History
The incubation period of coccidioidomycosis averages 10-16 days, with a range of less than 7 days to 30 days. [5] The natural history of Coccidioides infection usually is one of a self-limited respiratory tract infection. In most cases, symptoms do not occur or are so mild that the infected individual does not seek medical attention. [13, 42] Approximately 30-40% of patients develop symptomatic disease, ranging from a mild influenzalike illness, to subacute pneumonia, to, rarely, respiratory failure.
Common symptoms of primary infection are nonspecific and include fever, cough, chest pain, fatigue, dyspnea, headache, arthralgias, and/or myalgias. Skin manifestations also are seen in a small percentage of cases. In addition to the above symptoms, infection can progress to various presentations. The constellation of fever, arthralgias, erythema nodosum or erythema multiforme, and chest pain commonly is referred to as San Joaquin Valley fever (or simply Valley fever) or desert rheumatism.
A study by Johnson and colleagues reported the following frequency of symptoms [43] :
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Fever (76%)
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Cough (73%)
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Chest pain (44%)
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Fatigue (39%)
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Shortness of breath (32%)
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Chills (29%)
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Erythema nodosum (26%)
Other symptoms included the following:
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Night sweats
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Weight loss
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Urticaria
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Arthralgias
Primary pulmonary infection may progress to overt pneumonia and chronic lung infections; hematogenous spread may occur, leading to disseminated disease, with focal involvement such as arthritis, osteomyelitis, and meningitis. Patients who have disseminated disease present with dramatic sweats, dyspnea at rest, fever, and weight loss.
Exposure history
In patients with suspected coccidioidomycosis, a history of travel to, or residence in, an endemic area is very important in establishing the risk for exposure. The exposure may be as limited as driving through an endemic area. [5, 6, 7, 9, 10, 11, 12] The clinician should inquire about activities that involve increased exposure to dust or soil (eg, farming, construction work, archaeological digs). Rare cases of infection from contaminated fomites (eg, contaminated plaster cast, dusty clothing) have been reported. [7]
Coccidioidomycosis is considered an occupational hazard in endemic regions, and it is a compensable illness in such cases.
Severe 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. Some patients may have no radiographic evidence of previous pulmonary disease, or no history of a preceding respiratory illness.
Factors associated with increased risk for more severe coccidioidal disease include the following:
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HIV disease, especially when CD4+ cell counts are < 250/mL [35]
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Pregnancy; the risk increases slightly with each progressive trimester
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Lymphoma
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Immunosuppressive therapy in solid organ transplant recipients (especially during first year after transplantation)
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Long-term corticosteroid treatment (>20 mg prednisone)
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Treatment with tumor necrosis factor (TNF)-alpha inhibitors [40]
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Chemotherapy for solid tumors
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Diabetes mellitus
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Preexisting cardiopulmonary conditions
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Thymectomy
The male-to-female ratio in disseminated disease is 5:1, but this disparity reverses in pregnant women.
Physical Examination
No physical findings are pathognomonic for coccidioidal infection. However, in endemic areas, coccidioidal infection should be a strong consideration for patients who present with an influenzalike illness and a lower-extremity rash. Suggestive signs of disseminated disease include dramatic sweats, dyspnea at rest, fever, and weight loss.
In addition to nonspecific systemic signs (eg, fever), findings on physical examination reflect the organ system or systems involved.
Respiratory manifestations
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, erythema nodosum) are present in an endemic area.
Respiratory symptoms are related to the severity of lung involvement and destruction, and they range from cough, to mild respiratory distress, to respiratory failure and acute respiratory distress syndrome.
Pulmonary involvement may manifest as the following:
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Bronchial breath sounds
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Rales
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Rhonchi
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Dullness to percussion
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Increased tactile and vocal fremitus
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Decreased breath sounds from effusions
Less commonly, diffuse coccidioidal pneumonia in immunocompetent hosts manifests as respiratory failure. This is due to either inoculation with a large number of spores or to hematogenous seeding of the lung at several sites.
Approximately 5% of pulmonary infections result in the formation of nodules. These typically cause no symptoms but may be indistinguishable from a neoplasm on radiologic studies without histologic examination.
Approximately half of these nodules resolve spontaneously. However, persistent nodules eventually can degenerate into thin-walled cavitations, which may erode into adjacent small airways or the pleural space, resulting in hemoptysis or pneumothorax. Rupture of a peripheral coccidioidal cavity into the pleural space is a complication that is most common in young male patients.
Patients with diabetes mellitus or preexisting pulmonary fibrosis (eg, from cigarette smoking) may develop a chronic fibrotic pneumonia process. These patients may present with chronic cough and systemic symptoms such as fever, night sweats, and weight loss, as well as local symptoms.
Skin manifestations
Cutaneous hypersensitivity reactions are common in primary coccidioidomycosis. More than 50% of affected children, and 25% of infected individuals overall, develop diffuse, evanescent, maculopapular rashes or urticaria that may progress to erythema nodosum or erythema multiforme after 3-21 days. Erythema multiforme is more common in children, but erythema nodosum is the classic presentation in an endemic area.
Erythema nodosum presents as tender, erythematous nodules, 1-2 cm in diameter, on the anterior lower extremities, although they may develop virtually anywhere. Erythema multiforme consists of relatively symmetric erythematous, expanding macules or papules that evolve into classic iris or target lesions with bright-red borders. Central vesicle formation is common.
Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.
Ocular hypersensitivity reactions frequently accompany erythema nodosum. These include phlyctenular conjunctivitis, episcleritis, scleritis, and keratoconjunctivitis.
