Coccidioidomycosis among persons with human immunodeficiency virus infection in the era of highly active antiretroviral therapy (HAART).

Coccidioidomycosis remains an important opportunistic infection among individuals infected with human immunodeficiency virus (HIV) who live in the coccidioidal endemic area. There are several manifestations of coccidioidomycosis during HIV infection, but pulmonary disease, either diffuse or focal, is the most common. The most important factor associated with the risk for developing clinically active coccidioidomycosis is a CD4 peripheral blood lymphocyte count of less than 250/microL. The advent of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has changed our approach to the management of opportunistic infections, including coccidioidomycosis. Few data are available regarding the incidence of coccidioidomycosis since the initiation of HAART, but these suggest a decline. It is currently recommended that antifungal therapy for coccidioidomycosis during HIV infection be continued indefinitely, even among those with asymptomatic disease. Future studies should indicate whether this is necessary if immune function has been reconstituted through appropriate therapy for the HIV infection.

Dendritic cells pulsed with Coccidioides immitis lysate induce antigen-specific naive T cell activation.

Coccidioidomycosis, an infection endemic to the southwestern United States, is caused by the fungus Coccidioides immitis. Coccidioidal infection is overcome by the development of cell-mediated immunity. This study evaluated the role of dendritic cells (DCs) in the initiation of coccidioidal immunity in nonimmune individuals. It was demonstrated that DCs pulsed with the coccidioidal antigen preparation, toluene spherule lysate (TSL), induce DC maturation, autologous lymphocyte proliferation, and antigen-specific lymphocyte responses from nonimmune donors. Furthermore, TSL-primed lymphocytes secreted interferon-gamma after restimulation with TSL or antigen 2/proline-rich antigen, a subcomponent of TSL, but they did not do so when restimulated with ovalbumin or unpulsed DCs. The results demonstrate that DCs generated from individuals not exposed to C. immitis can specifically prime lymphocytes for coccidioidal antigens and that the response generated by the lymphocytes is characteristic of a cellular immune response.

Barriers to use of electronic adherence monitoring in an HIV clinic.

OBJECTIVE: To evaluate barriers to Medication Event Monitoring System (MEMS) measurement of adherence to combination antiretroviral therapy in an HIV clinic. DESIGN: Descriptive, cross-sectional study measured MEMS adherence to one antiretroviral for one month. SETTING: HIV clinic in a Veterans Affairs Medical Center. PARTICIPANTS: Sixty-four men on a stable antiretroviral treatment regimen. MAIN OUTCOME MEASURES: Decanting (removing >1 dose at a time) before and during monitoring over a 30-day observation period was used to determine the qualitative impact of MEMS on adherence. The adherence index was the proportion of prescribed doses not missed. RESULTS: Subjects were primarily white (73%) with mean CD4+ count 408 cells/mm3, log viral load 1.81 copies/mL, and duration of antiretroviral therapy 5.5 years. Twenty-seven (42%) had some decanting routine established prior to monitoring; 12(44%) of these patients used daily decanters and 15(56%) used weekly pillboxes. Of those who decanted prior to the study, 10(37%) did not stop decanting during monitoring, 14 (52%) stopped decanting only the capped medication, and three (11%) stopped decanting all antiretrovirals. Other adherence strategies did not accommodate MEMS. Eight (13%) subjects said MEMS made adherence more difficult, six (9%) said MEMS was a reminder to adhere, and two (3%) mentioned both. Two subjects attributed skipped doses or time changes to the MEMS cap. The majority who refused to participate used pillboxes. CONCLUSIONS: Personal adherence strategies incompatible with MEMS are common in persons on complex treatment regimens. Although MEMS data on decanters underestimate adherence, excluding decanters erodes applicability of descriptive measures. MEMS use may have affected adherence behavior. Measures in conjunction with MEMS should include self-reported adherence and decanting assessment.

Assessment of the human cellular immune response to T27K, a coccidioidal antigen preparation, by flow cytometry of whole blood.

Whole blood flow cytometry was performed among donors with various clinical forms of coccidioidomycosis using T27K, a coccidioidal antigen preparation protective in mice but not previously studied in humans. The median percent of CD3+ lymphocytes (CD3+) producing intracellular interferon-gamma (IFN-gamma) among healthy immune donors was 0.43%, significantly above that for non-immune donors (0.01%) and greater than that for subjects with other forms of coccidioidomycosis, including chronic pulmonary (0.11%), disseminated (0.09%) and concomitant human immunodeficiency virus (HIV) infection (0.07%) (P < or =0.002 for all). No increase in intracellular interleukin (IL)-10 production or apoptosis was noted in samples incubated with T27K. Among 14 HIV-infected patients with concomitant coccidioidomycosis, seven of eight patients whose peripheral blood CD4 concentration was > 200 cells microl(-1) had > 0.06% of CD3+ produce intracellular IFN-gamma, compared to none of six whose peripheral blood CD4+ lymphocyte concentration was < or =200 cells microl(-1) (P = 0.005). These data indicate that there is a specific human cellular immune response to T27K as a coccidioidal antigen and that this response can be categorized based on the clinical status of the coccidioidally infected patient.

