Caroline Milne MD
Merle Sande MD
Essentials of Diagnosis
Coccidioidomycosis was first described as a disease a little more than a century ago in Buenos Aires, Argentina. It was in San Francisco that the organism causing the clinical disease was given its name, Coccidioides immitis. Many diseases were later found to be caused by this organism, including San Joaquin Valley Fever.
Exposure to dust affects the incidence of coccidioidomycosis. Incidence is highest in the summer and fall when the soil is dry and dusty. Earthquakes and dust storms also increase incidence. In the United States an estimated 100,000 infections occur annually.
Infection doesn't necessarily mean clinical manifestation of disease. Infection has been studied among soldiers stationed in the San Joaquin Valley during WWII. The soldiers were skin tested and questioned about illnesses. Of all reported infections, 60% were found to be asymptomatic, another 35% were self-limited, and 5% resulted in disseminated disease.
A skin rash is common with primary infection. Both erythema nodosum and erythema multiforme are referred to as “specific erythemas” of coccidioidomycosis. These erythemas are associated with an intense immunologic response and with a good prognosis. People who exhibit these erythemas will likely not progress to disseminated disease.
The most common clinical manifestation of disease is pneumonia (Box 72-1). Most are self-resolved and likely go undiagnosed. Pulmonary complications occur infrequently and include asymptomatic nodules or thin-walled cavities, slow resolving pneumonia, or chronic lung infection.
Nodules occur in 5–7% of patients and are usually solitary and asymptomatic. The morbidity associated with these lesions occurs during surgical resection of the nodules to exclude cancer. More recently percutaneous fine-needle biopsy has been used for diagnosis.
Table 72-1. Clinical features of primary coccidioidal infection. 1
Cavities occur in younger patients, are most frequently asymptomatic, and are usually self-resolved, disappearing within 2 years of appearance. Complications, however, can occur and are usually associated with air fluid levels or infiltrates surrounding the cavity. Infection rarely spreads to other areas of the lung. If rupture of the cavity occurs, surgical repair is required.
Disseminated disease is unusual. Fewer than 5% of infected persons experience disseminated disease. Extrapulmonary disease includes granulomatous skin lesions or subcutaneous abscess, septic arthritis, osteomyelitis, and meningitis. Risk factors for extrapulmonary disease have been found to be male sex, pregnant women, immunosuppression, nonwhites (especially Filipinos and blacks), and possibly age (the very old or young).
Meningitis occurs in one-third to one-half of all patients with coccidioidal dissemination. The clinical symptoms are not specific to C immitis infection and include headache, vomiting, nuchal rigidity, confusion, and diplopia. Lumbar puncture is essential to diagnosis. The cerebrospinal fluid reveals a pleocytosis with a predominance of mononuclear cells. Most have an eosinophilia as well. Usually the glucose is low, and the protein elevated. The cerebrospinal fluid should be sent both for culture and serologic tests (complement-fixing antigen).
Coccidioidal meningitis should be suspected in patients with the clinical syndrome and a recent coccidioidal infection. Meningitis usually occurs within 6 months of initial infection; however, meningitis can occur late if immunosuppressed. Early diagnosis is important, and, if left untreated, coccidioidal meningitis is fatal. Even with diagnosis, treatment is difficult.
The vast majority of cases are asymptomatic and will be identified by a positive skin test only. Positive skin tests are neither definitive nor helpful in establishing the diagnosis of coccidioidomycosis, because of the high number of asymptomatic infections. Definitive diagnosis is established via culture of the organism or antibody or antigen detection. Antigen detection kits are not currently commercially available.
C immitis readily grows in the laboratory and is detectable as early as 2–5 days after inoculation. The fungal growth is further evaluated via a species-specific DNA probe. Results are available the day growth is detected. It is important to notify the laboratory of your suspicions, because laboratory identification may be dangerous to the lab technician. Arthrospores readily become airborne and may be inhaled.
There are two coccidioidal antigens that are targeted for antibody detection, the tube precipitin reading (TP) antigen and the CF antigen. Antibody detection kits are not available, and instead laboratories use immunodiffusion tests. Both tests are reported qualitatively; if immunodiffusion CF is positive, a follow-up quantitative test is necessary. The concentration of CF antibodies is proportional to the extent of the disease. Ordering physicians must be aware of false-negative results in detecting anticoccidioidal antibodies; these results are most prevalent in early primary infection or in immunosuppressed patients.
BOX 72-1 Coccidioidal Infection
BOX 72-2 Treatment of Coccidioidal Infection in Adults
BOX 72-3 Indications for Treatment of Coccidioidal Infection
Coccidioidal infections are suspected in patients with pulmonary symptoms and the appropriate travel or residence in an endemic area. Bacterial or other fungal pneumonias should be included in the differential.
Most coccidioidal infections are self-resolved. Pulmonary complications can occur and include asymptomatic nodules, slowly resolving pneumonia, or chronic lung infection. The most serious complication includes disseminated disease and can affect any organ system.
In most cases the decision to treat is the real question. Recall that even for patients who develop symptoms of initial infection, the disease is usually self-limited. In patients in whom treatment is indicated, coccidioidomycosis is very difficult to cure. Treatment for initial infection is indicated only for patients with deficiencies in T-cell immunity. A physician may decide to treat a severe pulmonary infection, but there is no expert consensus. Treatment is indicated for chronic pulmonary infection and extrapulmonary dissemination. Accepted-standard-of-care therapies include amphotericin B and oral azole antifungal agents (Boxes 72-2 and 72-3). Fluconazole and itraconazole have been shown to have similar success rates. Length of treatment is controversial, because relapse is common. Treatment may be lifelong. Most physicians will treat pulmonary and disseminated disease for 12–18 months. It has been found that negative serial coccidioidin skin tests and very high CF antibody titers are independently associated with increased risk of relapse. Rising CF titers after completion of therapy are an indication of relapse and warrant retreatment. Patients with meningitis are likely never cured and require indefinite treatment. Only fluconazole and amphotericin B have been shown to be effective therapies. If amphotericin B is used, both parenteral and intrathecal therapy is indicated.
There is no vaccine available against C immitis infection. General prevention includes avoiding exposure to the fungus in its natural setting and decreasing the amount of airborne dust. Environmental measures including paving dirt roads and planting grass may be implemented (see Kirkland and Fierer, 1996).
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