T-lymphocyte predominance in lesions of canine coccidioidomycosis.

Coccidioidomycosis is a systemic fungal infection endemic to the southwestern United States. Although cell-mediated immunity is considered critical in control of the infection, little is known of the cellular population in naturally occurring lesions. To characterize the lymphocytic infiltration, archived formalin-fixed, paraffin-embedded tissues (subcutis, pericardium/heart, lung, bone, and synovium) from 18 dogs with coccidioidomycosis were studied with immunohistochemistry for CD3 and CD79a. In nearly all lesions, T lymphocytes were more numerous than B lymphocytes and were distributed throughout the lesion with concentration in the periphery of granulomas, whereas B lymphocytes were mostly confined to the periphery of granulomas. The predominance of T lymphocytes in lesions of canine coccidioidomycosis was independent of the tissue evaluated, the number of intralesional organisms, and the nature or severity of the inflammatory response.

Evaluation of hepatic injury arising during fluconazole therapy.

Previous reports have described hepatotoxicity associated with ketoconazole therapy. There is also concern that therapy with fluconazole might cause the same side effect as ketoconazole. We describe two patients who developed unexplained liver test abnormalities after beginning fluconazole therapy. To determine whether fluconazole might have been responsible, liver biopsies were performed. Specimens from both patients demonstrated an absence of hepatocyte necrosis, which, if present, would have necessitated discontinuation of fluconazole therapy. A critical review of other case reports of fluconazole-associated hepatitis also failed to produce a consistent picture. Our experience indicates that a liver biopsy may be useful in selected patients to exclude clinically relevant hepatotoxicity due to fluconazole therapy and to allow its continued use.

Coccidioidomycosis in renal replacement therapy.

The potential risk of coccidioidomycosis has led to concern about the advisability of maintaining renal transplantation programs in endemic areas. We reviewed the charts of 721 patients undergoing dialysis and 260 renal transplant recipients in Arizona to determine the incidence, risk factors, and clinical course of coccidioidomycosis in these immunosuppressed populations. Symptomatic infection occurred in six (0.83%) patients undergoing dialysis and 18 (6.9%) transplant recipients. Male sex and blood type B predisposed to dissemination. Urine cultures for fungus were important diagnosis aids. Four of six patients with infection limited to the thorax and five of 18 patients with dissemination remained alive after seven months to 7 1/2 years. Although the rate of dissemination (75%) and mortality (63%) from coccidioidomycosis were high, the incidence of infection was low and does not preclude renal transplantation in Arizona. Those who have received transplants elsewhere should be advised not to move or to visit areas endemic for coccidioidomycosis.

Treatment of fungal meningitis with miconazole.

Twelve patients with fungal meningitis (ten cases were due to Coccidioides immitis, two were from Cryptococcus neoformans) were treated with brief courses of intravenous (IV) miconazole. Eleven patients, including patients with severe, chronic disease, had been treated unsuccessfully with amphotericin B. Four patients also received miconazole injected directly into the CSF. The drug was well tolerated by any route, with mild reversible side effects. After IV administration the miconazole concentration in the CSF rarely exceeded the minimal inhibitory concentration (MIC) of the infecting organism. Intra-CSF administration of 20 mg generally produced levels above the MIC for 24 hours. Five of ten patients with coccidiodial meningitis responded clinically. Of these five, four received only IV miconazole; three relapsed after therapy was stopped. Miconazole appears promising as a treatment of fungal meningitis, but trials of longer duration might prevent relapse.

Amphotericin B-induced myelopathy.

Two patients with coccidioidal meningitis experienced transient neurologic deficits shortly after receiving intrathecal injections of amphotericin B. Continuation of treatment eventually led to a severe flaccid paraparesis with a thoracic sensory level in one patient, and a partial Brown-Séquard's syndrome in the other. Myelography was normal in both, with no evidence of arachnoiditis. Autopsy findings in the first patient showed a focal area of necrosis in the left half of the spinal cord consistent with the patient's clinical findings during life. The distribution of the lesion corresponded to the area supplied by a central sulcal artery. Amphotericin B may exert a direct toxic effect on the spinal cord or its vascular supply when given intrathecally.

High-dose ketoconazole therapy and adrenal and testicular function in humans.

Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

Phaeohyphomycosis caused by the fungal genera Bipolaris and Exserohilum. A report of 9 cases and review of the literature.

