Excerpt from Coccidioidomycosis (Infectious Diseases)

Please click here to view the full topic text: Coccidioidomycosis (Infectious Diseases)

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.

Please click here to view the full topic text: Coccidioidomycosis (Infectious Diseases)