the infectious particles of coccidioidomycosis. These conidia require little nutrition and can withstand extreme heat, desiccation, and changes in soil salinity.
• When the soil is disrupted, the arthroconidia can become airborne and, if inhaled by a susceptible host, produce infection.
  • Localized in the pulmonary acinus, the arthrospore sheds its outer coating, swells, and becomes a spherical structure, ie, the spherule.
  • The spherule is the parasitic stage of the organism, which reproduces by a process known as endosporulation. Rupture of the spherule leads to release of contained endospores, each of which matures into spherules, repeating the cycle.
  • If the organism is cultured, it reenters the mycelial phase, with hyphae formation, hence its classification as dimorphic.

Differential Diagnoses

Other Problems to Be Considered

Bacterial lung abscesses with thick-walled cavities with extensive surrounding infiltrates
Chlamydial and mycoplasmal infections
Cold abscesses of skin tuberculosis
Pneumocystis jiroveci pneumonia in persons with HIV infection or AIDS

Workup

Laboratory Studies

• Routine laboratory examination
  • Elevated ESR
  • Blood eosinophilia
• Direct examination
  • The diagnosis can be made by observing spherules (≤70 μm in diameter) that contain endospores in clinical material of any body fluid, including sputum or lesion smears and biopsy material.
  • Identification on smears may be made by using calcofluor white or cytologic stains.
  • Identification in biopsy material may be made by using standard hematoxylin and eosin or fungal stains (silver or periodic acid-Schiff).
• 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 5 days. Identification of colonial morphology, a white and cottony mold, is not adequate 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 is no longer in common use because of the availability of nucleic acid probes.
  • Arthroconidia are infectious and therefore pose a significant risk to laboratory personnel. Always warn laboratory personnel in advance if coccidioidomycosis is suspected.
• Serology
  • 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. 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.
  • The 2 major antigens used to detect antibodies are the tube-precipitating (TP) antigens, so named because of the tube precipitant button at the bottom of the test tube when the test was originally performed, and the complement-fixation antigen, which reacts with immunoglobulin (Ig) G.
    • TP antibodies are serum IgM antibodies to mycelial-phase antigens that appear in more than 85% of patients with primary infection and are most commonly detected with enzyme immunoassay (EIA).
    • IgM antibodies are found early in infection, detected within the first week after the onset of symptoms, and peak after several weeks. In most patients, these antibodies dissipate within 6 months. A concern with IgM EIA antibodies is that the false-positive rate may be high, especially in conditions that stimulate humoral immunity.
    • IgG antibodies detected via complement fixation appear later, with results becoming positive in 85-90% of patients. However, serum positivity may occur only after 2 months of illness. The antibody usually disappears after several months.
    • Quantification of IgM antibodies is of no prognostic value, whereas the degree of elevation of complement-fixation antibody, IgG, is proportional to the disease extent. A titer of 1:32 or higher is a marker of dissemination.
    • These tests can be performed on CSF upon suspicion of coccidioidal meningitis.
  • Polymerase chain reaction (PCR) is a better alternative to handling highly virulent cultures of the organism, which can be performed only in biosafety level-3 laboratories and takes about 3 weeks to yield results. PCR amplification has been used successfully to identify the highly specific Ag2/PRA antigen gene of C posadasii in inappropriate samples of sputum⁵ and can be applied to both clinical specimens and cultures.^6,7 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.⁸
• Skin testing
  • The assessment of cutaneous reactivity to coccidioidal antigens has limited diagnostic utility because of its low sensitivity and specificity in endemic areas. Results in infected individuals may be falsely negative because of a lack of immune response, and results may be falsely positive in healthy individuals because of previous infection.
  • This delayed-type hypersensitivity reaction appears 2-21 days after the onset of symptoms and precedes the appearance of serologic markers.
  • Cutaneous reactivity to coccidioidal antigens has epidemiologic and prognostic implications. The lack of delayed-type hypersensitivity is a negative prognostic factor in infected individuals.

