a dimorphic fungus endemic in the southwestern United States and parts of Latin America, causes approximately 100,000 infections in the U.S. every year.(1) A recent epidemic in California that was attributed to climactic changes resulted in a 10-fold increase in the number of cases in that state.(1) Two other factors contribute to the rising number of cases of coccidioidomycosis seen in areas where the infection is endemic. The first is burgeoning population growth in the American southwest -- where, for example, the population of metropolitan Tucson had doubled over the past 25 years.(2) The second is the AIDS epidemic.
Cell-mediated immunity is critical to host defense against coccidioidomycosis. Even prior to the AIDS epidemic, it was recognized that immunosuppressed hosts were more susceptible to disseminated forms of the infection.(3) It is therefore not surprising that the first cases of coccidioidomycosis in HIV-infected persons began appearing shortly after the onset of the epidemic, although disseminated coccidioidomycosis was not recognized as an AIDS-defining illness until 1987.(4) Since its original description, an increasing number of patients have been found to be infected with both HIV and C. immitis, and coccidioidomycosis has become the third most frequently seen opportunistic infection in Arizona, following PCP and superficial candidiasis.(5)
Estimates of the risk that a person with HIV disease will acquire coccidioidomycosis were recently obtained from a prospective cohort study.(6) This study, which was conducted at several Arizona institutions, enrolled 170 HIV-positive subjects who had lived in the endemic area for a median of 7.7 years. Of this number, 13 had a prior history of coccidioidomycosis and 22% had a positive skin test at entry. During a median follow-up of 11.3 months, 13 subjects developed coccidioidomycosis. All but one of these 13 patients had CD4 counts that were less than 250 cells/mm3, and 11 of the 13 had coccidioidal skin tests at entry. Two of these patients had positive skin tests at the time of enrollment, and these two patients were still skin test-positive at the time they were diagnosed with active coccidioidomycosis.
Kaplan-Meier analysis revealed that 25% of this cohort would develop coccidioidomycosis after 41 months of follow-up. This very high rate is in striking contrast to the rate seen in healthy college students in this region, which is less than 0.5% per year.(7) In this cohort study, two factors were significantly associated with the development of active coccidioidomycosis: a CD4 count of less than 250 cells/mm3 or a diagnosis of C.D.C.-defined AIDS. Surprisingly enough, prior history of coccidioidomycosis, a positive skin test at baseline, development of a positive skin test, and residence in the endemic area for more than 25 months were not associated with the development of active disease.
It is noteworthy, however, that in at least two of these cases the development of acute coccidioidomycosis appeared to be related to reactivation of prior infection. Researchers had previously postulated that reactivation of prior coccidioidal infection -- under pressure of waning CD4 cell function -- was possible, a situation analogous to what is seen with histoplasmosis in HIV disease. The Tucson study makes it clear that reactivation can and does occur.
The median CD4 count in the Tucson study was 89 cells/mm3 (range: 4 to 531), which is similar to other studies dealing with coccidioidomycosis as a complication of HIV disease. In an earlier study conducted by Fish et al.,(5) the median was 101 cells/mm3 (range: 5 to 670), and in a Phoenix cohort the median was "less than 100" cells/mm3 and the range was 2 to 384.(8) This is not surprising, given that the Tucson and Phoenix studies shared a large number of patients.
Fever, chills, weight loss, night sweats, and cough are common symptoms of coccidioidal infection, followed in frequency by fatigue, diarrhea, dyspnea, and headache. Because this familiar constellation of symptoms can suggest any number of pathogens in HIV-positive patients, it is important for clinicians to suspect coccidioidomycosis in patients who live in -- or have traveled to -- regions where the disease is endemic. Signs of coccidioidal infection are lymphadenopathy (24%), splenomegaly (8%), and various neurologic findings in cases of meningitis.
Since primary coccidioidal infection is the result of inhalation of the infective particle, the lung is the most frequent organ involved (Table 1). The majority of patients with coccidioidomycosis have bilateral nodular or reticulonodular infiltrates (Figure 1). This diffuse pulmonary involvement, which frequently mimics PCP, may occur concurrently with PCP -- as it did in 12 of 77 patients in one series.(5) Diffuse pulmonary involvement is associated with a poor prognosis.
Patients with active coccidioidal infection may be dyspneic, but symptoms are often vague during all stages of active infection.
Although the diffuse nodular or reticulonodular pattern has been seen in immunosuppressed patients who do not have HIV disease, it is distinctly uncommon in patients with no known immunosuppression, occurring in approximately 1% of cases.(9) In HIV-infected patients, focal pulmonary disease is less common than the diffuse form. It may present as a nodule, a focal infiltrate, a pleural effusion, or as hilar lymphadenopathy and it is radiographically similar to the coccidioidal illness seen in HIV-negative patients. As a rule, HIV-positive patients who present with focal pulmonary disease tend to have better preserved CD4 cell function and median counts greater than 250 cells/mm3.