Flow cytometric assessment of human peripheral blood mononuclear cells in response to a coccidioidal antigen.

The in vitro responses of peripheral blood mononuclear cells (PBMC) from healthy immune and non-immune donors were assessed by flow cytometry after incubation with the coccidioidal antigen toluene spherule lysate (TSL). After 120 h of incubation with 100 microg ml(-1) of TSL, expression of the activation markers CD69, CD25 and human leukocyte antigen-DR were all significantly increased in CD3+ lymphocytes from immune donors compared to non-immune donors (P < 0.03 for all). No differences in the surface expression of the costimulatory molecules CD28, CD152 or CD154 was seen between immune and non-immune donors after either 24 or 120 h of TSL incubation, nor were differences detected in the expression of the B7 ligands CD80 or CD86 on CD14+ monocytes. The percent of CD3+ lymphocytes expressing intracellular interferon-gamma (IFN-gamma) was significantly increased in immune compared to non-immune donors and was further increased by the addition of 10 ng ml(-1) of human recombinant interleukin (IL)-12 (P < 0.05 for both). Both CD4+ and CD8+ lymphocytes contributed to IFN-gamma production. These data indicate that coccidioidal antigen stimulation of lymphocytes from healthy immune donors leads to specific expression of activation molecules and production of intracellular IFN-gamma. Addition of IL-12 leads to a significant recruitment of cells producing IFN-gamma among immune donors.

Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America.

Management of patients diagnosed with coccidioidomycosis involves defining the extent of infection and assessing host factors that predispose to disease severity. Patients with relatively localized acute pulmonary infections and no risk factors for complications often require only periodic reassessment to demonstrate resolution of their self-limited process. On the other hand, patients with extensive spread of infection or at high risk of complications because of immunosuppression or other preexisting factors require a variety of treatment strategies that may include antifungal therapy, surgical debridement, or both. Amphotericin B is often selected for treatment of patients with respiratory failure due to Coccidioides immitis or rapidly progressive coccidioidal infections. With other more chronic manifestations of coccidioidomycosis, treatment with fluconazole, itraconazole, or ketoconazole is common. Duration of therapy often ranges from many months to years, and, for some patients, chronic suppressive therapy is needed to prevent relapses.

Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention.

From 1 January 1995 through 31 June 1997, 153 cases of coccidioidomycosis in human immunodeficiency virus (HIV)-infected persons were identified in Arizona (incidence, 41/1000 persons living with AIDS). A case-control study was conducted to evaluate risk factors for coccidioidomycosis in HIV-infected persons. A case was defined as laboratory-confirmed, incident coccidioidomycosis in a person infected with HIV for > or =3 months, and each case patient had 3 control patients matched by county, age group, sex, HIV/AIDS status, and CD4 lymphocyte count. Multivariable analysis identified black race and a history of oropharyngeal or esophageal candidiasis to be associated with increased risk of coccidioidomycosis; protease inhibitor therapy was associated with a reduced risk. In persons with previous history of oropharyngeal or esophageal candidiasis, having received an azole drug was associated with a reduced risk (odds ratio, 0.4; 95% confidence interval, 0.2-0.9; P=.04). Physicians may need to consider azole chemoprophylaxis for HIV-infected persons who live in areas of endemicity, have CD4 cell counts <200/microL, are black, or have a history of thrush.

Risk factors for acute symptomatic coccidioidomycosis among elderly persons in Arizona, 1996-1997.

Because of the increase in incidence of coccidioidomycosis among the elderly in Arizona between 1990 and 1996, a case-control study was conducted to look at risk factors for disease among these persons. Cases (n=89) were persons aged > or =60 years with laboratory-confirmed coccidioidomycosis; 2 control groups were selected, the first by use of random-digit dialing (geographic controls, n=91) and the second by use of lists of persons with negative serologic coccidioidomycosis tests (laboratory-negative controls, n=58). Elderly persons with coccidioidomycosis had spent significantly less time in Arizona than did persons in either control group and were more likely than geographic controls to have congestive heart failure or cancer, to have smoked, or to have taken corticosteroids. Elderly persons who recently have moved to Arizona or who have chronic illnesses and their physicians need to be aware of their higher risk for coccidioidomycosis in order to improve their chances of early diagnosis and treatment. These persons may benefit from vaccination, once an effective vaccine for coccidioidomycosis is developed.

