INTRODUCTION	Section 2 of 11
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Background: Coccidioides immitis and Coccidioides posadasii are dimorphic fungi endemic to certain arid regions in the southwestern United States and in 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 southwest of the 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 in which it is acquired (eg, valley fever, San Joaquin fever, desert fever, California fever) or clinical manifestations with which it presents (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 who had 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 unusually susceptible to the most serious consequences of infection, specifically 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), 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 are 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 make 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: Numerous studies have established that immunity mediated by T cells is critical to controlling the infection. T-cell activation and cytokine formation stimulate inflammatory cells and facilitate killing of the organism. T-helper type 1 (TH-1) cytokines, in particular interferon-gamma, promote macrophage killing of endospores.

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

Frequency:

• In the US: An estimated 100,000 infections occur annually in the United States. 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 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 24% of the population in the southern San Joaquin Valley at present. This figure is lower than findings from epidemiologic studies performed 50 years ago, when the results from skin tests for coccidioidal antigens were positive for 68% of the population. Positive skin test results are related to the duration of residence in endemic areas and to occupational and recreational exposure to dust.

	CLINICAL	Section 3 of 11
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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.

• In symptomatic patients, the most frequent 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)

• These symptoms are nonspecific, but diagnosis may be aided by observing erythema nodosum, which is present in 25% of patients.

Physical: Findings on physical examination reflect the organ systems involved.

• Pulmonary involvement may reveal evidence of consolidation with bronchial breath sounds, rales, rhonchi, dullness to percussion, and increased tactile and vocal fremitus.

• Pleural effusion and pneumothorax yield the usual findings.

• Meningitis is often accompanied by nuchal rigidity, photophobia, and alteration in cognitive functioning. Less frequent presentations include focal neurologic deficits, cranial nerve palsies, seizure and coma.

• Ataxia or gait abnormalities may be present.

• Localized percussion tenderness occurs in patients with bone disease.

• If the vertebral column is involved, careful neurologic examination is warranted to detect cord impingement.

• Joint involvement is usually monoarticular or oligoarticular. Physical findings are not helpful in differentiating coccidioidomycosis from other causes of monoarthritis or oligoarthritis.

• Erythema nodosum appears as tender lesions, generally on the anterior surface of the lower extremities, though the lesions may occur virtually anywhere. The lesions are tender to palpation, erythematous, and 1-2 cm in diameter. Erythema multiforme occurs 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.

Causes:

• The Coccidioides organism grows in 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 extremes of 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.