We have reported 7 new cases of Bipolaris infection and 2 of Exserohilum infection, which demonstrate the capability of these 2 genera to cause invasive as well as "allergic" disease. As noted previously, it is likely that all of the cases of "Helminthosporium" and Drechslera infections reported in the literature were caused by Bipolaris or Exserohilum. Infections due to these 2 genera are probably more common than previously recognized. They should be included in the differential diagnosis of central nervous system and disseminated fungal disease, sinusitis, keratitis, peritonitis associated with continuous ambulatory peritoneal dialysis, and allergic bronchopulmonary disease. These various entities have distinct histopathologic characteristics. With disseminated disease in the immunocompromised patient, the most frequent findings are acute inflammation with prominent vascular invasion, thrombosis, and infarction. In contrast, granulomatous inflammation and leukocytoclastic vasculitis are seen in meningoencephalitis caused by these fungi. The histologic features of allergic bronchopulmonary disease and sinusitis are similar. A chronic inflammatory infiltrate of lymphocytes, plasma cells and eosinophils within edematous granulation tissue is found in addition to squamous metaplasia and thickening of the basement membrane. Infections caused by Bipolaris/Exserohilum and Aspergillus show many clinical and pathologic similarities despite the lack of taxonomic relationship between these fungi. Both cause disseminated disease in immunocompromised patients that is characterized by tissue necrosis and vascular invasion. Both cause central nervous system disease, osteomyelitis, and sinusitis and are associated with allergic bronchopulmonary disease. Sinusitis, the most common form of disease caused by Bipolaris and Exserohilum, occurs in otherwise healthy patients with nasal polyposis and allergic rhinitis. Although pathologic evidence of bone invasion may not be found, there frequently is radiographic evidence of invasive disease. Most patients who are treated initially with surgical debridement and amphotericin B have apparently been cured. However, longer follow-up will be necessary in these patients. Amphotericin B appears to be the treatment of choice for invasive infections caused by Bipolaris/Exserohilum species. Ketoconazole and other imidazole derivatives may also be effective in certain of the disease entities caused by these black moulds; however, their role has yet to be defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.

Through a retrospective review, we identified 77 previously unreported cases of coccidioidomycosis during HIV infection. Patients were classified into 1 of 6 categories based on their primary clinical presentation: 20 had focal pulmonary disease (Group 1), 31 had diffuse pulmonary disease (Group 2), 4 had cutaneous coccidioidomycosis (Group 3), 9 had meningitis (Group 4), 7 had extrathoracic lymph node or liver involvement (Group 5), and 6 has positive coccidioidal serology without a clinical focus of infection (Group 6). Coccidioidal serologies were positive on initial testing in 83% of the patients in whom such serologic testing was performed. Sera from 39% of patients were positive for TP antibodies while 74% had CF antibodies. Eleven of 12 seronegative patients had pulmonary disease (Group 1 or 2). Serologic results of other patients sent to a single reference laboratory were similar, with 26% positive for immunodiffusion TP antibodies and 79% positive for immunodiffusion CF antibodies. For the 77 patients in this study, the CD4-lymphocyte count was below 0.250 X 10(9) cells/L in 46 of the 55 patients who had this test performed, and a low CD4 count was significantly associated with mortality (p less than 0.01). At the time of follow-up, 32 of the 77 patients (42%) had died. There were significantly more deaths in those with diffuse pulmonary disease (Group 2) than in other groups (p less than 0.001). Amphotericin B, ketoconazole, fluconazole, and itraconazole were all used as antifungal therapies. Outcome could not be related to the therapy used. Of note, 3 patients developed coccidioidomycosis while receiving ketoconazole for other conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Coccidioidomycosis during human immunodeficiency virus infection: results of a prospective study in a coccidioidal endemic area.

PURPOSE: To determine the incidence of active coccidioidomycosis among subjects infected with the human immunodeficiency virus (HIV) living in an area endemic for coccidioidomycosis and to identify factors associated with the development of active coccidioidomycosis in these patients. PATIENTS AND METHODS: This was a prospective cohort analysis of HIV-infected subjects living in an area endemic for coccidioidomycosis in Arizona. On entry and at approximately 4-month intervals, subjects were interviewed and examined, and had spherulin skin testing and CD4 lymphocyte counts performed along with other tests. During each interval, it was determined whether the subject had developed active coccidioidomycosis according to established criteria. RESULTS: One hundred seventy subjects entered the study. Median follow-up was 11.3 months (range: 0 to 44 months). Thirteen subjects developed active coccidioidomycosis, with an estimated cumulative incidence of 24.6% by 41 months (95% confidence limits 8.2% and 41.1%). Risk factors associated with the development of active coccidioidomycosis in the cohort were a CD4 lymphocyte count of less than 0.250 x 10(9)/L and a diagnosis of acquired immunodeficiency syndrome. Factors associated with prior coccidioidal infection, including a positive spherulin skin test, length of residence in the endemic area for more than 25 months, and a prior history of coccidioidomycosis, were not associated with the development of active infection. CONCLUSION: Active coccidioidomycosis among individuals infected with HIV is common in the coccidioidal endemic area. Immunodeficiency appears to be the major risk factor for the development of disease. Evidence of prior coccidioidomycosis, including a positive spherulin skin test, does not appear to predict the development of active infection.

Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.

PURPOSE: The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis. PATIENTS AND METHODS: Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more. RESULTS: Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild. CONCLUSION: Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

Visceral fungal infections due to Petriellidium boydii (allescheria boydii). In vitro drug sensitivity studies.

Four patients with visceral infections due to the fungus Petriellidium boydii, who were recently hospitalized in our institutions, are described. Three of the patients were compromised hosts; in the fourth patient, infection occurred after trauma. All had received prior steroid and antibiotic therapy. Studies of patients with mycetoma or secondary infection of a pulmonary cavity due to this organism and of patients with visceral infections are reviewed. Because of histologic similarities to Aspergillus species, infections due to P. boydii may have been misdiagnosed in the past if the infecting fungus was not isolated in culture. The fungus has been shown to be resistant in vitro to currently available antifungal agents. Resistance to amphotericin and 5-fluorocytosine is demonstrated in our studies. There are few reports of successful chemotherapy of any manifestation of this infection, and no such reports of visceral disease. We demonstrate in vitro sensitivity of isolates in our cases and in others to micronazole, a new antimicrobial agent; this drug may be indicated for treatment of disease due to P. boydii.

Ketoconazole therapy of progressive coccidioidomycosis. Comparison of 400- and 800-mg doses and observations at higher doses.

One hundred and twelve patients with progressive pulmonary, skeletal, or soft tissue infections caused by Coccidioides immitis were randomly assigned to treatment with 400 or 800 mg per day dosages of ketoconazole. During therapy, if response was unsatisfactory, the protocol provided for treatment with higher doses. With 400 mg, ketoconazole resulted in 23.2 percent successes, which was similar to 32.1 percent successes with 800-mg treatments (p = 0.29). An additional six of 23 patients in whom initial therapy failed and who later received 1,200 or 1,600 mg per day of ketoconazole also showed improvement. However, among patients completing successful courses of therapy, relapses were more frequent in those requiring higher than 400-mg dosages for their success. From these studies, it is concluded that ketoconazole in doses above those currently recommended offer little or no benefit for most patients with non-meningeal forms of coccidioidomycosis.

Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. NIAID Mycoses Study Group.

PURPOSE: To determine the efficacy and safety of fluconazole as treatment for coccidioidomycosis. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm study. Of 78 patients enrolled, 22 had soft-tissue, 42 had chronic pulmonary, and 14 had skeletal coccidioidomycosis. Forty-nine had at least one concomitant disease, 7 of whom had HIV infection. Patients were given oral fluconazole 200 mg/d. Nonresponders were increased to 400 mg/d. Treatment courses were long: a mean of 323 +/- 230 days at 200 mg and 433 +/- 178 days at 400 mg. Predefined assessment of disease-related abnormalities was performed at the time of enrollment and repeated at least every 4 months. A satisfactory response was defined as any reduction of baseline abnormality by month 4 and at least 51% reduction by month 8. RESULTS: Among 75 evaluable patients, a satisfactory response was observed in 12 (86%) of the 14 patients with skeletal, 22 (55%) of the 40 patients with chronic pulmonary, and 16 (76%) of the 21 patients with soft-tissue disease. Five patients (7%) required modification of treatment due to toxicity. Forty-one patients who responded were followed off drug. Fifteen (37%) of them experienced reactivation of infection. CONCLUSION: Fluconazole 200 or 400 mg/d is well tolerated and a moderately effective treatment for chronic pulmonary or nonmeningeal disseminated coccidioidomycosis. The relapse rate following therapy is high. Treatment trials with higher doses appear warranted. The relative efficacy of fluconazole versus other azoles or amphotericin B remains unknown.

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Ketoconazole treatment of nonprimary coccidioidomycosis. Evaluation of 60 patients during three years of study.

Sixty patients with coccidioidomycosis were treated with ketoconazole rather than with another antifungal agent, and their responses were evaluated in relation to the predominant site of involvement. For the three main groups, improvement occurred in 12 of 19 patients with chronic pulmonary infections, in 20 of 23 with soft tissue lesions and in six of 11 with skeletal involvement. Infections in soft tissues improved most rapidly (average of 34 days) and often with 200 mg per day, whereas pulmonary and skeletal infections improved more slowly (63 and 165 days, respectively), usually requiring 400 mg per day. Of 12 patients with response in whom therapy has been discontinued, seven have had relapses. Recurrence was apparent usually within the first month and after six months or less of treatment. Patients in remission had received ketoconazole for six to 17 months. Untoward drug effects included abdominal complaints (23 percent) and gynecomastia (8 percent). Therapy was discontinued in only three patients for side effects. Our findings support the use of ketoconazole in the treatment of certain forms of chronic coccidioidal infections.

Ketoconazole in the treatment of coccidioidomycosis.

