Human Coccidioidomycosis Research Articles

In Vitro Production of Tumor Necrosis Factor-α by Adherent Human Peripheral Blood Mononuclear Cells incubated with Killed Coccidioidal Arthroconidia and Spherules

We examined the in vitro production of tumor necrosis factor (TNF) by adherent human peripheral blood mononuclear cells (MNL) incubated with arthroconidia or spherules derived from the dimorphic fungus Coccidioides immitis. Using a bioassay measuring the percentage cytotoxicity of L929 cells, arthroconidia and spherules induced the production of measurable amounts of TNF by MNL. Both the arthroconidial and spherule preparations contained <0.01 ng/ml of endotoxin, below that needed to induce cytotoxicity in the bioassay. Based on ELISA, the vast majority of TNF induced by arthtoconidia or spherules was TNF-α, with minimal production of TNF-β. These are the first data to show the production of TNF in human coccidioidomycosis.

In vitro assessment of cellular immunity in human coccidioidomycosis: relationship between dermal hypersensitivity, lymphocyte transformation, and lymphokine production by peripheral blood mononuclear cells from healthy adults.

Dermal hypersensitivity in coccidioidomycosis was compared with three simultaneous measures of in vitro cellular immunity using 35 healthy donors living in an area endemic for coccidioidomycosis. Twenty donors had greater than 5 mm induration to usual-strength spherulin and were considered skin test-positive. Mononuclear cells from these individuals were more responsive by lymphocyte transformation (12,541 +/- 3746 vs. -112 +/- 260 cpm, P = .007) and produced significantly more interleukin-2 (3481 +/- 1067 vs. -5 +/- 69 cpm, P less than .001) and interferon-gamma (1831 +/- 481 vs. 75 +/- 58 pg/ml, P less than .001) than cells from skin test-negative donors in response to a coccidioidal antigen. However, the correlation between the skin test size and the magnitude of the in vitro response among skin test-positive donors was poor (R2 = 0.08, P = .24). These results indicate that healthy individuals with dermal hypersensitivity to Coccidioides immitis can be distinguished from those without hypersensitivity by their cellular in vitro response to a coccidioidal antigen.

Cyclophosphamide effect on coccidioidomycosis in the rat.

Cocidioidomycosis is a systemic mycosis, endemic in arid areas of the American continent. The rat was employed as an experimental host, since it had been shown to reproduce human lesions and present a chronic course of disease with granulomas mainly restricted to lungs. Given the influence of immunosuppressive therapy on the clinical course of human coccidioidomycosis, we studied the effect of cyclophosphamide (CY) in the experimental rat model. Accordingly, animals were inoculated with 400 Coccidioides immitis arthroconidia of the Acosta strain, by intracardiacal route. As single CY doses failed to alter the course of disease, three schedules were used: A) 4 daily doses of 20 mg/kg each, prior to C. immitis inoculation; B) 4 similar daily doses after infection; and C); 6 doses of 20 mg/kg each, given from day +1 to +4 then on days +8 and +9, post infection (pi), taking day 0 as the time of fungal inoculation. The first two schedules inhibited antibody formation up to day 28 pi, without modifying cellular response to coccidioidin as measured by foodpad swelling. Initially, there was greater fungal spread than in controls receiving C. immitis alone, which proved self-limiting in the latter. In contrast, schedule C led to 55% mortality with both humoral and cellular response abrogation, accompanied by extensive C. immitis dissemination. Histology disclosed significant alterations, such as the persistence of primary infection sporangia, corresponding to the acute stage of coccidioidomycosis in the absence of granuloma development. Therefore, the observed depression in cellular immunity seems responsible for the lack of inflammatory reaction capable of restricting sporangia proliferation in tissues which, in turn, enhances pathogen spread and mortality rate.

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)

Agar-gel precipitin-inhibition test for coccidioidomycosis. II. Serological test antigen studies in agar-gel.

In this study of saprophytic and parasitic growth-phase extracts of Coccidioides immitis, an antigen from the spherule culture supernatant fluid detected a specific antibody in heretofore serologically negative suspect coccidioidomycosis human sera when diffused in agar-gel. This antigen-antibody reaction occurred also in some of the serologically positive human coccidioidomycosis sera. This study indicates that this antigen-antibody reaction should be utilized as a possible routine serological test for complete serodiagnosis.

ANTIBODIES IN HUMAN COCCIDIOIDOMYCOSIS: IMMUNOELECTROPHORETIC PROPERTIES.

SummaryAn immunoelectrophoretic study was undertaken on two types of antibody detectable in human coccidioidomycosis, early precipitins and later complement-fixing antibodies. By using concentrated precipitin sera and dilute coccidioidal antigen, arcs of precipitation were produced which appeared to correspond to the mobility of 19S β2 macro-globulin. Complement-fixing sera and cerebro-spinal fluids reacted with coccidioidal antigen to give precipitation arcs with the mobility of 7S γ2 globulin.

The comparison of four strains of Coccidioides immitis with diverse histories.

By the criterion of lethality in mice, a strain ofCoccidioides immitis recently isolated from a most devastating form of human coccidioidomycosis was of no greater virulence than another isolated from a much less severe case or even one cultured from soil fifteen years ago and which presumably had caused seven self-limited, benign cases of primary coccidioidomycosis. There was no enhancement of virulence to mice by twelve passages of a relatively avirulent strain which had been recovered twenty-one years ago from a fatal human case.

Surgical lesions of coccidioidomycosis.

Human coccidioidomycosis is a disease resulting from infection by the fungus Coccidioides immitis. This disease is endemic in the southwestern United States, northern Mexico, Argentina, and Uruguay. There is an increasing number of cases reported from the various areas in our country outside of the southwest. Most of these have had a history of visiting the southwestern section of the United States previous to the onset of their disease. Since travel to the southwest is common and on the increase and because the disease is usually considered a rarity by those living away from the endemic areas, it was thought that it would be of interest to present some of the features of the disease as well as review the related surgical problems. It should be emphasized that coccidioidal infection may appear in any individual who has been exposed to the fungus while in the southwestern portion of the United