In patients with AIDS, coccidioidomycosis may disseminate to extrapulmonary sites, leading to meningitis or brain abscess, fungemia, and involvement of the liver, spleen, lymph nodes, kidneys and, less commonly, other viscera. In one series, all five autopsy subjects had disseminated disease.(9)
In patients with pulmonary abnormalities, fresh sputum should be examined after 10% KOH digestion of the specimen, and this sputum sample should be examined microscopically after Papanicolaou stain has been applied. Sputum and other respiratory secretions should also be cultured on appropriate fungal media. In one recent series, cytology and culture of sputum were found to be comparably sensitive -- approximately 70% -- for the presence of C. immitis.(8)
The value of induced sputum examination for Coccidioides is unknown.(10) If sputum cannot be obtained, however, or if the sputum sample does not establish the diagnosis of coccidioidomycosis, the clinician should proceed expeditiously to bronchoscopy with bronchoalveolar lavage in cases where coccidioidomycosis is suspected. Should lavage prove negative, repeat bronchoscopy with transbronchial biopsy is indicated. The latter had 100% sensitivity and specificity in one series .(8)
Although the use of BAL has been established for the diagnosis of diffuse infiltrates in AIDS patients from Coccidioides-endemic areas, BAL is more likely to identify pneumocystis than coccidioidomycosis. In one study, the detection rate was 26 cases of PCP versus one case of coccidioidomycosis.(11)
The evidence suggests that blood cultures will be positive for C. immitis in 12% of patients who present with evidence of diffuse pulmonary disease or extrapulmonary dissemination,(10) and such cultures should therefore be obtained. Enlarged lymph nodes (Figure 2) should be biopsied, examined histopathologically, and cultured. In one series, inguinal lymph nodes were involved in all patients with lymph nodes infection outside the thorax.(5)
In patients with neurologic signs or symptoms, CT or MRI scanning may reveal enhancement of basilar meninges, hydrocephalus, or focal lesions consistent with infarct or abscess. The CSF findings in such cases are similar to those seen in non-immunocompromised patients, with 8 of 9 patients in one series showing a mononuclear cell pleocytosis (range: 2 to 772 cells/mm3). In that series, 7 of the 9 had elevated protein (range: 19 to 348 mg/dL) and 4 had low CSF glucose (range: 5 to 67 mg/dL).(5)
It is noteworthy that, in another study, complement fixing antibody to C. immitis was found in the CSF of all the subjects, whereas culture of spinal fluid yields the organism only about 60% of the time.(10) This finding is in direct contrast to the experience with HIV-negative patients who develop coccidioidomycosis; in these subjects CSF cultures are rarely positive. Because the cutaneous manifestations of disseminated Coccidioides can be diverse,(12) suspicious skin lesions should be biopsied.
The use of serodiagnosis is important in HIV-positive patients who are thought to have coccidioidomycosis. Even though the majority of patients in several recent studies did have positive serology, it may be negative 17% to 23% of the time -- even in the presence of diffuse pulmonary disease or extrapulmonary spread.(5, 8) Nevertheless, a positive serologic test may be the first evidence of coccidioidal infection. In one large series the levels of positive complement fixation titers ranged from positive in undiluted serum to 1:4,096, with a geometric mean of 1:27.(5)
Coccidioidal skin tests are usually negative, with the percent of positive tests in infected patients ranging from 7% to 30%.(5, 6, 8) In a large study of HIV-positive patients, 84% of the cases of coccidioidomycosis were diagnosed on the basis of a positive culture or demonstration of the organism in histopathology specimens.(5)
Some patients with reactive serology who are free of signs and symptoms and who have no obvious site of infection may remain stable for a period of time without specific antifungal therapy.(10) Therapy for patients with active disease should begin with amphotericin B at a dose of 1 to 1.5 mg/kg/day, with adjustment made for azotemia.(13) In one group's experience, amphotericin B therapy stabilized or improved conditions in all six patients, and their chest radiographs showed mild to moderate improvement.(9) Successful treatment may require a total amphotericin dose of 1 to 2.5 grams.
When the patient's condition stabilizes, therapy may be changed to an oral triazole. With cessation of oral triazole therapy, patients may relapse and die, however, and for this reason we recommend that suppressive therapy with a triazole be continued for the remainder of the patient's life.(14)
Ketoconazole may be poorly absorbed by AIDS patients due to gastric achlorhydria, and AIDS patients have developed coccidioidomycosis while taking ketoconazole for thrush.(5) The newer triazoles are therefore preferable, but they are not without problems. Itraconazole, when administered at the standard dose of 200 mg b.i.d., has been associated with a number of drug-drug interactions, among them elevation of serum levels of digoxin, cyclosporine, terfenadine, and astemizole. The interaction of these last two drugs with itraconazole can result in dangerous cardiac arrhythmias.