A major cell surface antigen of Coccidioides immitis which elicits both humoral and cellular immune responses.

Multinucleate parasitic cells (spherules) of Coccidioides immitis isolates produce a membranous outer wall component (SOW) in vitro which has been reported to be reactive with antibody from patients with coccidioidal infection, elicits a potent proliferative response of murine immune T cells, and has immunoprotective capacity in a murine model of coccidioidomycosis. To identify the antigenic components of SOW, the crude wall material was first subjected to Triton X-114 extraction, and a water-soluble fraction derived from this treatment was examined for protein composition and reactivity in humoral and cellular immunoassays. Protein electrophoresis revealed that the aqueous fraction of three different isolates of C. immitis each contained one or two major glycoproteins (SOWgps), distinguished by their molecular sizes, which ranged from 58 to 82 kDa. The SOWgps, however, showed identical N-terminal amino acid sequences, and each was recognized by sera from patients with C. immitis infection. Antibody raised against the purified 58-kDa glycoprotein (SOWgp58) of the Silveira isolate was used for Western blot and immunolocalization analyses. Expression of SOWgp was shown to be parasitic phase specific, and the antigen was localized to the membranous SOW. The water-soluble fraction of SOW and the purified SOWgp58 were tested for the ability to stimulate proliferation of human peripheral monocytic cells (PBMC). The latter were obtained from healthy volunteers with positive skin test reaction to spherulin, a parasitic-phase antigen of C. immitis, and from volunteers who showed no skin test reaction to the same antigen. The SOW preparations stimulated proliferation of PBMC from skin test-positive but not skin test-negative donors, and the activated cells secreted gamma interferon, which is indicative of a T helper 1 pathway of immune response. Results of this study suggest that SOWgp is a major parasitic cell surface-expressed antigen that elicits both humoral and cellular immune responses in patients with coccidioidal infection.

Airway coccidioidomycosis--report of cases and review.

Infection due to Coccidioides immitis usually begins in the lungs. Despite the initial pulmonary portal of entry, endotracheal and endobronchial coccidioidomycosis has rarely been described. Since the introduction of fiberoptic bronchoscopy and the AIDS epidemic, more C. immitis lesions of the large airways have been noted. We present data on 38 cases of coccidioidomycosis of the airways, including 6 cases detailed from our own experience and 32 from the literature. Direct infection of the airways (28 cases) is a more common mechanism of airways disease than is erosion into the airways from a lymph node (5 cases). Bronchoscopic findings vary and may show mucosal involvement or intrinsic obstruction. Endotracheal and endobronchial disease is not a self-limited disease and requires antifungal therapy. Disseminated disease in these patients is common. Coccidioidomycosis must be considered in the differential diagnosis of airway pathology.

Delayed-type hypersensitivity, in vitro T-cell responsiveness and risk of active coccidioidomycosis among HIV-infected patients living in the coccidioidal endemic area.

The prognostic importance of specific and general tests of immune function were examined among a cohort of 170 subjects infected with human immunodeficiency virus type-1 (HIV), living in an area endemic for the fungal infection coccidioidomycosis. Using the proportional hazards model and multivariate analysis, lack of expression of coccidioidal delayed-type hypersensitivity (DTH) was found to be dependent on anergy in response to the non-coccidioidal antigens mumps, Trichophyton and Candida (relative hazard 4.2, 95% CI 1.8-9.8, P=0.001). Among subjects with CD4 lymphocyte counts >/=250 microl-1 on entry into the study, the in vitro lymphocyte transformation (LT) response to the coccidioidal antigen toluene spherule lysate was 4967+/-1652 (mean counts per minute (c.p.m.)+/-SEM) in subjects with coccidioidal DTH compared with 136+/-222 in those with negative DTH (P<0.001). However, amongst those whose CD4 count was <250 microl-1, LT responses were low and there was no significant difference based on coccidioidal DTH (P=0.965). Using the proportional hazards model and multivariate analysis, only a CD4 count <250 microl-1 was prognostically associated with the development of either active coccidioidomycosis or AIDS. These data indicate that immunodeficiency, particularly a CD4 lymphocyte count <250 microl-1, is the most important factor in the lack of expression of specific immunity to coccidioidomycosis and in the development of active coccidioidomycosis among HIV-infected individuals living in the coccidioidal endemic area.