Imaging Studies

• Obtain chest radiography in all patients with suspected or confirmed coccidioidomycosis. The most common finding is a localized infiltrate. Less-common findings include diffuse reticulonodular disease, pleural effusion, hilar adenopathy, single or multiple cavities (thin-walled and usually apical), miliary disease, or pneumothorax with associated pleural effusion.
• Perform neuroimaging studies in patients with suspected meningitis.
• MRI is more sensitive than other studies for CNS involvement, yielding positive findings in approximately 75% of patients with coccidioidal meningitis, whereas CT scanning yields only 42%. The 3 most common findings include hydrocephalus with ventricular enlargement, basilar meningitis, and vascular occlusion. The detection of hydrocephalus and vascular occlusion has negative prognostic implications.
• Skeletal images usually reveal an osteolytic lesion in patients with symptomatic bone disease. The MRI appearance of coccidioidomycosis varies; findings may include heterogeneous marrow signal intensity and soft tissue involvement.
• In patients with confirmed skeletal involvement or highly suspected osseous dissemination, a bone scan should be obtained to assess concurrent silent or multifocal osteomyelitis. Abnormal uptake on a bone scan should be investigated further with additional imaging modalities, such as CT scanning or MRI.
• CT imaging provides information on bony destruction that is more precise than that on MRI, but CT imaging yields less information on spinal and soft tissue damage. MRI is the preferred modality if spinal cord impingement is considered. Both modalities are useful in establishing the extent of disease and in planning surgical debridement of the infected area.

Procedures

• Lumbar puncture (This is mandatory in patients with suspected meningitis. Many physicians perform lumbar puncture in all patients with extrapulmonary disease or significantly elevated compliment-fixation titers.)
• Bronchoscopy
• Fine-needle biopsy (Open lung biopsy and video-assisted thoracoscopy [VATS] are usually unnecessary because the diagnosis can be obtained with noninvasive or minimally invasive procedures.)
• Pleural, bone, skin, and lymph node biopsy, when indicated

Histologic Findings

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

The characteristic tissue form of the organism is the spherule. 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.

Treatment

Medical Care

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. Which surgical procedure is necessary for debridement and reconstruction of destructive lesions?

Because most infections resolve without specific therapy, few clinical trials have assessed outcomes of individuals with less-severe disease. Even physicians in endemic regions disagree on who should be treated, the length of treatment, and what agent should be used. However, evidence and guidelines do address which patients should be treated.⁹

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, lack of cutaneous reactivity to spherulin), and a serum complement-fixation titer of at least 1:32.

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

• Body-weight loss of more than 10%
• Intense night sweats that persist for more than 3 weeks
• Infiltrates that involve more than half of one lung or portions of both lungs
• Prominent or persistent hilar adenopathy
• Anticoccidioidal complement-fixing antibody concentrations in excess of 1:16
• Absence of dermal hypersensitivity to coccidioidal antigens
• Inability to work
• Symptoms that persist for more than 2 months
• Patients of African or Filipino descent (Such populations are at a greater risk of early dissemination.)

If the option to treat is chosen, numerous medications are available for management. Before the introduction of amphotericin B in 1957, no effective therapy for coccidioidomycosis existed. Although the introduction of azoles revolutionized therapy for cocci, amphotericin B remains the treatment of choice for severe infections, either in the classic amphotericin B deoxycholate formulation or as a lipid formulation. The lipid preparations were developed to lower the agent’s toxicity and to provide efficacy at least equivalent to that of the parent compound. Amphotericin B is usually reserved for worsening disease or lesions located in vital organs such as the spine.

The treatment of coccidioidal meningitis may require a combination of intravenous and intracisternal or intrathecal therapy. These modalities cause headache, nausea, and fever beginning about 30 minutes following the injection and may last for hours. Corticosteroids (25 mg cortisone succinate) are added to the amphotericin injection to reduce these drug-related inflammation symptoms. Azoles, (triazoles) are usually the first line of therapy. Among these, ketoconazole is the only one that is FDA-approved for treatment of coccidiomycosis. Although ketoconazole was initially used in the long-term treatment of nonmeningeal extrapulmonary cocci, more-potent, less-toxic triazoles (fluconazole and itraconazole) have replaced it.

Fluconazole can be used in the treatment of mild-to-moderate disease and, occasionally, life-threatening disease in patients who opt against amphotericin B or who have contraindications to its use. Because of its excellent penetration into the CSF, fluconazole has become the drug of choice for long-term therapy of meningeal infection.

Itraconazole 400 mg/d 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, while fluconazole performs better in pulmonary and soft tissue infection. Serum levels of itraconazole are commonly obtained at the onset of long-term therapy, as its absorption is sometimes erratic and unpredictable.

