eMedicine Specialties > Infectious Diseases > Fungal Infections

Coccidioidomycosis (Infectious Diseases)

Author: Edward L Arsura, MD, Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center
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; Ana Paula Oppenheimer, MD, MPH,, Staff Physician, Department of Medicine, Richmond University Medical Center
Contributor Information and Disclosures

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.

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