eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Coccidioidomycosis

Author: Michele M Cheung, MD, Department of Pediatrics, Division of Pediatric Infectious Diseases, Consulting Staff, University of California at San Francisco
Coauthor(s): Peggy Weintrub, MD, Chief, Division of Pediatric Infectious Diseases, Clinical Professor, Department of Pediatrics, University of California at San Francisco
Contributor Information and Disclosures

Updated: Jun 22, 2009

Introduction

Background

Coccidioides immitis is a dimorphic fungus endemic in the soil of the southwestern United States and some areas of Mexico, Central America, and South America. Inhalation of spores of C immitis results in coccidioidomycosis, which is an acute pulmonary infection that is often asymptomatic but may manifest as a flulike illness or pneumonia. Occasionally, severe progressive pneumonia or residual pulmonary sequelae can result.^1,2,3

Although occurring rarely, dissemination is most commonly observed in a host with underlying immunosuppression or other risk factors. Common sites of dissemination include skin, bone, joint, and meninges.

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

Pathophysiology

C immitis is found in a saprophytic or vegetative phase in the soil and in laboratory culture and in a parasitic or tissue phase in the host. In the saprophytic phase, the organism is described as mycelia with branching septate hyphae. The aerial mycelia contain rectangular spores (ie, arthroconidia) surrounded by nonviable cells, thus creating a fragile structure. Upon fragmentation of the hyphae, the infectious arthroconidia become airborne spores measuring 2-8 μ m in diameter. These spores are inhaled by the host and reach the pulmonary alveoli; however, they also can be introduced into skin or soft tissue by inoculation into wounds or by trauma.

Pulmonary infection can result from inhalation of a single spore in humans. Increased exposure occurs with disruption of soil, which can occur with earthquakes, wind or dust storms, farming, construction, archeological excavations, or with drought following heavy rains. High inoculum exposures are more likely to result in symptomatic disease. Primary infection most often occurs in the dry months of the summer or fall. Person-to-person transmission does not occur. Rare cases of infection from contaminated fomites (eg, contaminated plaster cast, dusty clothing) have been reported.

The incubation period of coccidioidomycosis averages 1-3 weeks, with a range from less than 7 to 30 days. The spores enlarge to spherules that are round double-walled structures measuring approximately 20-100 μm in diameter. The spherules undergo internal division within 48-72 hours until they are filled with hundreds to thousands of offspring (ie, endospores). Rupture of the spherules leads to the release of endospores, which mature to form more spherules. The spherules and endospores are not infectious.

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

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

Frequency

United States

Incidence averages approximately 150,000 cases of coccidioidomycosis per year. This estimate is greater than the 100,000 cases per year previously cited in the literature as a result of population increases in southern Arizona and central California, where the organism is endemic.⁴ C immitis is endemic in soil in the southwestern United States, including California (especially the San Joaquin Valley), western Texas, New Mexico, and the deserts of Arizona. In endemic areas, the annual risk of infection is 2-4% among healthy individuals. The organism's habitat is characterized as the lower Sonoran life zone, with an arid-to-semiarid climate, alkaline dry soil, hot summers, and moderate-to-low rainfall of 5-20 in/y.

Coccidioidomycosis can be observed in nonendemic areas due to travel, population mobility, immunosuppression, and reactivation. Diagnosis often is delayed in nonendemic areas because coccidioidal infection initially is not considered in the differential. Domesticated, zoo, and wild animals can also be infected with C immitis.

Coccidioidal disease has a significant socioeconomic impact in the United States. An otherwise healthy individual diagnosed with symptomatic coccidioidomycosis may miss more than 1 month of school or work. Recent estimates of antifungal medication costs range from $5000-20,000 per person per year of therapy for the disease.

International

C immitis also is found in northern Mexico and some parts of Central and South America; all areas are located between 40° latitude, north and south.^5,6

Mortality/Morbidity

Mortality is extremely uncommon with primary coccidioidomycosis. Approximately 90-95% of infections resolve without sequelae; however, 5-10% have severe or progressive pneumonia, including nodules or peripheral thin-walled cavities, with a smaller proportion resulting in chronic pulmonary or extrapulmonary disease. Dissemination is uncommon (approximately 0.5% of infections in whites), typically involves infection of the skin, bone or joint, lymph nodes, or CNS, and is associated with increased morbidity and mortality. In the host who is immunocompromised, the risk of dissemination is much higher (up to 30-50%), and mortality can be as high as 70% even with appropriate therapy.