• Anecdotal reports show that 800 mg/d 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 y) was well-tolerated. In another study, 17 of 20 patients with pulmonary and nondisseminated disease responded well to posaconazole 400 mg/d, and no adverse events were noted.¹⁰ The drug has been approved by the European Commission as salvage therapy for refractory coccidioidomycosis.¹¹ Clinical trials are now ongoing for further evaluation.^12,13,14
• 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.¹⁵
• Several case reports have studied caspofungin, with differing results. Caspofungin 50 mg/d following administration of amphotericin B in a patient with acute pulmonary coccidioidomycosis who had undergone transplant showed promising results.¹⁶ 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.¹⁷ 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/d after a loading dose of 70 mg IV was also unsuccessful.¹⁸

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.¹³ Clinical trials are necessary to evaluate promising in vitro findings against Blastomyces, Paracoccidioides, Candida, and Histoplasma infections.

Recombinant vaccines against coccidioidomycosis are also a possibility in the future if the right financial support is in place.¹⁹

The duration of therapy ranges from months to years, and long-term suppressive doses are necessary to prevent relapses. Immunocompromised patients require life-long therapy. Regular follow-ups with a primary physician are necessary to document resolution or development of complications, usually every 3-6 months for up to 2 years after the initial infection. Further follow-up is dictated by the patient’s response and the development of signs of disseminated disease.

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.

None of the azoles is safe to use in pregnancy and lactation, as they have shown teratogenicity in animal studies.

Several case series have highlighted the importance of corticosteroids in the treatment of patients with vasculitis; however, this information is anecdotal.

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.

• Over the past 10 years, therapies with toxic-to-therapeutic ratios substantially better than those of amphotericin B have emerged.
  • A retrospective study showed several important outcomes in 224 patients with moderately severe pulmonary disease who were treated within 30 days of onset of symptoms with oral azoles or were treated 30 days after the onset of symptoms.²⁰
  • The incidence of dissemination and the need for chronic antifungal therapy for longer than 1 year were significantly reduced in the group who received early treatment with azoles. However, mortality rates were reduced insignificantly in this group, and only 27% of patients developed a complement-fixation titer of 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.
• Meningeal disease
  • Meningitis remains difficult to treat, and, because treatment is suppressive rather than curative, prolonged or indefinite therapy is required.
  • The 2005 guidelines of the Infectious Diseases Society of America recommend fluconazole as initial therapy. The usual dose is 400 mg/d, but many physicians start with 800 or 1000 mg/d. Itraconazole 400-600 mg/d offers comparable efficacy. Some physicians initiate intrathecal amphotericin B along with the azole, while others reserve amphotericin B for cases in which azoles fail. The intrathecal dose of amphotericin, administered via cisternal injection, is 0.01-1.5 mg/dose administered at intervals that range from daily to ever 48 hours to once per week. These injections continue until signs of intolerance appear, including vomiting, prostration, and dose-related mental-status changes.
  • If azole therapy elicits a response, treatment is continued indefinitely.
  • Liposomal amphotericin is lipid-based and has less nephrotoxicity than the deoxycholate formulation.
• Bone and joint disease: This is treated as disseminated coccidioidomycosis, although itraconazole is thought to perform better than fluconazole in bone disease. This may also require surgical treatment.

Surgical Care

Surgical intervention may be required in cases of complicated pulmonary disease, bone disease, and hydrocephalus.

• Surgical reduction of cavities is usually performed after 4 weeks of amphotericin treatment.
• Ruptured nodules may require lobectomy with decortication.
• The management of bone and joint disease generally involves surgical procedures with curettage of the bone. Surgical debridement of bone and soft tissue is often necessary.
• If fracture is imminent, stabilization of the bony structures is warranted.
• 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.

Consultations

Consultation with infectious disease or pulmonary specialists should be pursued if the treating physician does not have experience with this disease.

Consultation with a neurosurgeon, neurologist, orthopedic surgeon, and/or wound surgeon may be needed to manage complications.

Medication

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection.

Antifungals

Their mechanism of action involves preferentially binding to the primary fungal cell membrane sterol, ergosterol, and increasing the permeability of the cell membrane, which in turn causes intracellular components to leak (amphotericin B), interfering with an enzyme in the sterol biosynthesis pathway production of cell membrane ergosterol (azoles) or blocking fungal cell wall synthesis by inhibiting 1,3-beta glucan synthase (echinocandins).