Cisapride administration is also contraindicated in patients receiving itraconazole. H2 antagonists, omeprazole, sucralfate, and antacids all interfere with the drug's absorption, and coadministration of itraconazole and rifampin or anticonvulsants that induce cytochrome P-450 will result in significantly lowered serum levels of the triazole.(15)
Fluconazole, at a minimum dose of 400 mg q.d., has fewer drug-drug interactions, but the dose must be adjusted downward in the patients with renal insufficiency. There are no established differences in efficacy between these two agents for the treatment of nonmeningeal coccidioidomycosis.(16) Investigators who have substantial experience with these two newer triazoles have often used higher doses, particularly of fluconazole, in seriously ill patients. For example, doses of 800 mg or more of fluconazole per day have been used in patients with coccidioidal meningitis.(17) When patients with meningeal or extra-meningeal disease are treated with amphotericin B, intra-cerebrospinal fluid as well as intravenous administration is required.(16)
Patients with coccidioidomycosis should be followed clinically and radiographically while on therapy. Clinicians will also find it useful to monitor these patients' complement fixation antibody titers, since the titer diminishes with successful therapy.(1, 14) Patients who have diffuse lung disease, those with CD4 counts less than 50 cells/mm3, and those who are fungemic all have worse outcomes (Table 2). Those with diffuse lung disease often die within a month of diagnosis.(5) Patients with meningitis are also at grave risk, with over 90% mortality noted in one recent study.(8)
Coccidioidomycosis must be considered by all clinicians who treat HIV-infected patients who live in, or have traveled to, areas where the disease is endemic. The most common manifestation of coccidioidomycosis is pulmonary infection, but meningitis and disseminated disease are also common. Negative skin tests for C. immitis are the norm, and even negative serology does not exclude the diagnosis. Diagnosis often requires recovery of the organism in culture or demonstration of the organism in histopathologic specimens. The therapy of choice in critically ill patients, such as those with diffuse lung infiltrates, is amphotericin B, with the newer triazoles used in patients who are less gravely ill or as maintenance therapy after induction with amphotericin B. There is a desperate need for newer, more effective antifungal drugs to treat these patients.
1. Stevens DA. Coccidioidomycosis. N Engl J Med 1995; 332: 1077-82.
2. Greater Tucson Economic Council. Tucson Profile, 1992.
3. Deresinski SC and Stevens DA. Coccidioidomycosis in compromised hosts. Medicine 1974; 54: 377-95.
4. Centers for Disease Control. Revision of the CDC Surveillance Case Definition for Acquired Immunodeficiency Syndrome. MMWR 1987; 36: 1S-14S.
5. Fish DG, Ampel NM, Galgiani JN, et al. Coccidioidomycosis during human immunodeficiency virus infection: A review of 77 patients. Medicine 1990; 69: 384-91.
6. Ampel NM, Dols CL, Galgiani JN. Coccidioidomycosis during human immunodeficiency virus infection: Results of a prospective study in a coccidioidal endemic area. Am J Med 1993; 94: 235-40.
7. Kerrick SS, Lundergan LL, Galgiani JN. Coccidioidomycosis at a university health service. Am Rev Respir Dis 1985; 131: 100-02.
8. Singh VR, Smith DK, Lawerence J, et al. Coccidioidomycosis in HIV-infected patients: A review of 91 patients from a single institution. Manuscript submitted.
9. Bronnimann DA, Adam RD, Galgiani JN, et al. Coccidioidomycosis in the acquired immunodeficiency syndrome. Ann Intern Med 1987; 106: 372-9.
10. Galgiani JN and Ampel NM. Coccidioidomycosis in human immunodeficiency virus infected patients. J Infect Dis 1990; 162: 1165-9.
11. Sobonya RE, Barbee RA, Wiens J, et al. Detection of fungal and other pathogens in immunocompromised patients by bronchoalveolar lavage in an area endemic for coccidioidomycosis. Chest 1990; 97: 1349-55.
12. Prichard JG, Sorotzkin RA, James RE. Cutaneous manifestations of disseminated coccidioidomycosis in the acquired immunodeficiency syndrome. Cutis 1987; 39: 203-5.
13. Spitz BL, Thomas AR, Sarosi GA, et al. Coccidioidomycosis in HIV-infected patients. Am Rev Respir Dis 1991; 143 (suppl): A720.
14. Sarosi GA, Davies SF. Endemic mycosis complicating HIV infection. Western J Med. In press.
15. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine. Clin Infect Dis 1992; 14: 165-74.*
16. Denning DW, Ampel NM, Stevens DA. Aspergillosis and coccidioidomycosis in patients with HIV infection. HIV Advances Research and Ther 1994; 4: 22-9.
17. Galgiani JN, Catanzaro A, Cloud GA, et al. Fluconazole therapy of coccidioidal meningitis. Ann Intern Med 1993; 119: 28-35.
*For additional information on drug-drug interactions with axole administration see: van der Horst C. Fluconazole prophylaxsis for Cryptococcus neoformans. HIV Newsline 1995; 1: 20-3.
Jon E. Lutz, M.D., is a Fellow, Infectious Diseases and Geographic Medicine, Santa Clara Valley Medical Center, Stanford University School of Medicine.
David A. Stevens, M.D., is Chief, Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center and Professor of Medicine, Stanford University School of Medicine.
George A. Sarosi, M.D., is Chairman, Department of Medicine, Santa Clara Valley Medical Center and Professor of Medicine, Stanford University School of Medicine.