Ketoconazole is the newest antifungal agent evaluated for efficacy in the treatment of coccidioidomycosis and the only one used by oral administration. The inhibition of Coccidioides immitis observed by in vitro susceptibility testing has been corroborated in murine studies in which ketoconazole therapy has led to survival in otherwise lethally infected animals. In man, absorption of ketoconazole from the gastrointestinal tract is generally favourable. However, there is considerable variation between patients in achieved serum concentrations, the causes of which may be multiple and as yet are incompletely understood. All completed studies of ketoconazole treatment of human coccidioidomycosis have been non-comparative in design. Entry criteria have selected patients that would have been treated otherwise with another antifungal agent. Dosages were usually 200 or 400 mg/day and treatment was continued for many months. Soft tissue infections improved more frequently and after less ketoconazole than did pulmonary or skeletal infections. No effect on coccidioidal meningitis has been found at these dosages. In skeletal infections, symptoms, physical findings and coccidioidal antibody levels commonly improved, but radiographs of skeletal lesions frequently did not change. Repeat culture of treated lesions, even those that had improved, often continued to grow C. immitis. Relapses after stopping ketoconazole have occurred in a significant number of patients. Untoward effects were usually manageable without discontinuing therapy. Ketoconazole appears to be of use in the treatment of progressive forms of coccidioidomycosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative pathology of coccidioidomycosis in acquired immunodeficiency syndrome.

This study examines the laboratory aspects of diagnosis of coccidioidomycosis in 11 patients with acquired immunodeficiency syndrome (AIDS) and the qualitative and quantitative differences between host responses of AIDS and non-AIDS patients who died with disseminated coccidioidomycosis. Material obtained at bronchoscopy confirmed the diagnosis of pulmonary coccidioidomycosis in 67% (6/9) of the patients. Patients with AIDS had a generally poor granulomatous response and statistically significantly increased numbers of spherules in lung tissue compared with non-AIDS patients. Neither antifungal therapy nor duration of clinical disease influenced the number of organisms present. The findings suggest a parallel between AIDS-associated coccidioidomycosis and other granulomatous diseases such as leprosy and schistosomiasis, in which the type of granuloma formation and organism numbers are influenced by the T-lymphocyte milieu.

Fungal endocarditis: need for guidelines in evaluating therapy. Experience with two patients previously reported.

Successful treatment of fungal endocarditis is being described with increasing frequency. Two patients, previously reported as free of disease by two different groups of investigators, subsequently died in our institutions with evidence of continued disease. Both patients had been receiving antifungal chemotherapy at the time their case histories were reported. The lack of clinical signs and symptoms in fungal endocarditis, the suppression of manifestations of infection by chemotherapy, and the uncertain reliability of laboratory aids led us to suggest guidelines in reporting results of therapuetic regimens. These include avoidance of terms implying cure in patients who are concurrently maintained on chemotherapy, indication of attempts to evaluate fungemia, and minimum follow-up of 1-2 years' duration. The potential utility of serologic studies is illustrated by the course of one of these patients.

Coccidioidomycosis during pregnancy. An analysis of ten cases among 47,120 pregnancies.

Previous studies have suggested that coccidioidomycosis during pregnancy is a devastating illness associated with high maternal mortality. However, this concept recently has been challenged. We examined the incidence of coccidioidomycosis during pregnancy in Tucson, Arizona, an area endemic for this infection. After reviewing the records of three separate health care facilities, we found ten cases of coccidioidomycosis among 47,120 pregnancies. Nine of the ten women had no underlying disease. Seven were diagnosed with coccidioidomycosis during either the first or second trimester. Illness resolved in all seven. Three other patients were diagnosed during the first ten days postpartum. While infection was self-limited in one woman, two others developed severe disseminated coccidioidomycosis associated with meningitis. Despite this, there were no maternal deaths. Of eight deliveries, all were uncomplicated and produced healthy infants. In summary, diagnosing coccidioidomycosis during pregnancy is rare. Although we observed no maternal death, our experience suggests that women who develop coccidioidomycosis late in pregnancy are at risk for developing severe disseminated infection.

Cavitary coccidioidomycosis with fungus ball formation. Diagnosis by fiberoptic bronchoscopy with coexistence of hyphae and spherules.

Pulmonary cavitary coccidioidomycosis with fungus ball formation was observed in two individuals with hemoptysis. The first patient had no overt compromise; the second was an insulin-dependent diabetic. In both, fiberoptic bronchoscopy was performed and cultures yielded Coccidioides immitis. The coexistence of spherules and hyphae of C immitis was seen histologically on bronchoscopic biopsy specimen of one cavitary lesion. Specific antifungal therapy and surgical excision were withheld and each patient has done well. This report provides for the first time nonsurgical confirmation that C immitis can produce an intracavitary fungus ball.