Amphotericin B (Amphocin, Fungizone)

Polyene antifungal agent for IV or intrathecal administration for severe and life-threatening infections. Metabolic clearance prolonged and not affected by renal or hepatic insufficiency. Produced by a strain of Streptomyces nodosus; fungistatic or fungicidal. Binds to sterols (eg, ergosterol) in fungal cell membrane, causing intracellular components to leak, with subsequent cell death.
Three lipid formulations promising for reducing toxicity (Ambisome, Abelcept, Amphotec) are currently licensed for use when amphotericin B fails or is unacceptably toxic. How they compare with 24-h continuous infusion is being investigated.
Significant reduction in nephrotoxicity and infusion-related reactions with continuous 24-h infusion vs conventional 2- to 6-h infusion.

Dosing

Adult

IV: 0.5-0.7 mg/kg/d in 5% glucose over 2-6 h, often to total dose of 1.5-3 g (if amphotericin B is sole agent); test dose of 0.5-1.0 mg sometimes administered (not in acutely ill patients) to assess for possible severe constitutional response though this is severely questioned

Intrathecal: Start at 0.01-0.1 mg; titrate to 0.5 mg q48-72h; frequency adjusted to clinical symptoms and CSF results

Pediatric

0.25 mg/kg/d IV infused over 2-6 h, titrated to 1 mg/kg/d

Interactions

Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; cyclosporine increases risk of renal toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administration usually accompanied by fever, chills, and other constitutional signs; some attempt to limit symptoms with premedication with acetaminophen or aspirin, diphenhydramine, meperidine, or hydrocortisone; significant adverse effects include renal insufficiency (frequent, usually responds to saline volume repletion); reasonable guideline is cessation when serum creatinine level >3 mg/dL and reinstating when <2 mg/dL (or change to lipid-based preparation if creatinine level >2.5-3.0); non-anion gap acidosis related to distal acidification defect common, as is hypokalemia and hypomagnesemia

Fluconazole (Diflucan)

Triazole antifungal agent to treat mild-to-moderate infections or severe or life-threatening infections in patients intolerant of amphotericin B. May be used for maintenance after course of amphotericin B in coccidioidal meningitis. Penetrates CSF well. Metabolic clearance is prolonged in renal dysfunction.

Dosing

Adult

400 mg PO/IV qd; in some cases, 800 mg/d or higher have been given

Pediatric

3-6 mg/kg PO/IV qd

Interactions

Hydrochlorothiazides may increase levels; long-term coadministered rifampin may decrease levels; may increase theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide levels; effects of anticoagulants may increase with coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor closely if rash develops, and discontinue if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) with underlying medical conditions (eg, AIDS, malignancy) and with multiple concomitant drugs; not recommended for nursing mothers; weigh convenience and efficacy of single-dose regimen for vaginal yeast infections vs increased incidence of adverse reactions reported with oral fluconazole vs intravaginal agents

Ketoconazole (Nizoral)

Azole antifungal; used infrequently. Administer PO for mild-to-moderate infections that warrant treatment. Penetrates CSF poorly, but in unusual cases used to treat coccidioidal meningitis.

Dosing

Adult

400 mg PO qd

Pediatric

<2 years: Not established
>2 years: 3.3-6.6 mg/kg PO qd

Interactions

Interference with drugs metabolized in P450 pathway is significant concern; isoniazid may decrease bioavailability; coadministration of rifampin decreases effects of either; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (can adjust cyclosporine dose); may decrease theophylline levels

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hepatotoxicity (primarily hepatocellular damage or mixed hepatocellular and cholestatic changes) reported in about 1 case per 10,000 people and is major concern; may reversibly decrease corticosteroid levels (adverse effects avoided with 200-400 mg/d); administer antacids, anticholinergics, or H2-blockers at least 2 h after dose

Itraconazole (Sporanox)

Triazole analogue of ketoconazole and preferred to parent compound because of enhanced safety and efficacy. Used for mild-to-moderate infections that warrant treatment. Penetrates CSF poorly, but successfully used to treat coccidioidal meningitis.