Race

No race predilection for primary infection with C immitis is observed. Dissemination is more common in Filipinos and blacks and possibly in other Asians, Hispanics, and Native Americans. The risk of dissemination is 175 times greater in Filipinos and 10 times greater in blacks than in non-Hispanic whites. Some studies have suggested genetic bases to the predisposition to dissemination, including a possible association with blood group type B. In addition, uncharacterized factors that predispose these races to dissemination may be noted.

Sex

Increased incidence of primary coccidioidal infection may be apparent in older boys and men because of occupational exposure. Women who are pregnant, especially during the third trimester and in the peripartum period, are at higher risk for dissemination than the general population.⁷

Age

In general, dissemination is less common in children than in adults; however, infants can experience severe disease within the first few months of life, especially if exposed to a large respiratory inoculum.

Clinical

History

In patients with suspected coccidioidomycosis, a history of travel or residence in an endemic area is very important in establishing the risk of exposure. The exposure may be as limited as driving through an endemic area.

• Patients with primary pulmonary coccidioidal infection may have the following:
  • Fever
  • Localized adventitious breath sounds
  • Mild respiratory distress
  • Arthritis and rash (classic rash is erythema multiforme [EM] or erythema nodosum [EN])
• In general, a patient with disseminated coccidioidomycosis may have signs of the following:
  • Chronic illness
  • Weight loss
  • Fever
  • Lymphadenopathy: The physical examination depends on the site of involvement and is relatively nonspecific.

Physical

In most patients with coccidioidal infection, the primary infection is in the lungs. In 60-65% of individuals affected with coccidioidomycosis, primary pulmonary infection is asymptomatic. Extrapulmonary primary infections can occur with trauma causing a puncture wound from a contaminated object. Laboratory workers and children are especially at risk for cutaneous or soft tissue lesions, including chancres, with regional lymphadenitis.