These cutaneous hypersensitivity reactions are a favorable prognostic sign; they suggest a low risk for dissemination because they correlate with development of cell-mediated immunity. Erythema nodosum occurs less often in persons outside of endemic areas and occurs infrequently in Blacks, Hispanics, and Filipinos. Among adults, women experience erythema nodosum much more frequently than men.
Cutaneous hypersensitivity reactions must be distinguished from cutaneous Coccidioides infection, in which the organism is present in the lesion. The skin eventually is involved in most types of disseminated disease. Cutaneous infection usually results from hematogenous seeding, but direct inoculation may occur, evidenced by lymphangitis.
Cutaneous coccidioidal infection has a variable appearance; papules, plaques, and verrucous lesions are the most common. 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 (see the image below).
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.
Disseminated infection also can result in ulceration and fistulas from underlying infection.
Musculoskeletal manifestations
Musculoskeletal involvement occurs in one third of patients with dissemination and includes the following:
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Unifocal bone lesions (lytic or sclerotic in 60% of cases)
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Unifocal joint lesions (monoarticular arthritis in 90% of cases)
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Rarely, infected tendon sheaths demonstrating a villonodular synovitis
Although arthritis usually is monoarticular, it can be migratory in nature. Knees are the most common joints involved, followed by ankles and wrists. Physical findings are not helpful in differentiating coccidioidomycosis from other causes of monoarthritis or oligoarthritis.
Arthrocentesis samples typically reveal an exudative effusion. The presence of organisms varies, and reports suggest that direct visualization of organisms is rare but can occur in up to half of cases.
Coccidioidomycosis affects joints, causing synovitis. Infection of the bone typically causes a chronic osteomyelitis, often draining to soft tissue and creating fistulae. Long bones, and 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 for meningitis. [44]
Although osteomyelitis can occur from direct inoculation of bone from contaminated penetrating objects, it more commonly is due to hematogenous spread and disproportionately affects the vertebra; paraspinal abscesses are a possible complication. Local pain and tenderness may be evident with vertebral osteomyelitis or paraspinous abscesses. Progressive bony destruction in the vertebrae can lead to spinal cord compression that may require urgent surgical intervention.
Other common sites of involvement include the tibia, femur, skull, and bones of the hands and feet. Other 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. 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.
Lymph node involvement can be prominent; occasionally, such cases lead to a mistaken diagnosis of lymphatic malignancy. Supraclavicular and cervical lymphadenopathy are common and probably result from lymphatic drainage from the pulmonary infection site. 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. Hepatic infection usually is asymptomatic but can be part of a hepatic-pulmonary syndrome with a brief hepatitis-like 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 also have been reported to be secondary to coccidioidal infection. [45]
Cardiovascular complications account for an extremely small percentage of clinical presentations. In the rare cases in which they do occur, however, they can be devastating. Pericardial effusions can produce cardiovascular compromise and tamponade in extreme cases. [46] Myocardial involvement most often is discovered at autopsy.
Urinary tract involvement is rare (with the exception of asymptomatic coccidiuria) and usually is 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 coccidioidomycosis is rare but is probably underappreciated. Ocular involvement usually occurs in the context of disseminated disease. Ocular coccidioidomycosis can present as a lacrimal gland fossa mass or with eye pain, photophobia, and other symptoms of chorioretinitis or iridocyclitis. Anterior uveitis and posterior uveitis (choroiditis and chorioretinitis) are uncommon; endophthalmitis is rare and can occur without systemic involvement. [47]
Meningitis
Approximately 50% of patients with disseminated coccidioidomycosis acquire CNS disease. It can occur acutely with primary infection or later with dissemination. The meninges can be the only site of dissemination, in which case the patient is at increased risk for complications and death. [48]
Coccidioidal meningitis can present as an acute process but it is usually chronic with insidious onset, in contrast to meningitis from bacterial causes. Persistent headaches should be evaluated thoroughly upon worsening, especially in cases of 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. [49]
Typically a granulomatous and suppurative basilar process, coccidioidal meningitis also can involve the brain parenchyma and spinal cord with granulomas and abscesses. Hydrocephalus is a common sequela and often is present at initial diagnosis in children.
Septic shock
Septic shock generally develops in older individuals or immune-compromised patients. For example, patients with advanced HIV disease may present with a fulminant picture of respiratory failure, diffuse pneumonia, fungemia, and septic shock that resembles a gram-negative infection.
This condition is diagnosed on the basis of established criteria and hemodynamic monitoring. Cytokine assays reveal elevated levels of tumor necrosis factor (TNF) and interleukin-6, as in bacterial sepsis.
Coccidioidal fungemia
This is a very rare, fulminant complication of disseminated coccidioidomycosis. Coccidioidal fungemia seems to be more common in patients with comorbidities and immunosuppressive states. The literature notes 113 cases, with about 38% associated with HIV; 18% with corticosteroids; 10% with solid organ transplants; and 4% with pregnancy. Dissemination occurred to the liver, spleen, and meninges/CNS, but endocarditis was not found. Serologic tests were positive in 87% patients. Overall mortality at 30 days was 62%, with a mean survival of 11.4 days. Survival is poorest in immunocompromised patients or those not receiving antifungal therapy. [50]
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Soft tissue abscess due to cocci.
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Pulmonary cocci spherule (Hematoxylin-eosin stain).
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Pulmonary cocci spherule, periodic acid-Schiff stain.
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Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.
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A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.
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Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.
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A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).
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A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
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Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.