Dosing

Adult

200-400 mg PO qd, administer with food to enhance absorption

Pediatric

Not established; suggested dose of 100 mg/d for systemic fungal infections

Interactions

Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; high doses may increase tacrolimus and cyclosporine plasma concentrations; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity; coadministration with cisapride (no longer available) may cause adverse cardiovascular effects (possibly death)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies

Voriconazole (Vfend)

Triazole antifungal structurally related to fluconazole for PO/IV administration. Some case reports detail in disseminated disease or meningitis refractory to first-line agents.

Dosing

Adult

200 mg PO bid or 3-6 mg/kg IV q12h; actual range limited by limited experience

Pediatric

Not established; passage into breast milk unknown

Interactions

Metabolized by CYPP450 enzymes, CYP2C19, CYP2C9 and CYP3A4; may significantly increase plasma drug levels of tacrolimus, cyclosporine, methadone, phenytoin and omeprazole; anticoagulation may be markedly increased with warfarin

Contraindications

Known hypersensitivity to drug or excipients; drug interactions with ritonavir and efavirenz; coadministration with rifampin, carbamazepine, and long-acting barbiturates (significantly decrease plasma levels); significant interactions with pimozide, quinidine and ergot alkaloids (do not coadminister)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, and headache

Posaconazole (Noxafil)

Triazole antifungal agent that possesses structural similarities to itraconazole. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption.

Dosing

Adult

Available as oral susp (200 mg/5 mL), given 200 mg (5 mL) PO 3 times daily with meals to enhance absorption

Pediatric

<13 years: Not established
>13 years: Administer as in adults

Interactions

Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor
UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk)
Inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers, HMG-CoA reductase inhibitors, ergot alkaloids, terfenadine (withdrawn from US market), astemizole (withdrawn from US market), cisapride, pimozide, halofantrine, quinidine, and vinca alkaloids (eg, vincristine, vinblastine)

Contraindications

Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding.

Caspofungin (Cancidas)

Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.

Dosing

Adult

Empiric therapy:
Initial dose: 70 mg IV day 1
Subsequent dosing: 50 mg/d; may increase to 70 mg/d if tolerated, and clinical response inadequate
Dosage adjustment with concomitant use of enzyme inducer:
Patients receiving rifampin: 70 mg caspofungin IV qd
Patients receiving carbamazepine, dexamethasone, efavirenz, nevirapine, or phenytoin (and possibly other enzyme inducers): May require increased daily dose of caspofungin (70 mg/d)

Limited data are available concerning treatment durations longer than 4 wk; however, treatment appears to be well tolerated
Renal impairment: No specific dosage adjustment required; supplemental dose not required following dialysis
Hepatic impairment:
Mild hepatic insufficiency (Child-Pugh score 5-6): No adjustment necessary
Moderate hepatic insufficiency (Child-Pugh score 7-9): 35 mg/d; initial 70 mg loading dose should still be administered in treatment of invasive infections
Severe hepatic insufficiency (Child-Pugh score >9): No clinical experience

Pediatric

Not established

Interactions

Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, and dexamethasone may decrease levels of caspofungin; caspofungin may decrease levels of tacrolimus; rifampin decreases caspofungin levels by 30% (ie, adjust dose to 70 mg/d)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in moderate hepatic dysfunction (ie, decrease dose to 35 mg/d); may exacerbate pre-existing renal dysfunction or myelosuppression

Follow-up

Further Inpatient Care

• In a retrospective assessment of 536 patients identified during the first 4 months of the great coccidioidal epidemic, 158 patients required hospitalization.³
  • Various factors, as evaluated with univariate analysis, were associated with hospitalization.
  • The most important factor was shortness of breath; followed by age older than 50 years; African American 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.

Further Outpatient Care

• Patients with complications such as chronic pulmonary and all extrapulmonary infections should receive routine follow-up for several years after diagnosis. Many clinicians obtain serial complement-fixation titers in such patients.
• Patients receiving antifungal therapy require continued monitoring for adverse effects of these agents.
• Monitoring visits should be scheduled every 1-3 months and should include patient interview, physical examination, serologic testing, radiographic examinations, and procedures, as necessary. The decision to treat should be evaluated and current treatment should be re-evaluated. Expert consultations should be considered if needed.