• Pulmonary coccidioidomycosis
  • Pulmonary coccidioidomycosis may be difficult to differentiate from other acute or subacute respiratory infections with fever. Most symptomatic primary infections are not easily diagnosed as coccidioidomycosis unless classic findings (eg, EM, EN) are present in an endemic area.
  • Because most patients recover spontaneously, pursuing documentation of coccidioidal infection is not imperative unless the patient is immunocompromised or has signs of severe progressive disease or dissemination.
• Primary coccidioidomycosis
  • Symptomatic patients with primary coccidioidomycosis have a range of presentations from brief upper respiratory infection or flulike illness to lobar pneumonia. The most common symptoms are cough, fever, fatigue, chest pain, dyspnea, and hemoptysis. More severe manifestations include pleural effusions, pericarditis, and rare presentations mimicking bacterial pneumonia and sepsis.
  • Skin manifestations are common with primary infection. More than 50% of children with primary coccidioidomycosis develop rashes that begin as diffuse, evanescent, maculopapular rashes or urticaria. The host may develop EM or EN after 3-21 days. EM is more common in children. Although nonspecific, EN is the classic presentation in an endemic area. Prognostically, EN is suggestive of low risk of dissemination since it correlates with development of cell-mediated immunity. EN occurs less often in persons outside of endemic areas and occurs infrequently in blacks, Hispanics, and Filipinos. In adults, females are affected with EN much more frequently than males.
  • Other common symptoms of primary coccidioidomycosis include arthralgias, arthritis, and myalgias. The syndrome of valley fever includes fever, arthralgias, and EN or EM. Headaches and anorexia also can be present. Infants and older children can present with stridor from laryngeal infection.
  • Primary infection of the newborn rarely occurs. Infection of the genital tract of the mother can result in placental involvement, coccidioidal endometritis, and aspiration of infected amniotic fluid by the fetus. Both congenital and perinatal transmission of C immitis have been reported.
  • Although the illness, especially the fatigue, may persist for weeks to months, 90-95% of primary pulmonary infections resolve without sequelae. Of patients with primary coccidioidomycosis, 5-10% have persistent pulmonary nodules or cavities on chest radiography. The cavitary pulmonary lesions often are thin-walled, asymptomatic, and resolve spontaneously. Cavities larger than 6 cm in diameter are at greater risk for rupture and require surgery.
  • Occasionally, the pneumonia can be severe or progressive or dissemination can occur. In addition, chronic pulmonary infection can occur, particularly in hosts who are immunocompromised or those with underlying diabetes. Children rarely develop chronic pulmonary lesions.
• Disseminated coccidioidomycosis
  • Consider disseminated coccidioidomycosis in individuals with persistent fevers or malaise; chronic pulmonary infiltrates or nodules; or skin, soft tissue, or bone lesions in the appropriate epidemiologic setting.
  • A higher risk of infection is suggested after a large inoculum exposure to soil, such as from windstorms, digging, farming, and construction.
  • Approximately 0.5-1% of individuals with coccidioidomycosis develop disseminated disease. Dissemination usually occurs weeks to months after the initial infection but may occur after 1 year in a host who is immunocompromised. In addition, reactivation of treated primary disease may occur at any time in a host who is immunosuppressed.
  • Widespread miliary disease is very rare but may progress rapidly and is often fatal. The presence of diffuse reticulonodular or miliary pulmonary infiltrates from coccidioidomycosis suggests an underlying immunodeficiency. Hosts who are immunocompromised can have concurrent aggressive primary pulmonary disease and dissemination.
  • Infection in the host who is immunocompromised is fulminant, especially with T-cell dysfunction in patients with HIV, solid organ transplantation, and/or lymphoma. Patients who are immunosuppressed from high-dose corticosteroid or anti-tumor necrosis factor (TNF) therapy are also at increased risk for dissemination. Patients with organ transplants are at the greatest risk for disseminated coccidioidomycosis in the first year posttransplant. Ten percent of patients who are HIV positive and reside in endemic areas contract active coccidioidal disease each year. In particular, adults infected with HIV with CD4 counts less than 250 are at significant risk for active disease.
  • Signs of dissemination include persistent fever, toxicity, and development of extrapulmonary lesions. C immitis has a predilection for the lungs, skin, soft tissue, joints, and CNS, especially the meninges.
  • The skin is the most common site of extrapulmonary disease. In most types of disseminated disease, the skin eventually is involved. The classic skin manifestation of coccidioidomycosis is a verrucous granuloma at the nasolabial fold. Other typical lesions include granulomatous papules, nodules, and plaques, especially on the head. These lesions can progress to subcutaneous involvement, sinus tracts, abscesses, and chronic ulcers. Differential diagnoses of coccidioidal skin lesions include tuberculosis, syphilis, other fungi, actinomycetes, sarcoid, warts, and squamous cell carcinoma.
  • Coccidioidomycosis also affects joints, causing synovitis. Knees are the most common joints involved, followed by ankles and wrists. Infection of the bone typically causes a chronic osteomyelitis, often draining to soft tissue and creating fistulae. Long bones, as well as bones of the hands, feet, pelvis, and skull, may be involved. Approximately 60% of incidents of coccidioidomycosis are limited to a single bone, with 20% involving 2 bones and 10% involving 3 bones. Vertebral osteomyelitis can affect any part of the vertebra, sparing the disc, but putting the patient at risk of meningitis.
  • Approximately 50% of patients with disseminated coccidioidomycosis acquire CNS disease. It can occur acutely with primary infection or later with dissemination and can be the only site of dissemination. CNS coccidioidomycosis can present with headache, vomiting, nuchal rigidity, change in mental status, lethargy, confusion, ataxia, diplopia, and focal neurologic signs. Coccidioidal meningitis is usually chronic with insidious onset, in contrast to meningitis from bacterial causes. Typically a granulomatous and suppurative basilar process, coccidioidal meningitis can also involve the brain parenchyma and spinal cord with granulomas and abscesses. Hydrocephalus is a common sequela and is often present at initial diagnosis in children.
  • Although the skin, lungs, joints, soft tissue, and meninges are the most common sites for coccidioidal dissemination, infection of almost every other organ system has been reported. At autopsy, involvement of the liver, spleen, kidney, adrenal glands, psoas muscle, heart, thyroid, and prostate has been noted. These infected sites rarely are responsible for the presenting signs or symptoms. Infection of the thyroid gland has been reported to result in a thyroid abscess and thyrotoxicosis.
    • Ocular coccidioidomycosis can present as a lacrimal gland fossa mass or with eye pain, photophobia, and other symptoms of chorioretinitis or iridocyclitis.
    • Hepatic infection is usually asymptomatic but can be part of a hepatic-pulmonary syndrome with a brief hepatitislike illness, hepatic granulomas, and eosinophilia.
    • Coccidioidal infection of the biliary tree is uncommon but has been reported to present as abdominal pain and obstructive jaundice. Intestinal obstruction and peritonitis have also been reported to be secondary to coccidioidal infection.
    • Coccidioidal infection of the genitourinary tract can result in nodules or granulomas, abscesses, or fistulae in the kidney, ureter, bladder, prostate, epididymis, or testes.

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