Complications

• After acute infection
• In more than 90% of symptomatic individuals, no further sequelae develop. In approximately 8% of symptomatic individuals, serious pulmonary disease or extrapulmonary spread with or without pulmonary disease ensues.
• Reappearance of fever, shortness of breath, and hemoptysis indicate complications of residual lung disease.
• Rupture of nodules or cavities into the pleural space leads to bronchopulmonary fistula and/or empyema. 
• Septic shock
• One manifestation of coccidioidomycosis is septic shock, which generally develops in older individuals.
• This condition is diagnosed based on established criteria and hemodynamic monitoring. Cytokine assays reveal elevated levels TNF and interleukin-6, as in bacterial sepsis. Unfortunately, the outcome of these patients is uniformly poor.
• Disseminated disease: Disseminated disease can be fatal if dissemination occurs rapidly. Suggestive signs include dramatic sweats, dyspnea at rest, fever, and weight loss. Diffused miliary lesions on chest radiograph are associated with rapid clinical deterioration and death.
• Meningitis
• The most significant complication of Coccidioides infection is meningitis. Patients present with subacute-to-chronic (or occasionally acute) symptoms. More so than with other extrapulmonary manifestations, meningitis may be the only overt infection without concomitant pulmonary manifestations.
• CSF analysis reveals a lymphocytic pleocytosis with elevated protein levels and hypoglycorrhachia. In up to 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, which are present in 90% of patients. Coccidioidal meningitis preferentially involves the basilar meninges.
• Untreated, it is fatal in 90% of patients within 1 year and universally fatal within 2 years. Mortality rates can be 20-40%, even with treatment. Mortality is significantly increased in patients with complications such as hydrocephalus or infectious arteritis.
• Hydrocephalus is most common (30%), and MRI may facilitate its diagnosis. Hydrocephalus 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. 
• Cutaneous infection
• The skin is the most common site of extrathoracic spread. Direct cutaneous Coccidioides infection has a variable appearance, with papules, plaques, and verrucous lesions being the most common. They can be single or multiple and persist for a long period. Vesicular lesions, pustules, and subcutaneous abscesses may also develop.
• Spread is usually hematogenous, but direct inoculum may occur, evidenced by lymphangitis.
• 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. 
• Bone and joint disease
• Bones and joints are common sites of extrapulmonary infection. Bony lesions are most common in the axial skeleton and usually produce osteolytic lesions. The contiguous joints and surrounding soft tissues may be involved. The most frequently involved bones include the vertebrae, skull, bones of the digits, and long bones.
• Progressive bony destruction in the vertebrae can lead to spinal cord compression that may require urgent surgical intervention. Destructive bony lesions can lead to diagnostic confusion. Isolated joint involvement also occurs. The most frequently involved joints are the knee and the ankle. Bone and articular involvement also may be associated with tendonitis and inflammatory muscle involvement.
• 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. Lymph node involvement can be prominent; occasionally, such cases lead to a mistaken diagnosis of lymphatic malignancy. 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. In rare cases, intestinal and peritoneal involvement, with ascites, is a manifestation of widespread disease. Peritoneal mass lesions may be noted.
• Bone marrow involvement may yield various hematologic disturbances with a myelophthisic pattern.
• Myocardial involvement is uncommon and is most usually discovered at autopsy. About 20 reported cases of pericardial involvement have been described.²¹
• 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 involvement is probably underappreciated and usually occurs in the context of disseminated disease. Anterior uveitis and posterior uveitis (choroiditis and chorioretinitis) are uncommon, and endophthalmitis is rare.
• Congenital infection is rarely reported, although the placenta is frequently involved. The literature on pediatric infection is not nearly as extensive as that on adult disease. Dissemination is more common in neonates and infants than in adults. The mortality rate in children appears higher than that in adults. In neonates who do not have a fully developed immune system, the serologic response to infections may be impaired.
• Cutaneous hypersensitivity
• Cutaneous hypersensitivity reactions must be distinguished from direct cutaneous involvement by identifying the organism. Hypersensitivity reactions are immunologic phenomena and are linked to improved outcomes.
• Erythema nodosum, or tender and discolored nodules (generally on the lower extremities), is the most common hypersensitivity reaction and affects 25-30% of patients. Erythema multiforme (the characteristic finding being target lesions) can coexist with erythema nodosum but is less common. A diffuse erythematous rash (<1%) is the least common cutaneous hypersensitivity manifestation. Ocular hypersensitivity reactions, such as phlyctenular conjunctivitis, episcleritis, scleritis, and keratoconjunctivitis, frequently accompany erythema nodosum.

Miscellaneous

Medicolegal Pitfalls

• The most common medicolegal pitfall is mistaking viral meningitis for coccidioidal meningitis in patients with meningitis and lymphocytic pleocytosis.
  • The patient's travel history and area of residence have a major role in leading the clinician to the correct diagnosis.
  • Findings of eosinophils in the CSF or hypoglycorrhachia are important.
  • The progressive nature of the disease is inconsistent with a viral etiology.
• The differential diagnoses of erythema nodosum are extensive.
  • Coccidioidomycosis is perhaps one of the most significant associated conditions, and, once again, the patient's travel history and area of residence are important.
  • Patients with erythema nodosum generally have a benign course.
• Pregnancy can pose a clinical challenge.
  • Some of the older literature recommended that abortion be considered in pregnant women with coccidioidomycosis because of the virulent nature of the disease in these patients.
  • One group examined a series of pregnant women with coccidioidomycosis.²² Although the disease can complicate pregnancy, appropriate management led to satisfactory outcomes for the mother and child, suggesting that abortion need not be recommended.

Special Concerns

• Infection in immunocompromised individuals and specific groups of immunocompetent individuals follows a more aggressive course than in other groups.
• Patients receiving immunosuppressive agents for cancer chemotherapy, organ transplant, and/or autoimmune diseases or patients taking corticosteroids that impair cell-mediated immunity are at an increased risk of dissemination. For example, organ transplant recipients are at a significant risk for dissemination, with the possibility of 25% developing disseminated disease. Previously resolved infections in organ transplant recipients reactivate at a rate of approximately 10% per year.
• These rates mirror those observed in patients who are HIV positive and in the later stages of the illness, when opportunistic infection is likely.
• In immunocompromised individuals, progressive pulmonary disease is common, occurring in 40%.
• Although skin reactivity to coccidioidal antigens may be impaired, serologic response in all patients, except those with the most profound immunocompromise, remains intact.
• Older patients are at an increased risk for disseminated disease and diffuse progressive pulmonary disease. The mortality rate in patients older than 65 years is elevated, with one report describing a mortality rate of 15%.
• Patients with diabetes are also at an increased risk for diffuse progressive pulmonary disease and mortality.
• Historically, pregnancy has been considered an extremely perilous time for Coccidioides infection.
• Before the most recent epidemic, dissemination was believed to be 40-100 times more common in pregnant women than in the general population, and it was believed that 1 in 8 women who became infection during pregnancy would succumb to it. However, a study of a numerous individuals treated during the California epidemic showed that most pregnancies were carried to full term. Furthermore, pregnant women who develop infection and present with erythema nodosum are extremely unlikely to have a negative outcome.
• Dissemination and mortality rates are increased late in pregnancy, particularly in the third trimester, and true concern exists regarding maternal and fetal outcomes. Early recognition and treatment, when necessary, are important.
• Patients who have a history of resolved infection prior to pregnancy do not have a significant rate of recrudescence.
• See Medical/Legal Pitfalls.

Multimedia

Media file 1: Chest radiograph with a thin-walled cavity in the left upper lobe consistent with coccidioidomycosis.

Media file 2: Soft tissue abscess due to cocci.

Media file 3: Pulmonary cocci spherule (Hematoxylin-eosin stain).

Media file 4: Pulmonary cocci spherule, periodic acid-Schiff stain.

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Keywords

coccidioidomycosis, primary pulmonary coccidioidomycosis, primary coccidioidomycosis, chronic coccidioidomycosis, valley fever, desert fever, San Joaquin Valley fever, California fever, Coccidioides immitis, C immitis, Coccidioides posadasii, C posadasii, desert rheumatism, cocci, coccidioidal granuloma, coccidioidal nodule, coccidioidal cavity, coccidioidal mycosis, coccidioidal meningitis, coccidioidal pneumonia

Contributor Information and Disclosures

Author

Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center
Edward L Arsura, MD is a member of the following medical societies: American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Heart Association, American Medical Association, California Medical Association, Society of General Internal Medicine, and Southern Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences
Duane R Hospenthal, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Society for Infectious Diseases, International Society of Travel Medicine, and Medical Mycology Society of the Americas
Disclosure: Nothing to disclose.

Ana Paula Oppenheimer, MD, MPH,, Staff Physician, Department of Medicine, Richmond University Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Thomas Herchline, MD, Professor of Medicine, Wright State University Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio
Thomas Herchline, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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