Coccidioidomycosis in Arizona: increase in incidence from 1990 to 1995.

The number of cases of coccidioidomycosis (incidence) reported to the Arizona Department of Health Services increased from 255 (7.0 per 100,000 population) in 1990 to 623 (14.9 per 100,000 population) in 1995 (P < .001). Four counties in the south central region of the state, which contained 80% of the state's population, had the largest increase and accounted for 95% of all cases in 1995. Cases in persons aged 65 years or older and men were reported more frequently (for both, P < .001). During 1995, 890 patients were discharged from Arizona hospitals with a diagnosis of coccidioidomycosis. Rates of hospitalization were greater among persons aged 55 years or older, men, and African-American (for all three, P < .01). Of the hospitalized patients, 48 died, and 12 (25%) of these patients had a concurrent diagnosis of human immunodeficiency virus infection. These data demonstrate that coccidioidomycosis is a growing health problem in Arizona.

Identification and voluntary reduction of vancomycin use for perioperative antibiotic prophylaxis during coronary artery bypass graft surgery.

Vancomycin prophylaxis for coronary artery bypass graft surgery without prosthetic valve implantation voluntarily decreased from 94% to 18% in one medical center. Median hospital stay (10 vs 9 days, P = .30) and number of postoperative infections (17.0% vs 14.3%, P = .60) did not differ among patients who received vancomycin and those who did not.

Clinical and microbiological assessment of Mycobacterium simiae isolates from a single laboratory in southern Arizona.

Mycobacterium simiae was the third most common mycobacterium identified over a 2-year period from a single clinical laboratory in southern Arizona. Thirty-three isolates from 25 patients were identified over 1 year. The isolation of M. simiae was considered clinically significant for only two of 23 evaluable patients. None of five patients with human immunodeficiency virus infection had clinical disease associated with M. simiae. Twenty isolates were available for detailed study. All but one of the 20 isolates were niacin-negative, and 11 were nonphotochromogenic. All 20 isolates had a triple-cluster pattern consistent with M. simiae by high-performance liquid chromatography, and restriction fragment patterns were identical for 16 isolates. Analysis of 16S rDNA confirmed the identity of all the tested isolates as M. simiae. In this study, M. simiae was a frequent clinical isolate but was rarely associated with disease. The organisms isolated were confirmed to be M. simiae but appeared to be phenotypically distinct strains of low virulence.

Recent advances in cryptococcosis, candidiasis and coccidioidomycosis complicating HIV infection.

Concomitant with the decline in CD4+ T-cells seen as human immunodeficiency virus (HIV) infection progresses, the prevalence of opportunistic mycoses increases dramatically. This article reviews selected recent advances in our understanding of the immunology, molecular epidemiology and treatment of fungal infections in patients infected with HIV. For cryptococcosis, studies are reported on how HIV infection affects the immune response to Cryptococcus neoformans and, conversely, how stimulation with C. neoformans induces HIV production from latently HIV-infected cells. In addition, studies are presented examining the efficacy of triple combination antimycotic chemotherapy in cryptococcosis. For candidosis, investigations into genetic profiles of Candida albicans isolates obtained from patients, with resistance to antifungal agents, are demonstrated. Finally, for coccidioidomycosis, prospective studies are presented examining the clinical, epidemiological and immunological characteristics of a cohort of HIV-infected subjects residing in an endemic area.

In vitro modulation of proliferation and cytokine production by human peripheral blood mononuclear cells from subjects with various forms of coccidioidomycosis.

Using peripheral blood mononuclear cells (PBMC) from individuals with or without coccidioidal delayed-type hypersensitivity (DTH), we examined and attempted to modulate the in vitro responses of PBMC from various donors to the coccidioidal antigen toluene spherule lysate (TSL). Among healthy DTH-positive donors, 100 ng of human recombinant interleukin-10 (IL-10) per ml suppressed both PBMC proliferation (P = 0.01) and gamma interferon (IFN-gamma) and IL-12 production (for both, P < 0.05). In vitro proliferation and production of IFN-gamma and IL-12 by PBMC were significantly higher in DTH-positive donors with active coccidioidomycosis than in healthy, nonimmune controls (P < 0.05) but not in active DTH-negative donors with or without human immunodeficiency virus infection (for both, P > 0.05). Human recombinant IL-12 increased IFN-gamma production by PBMC from active, DTH-positive donors (P = 0.01) but not by PBMC from DTH-negative groups. For healthy DTH-positive donors, the median antigen-reactive cell frequency per 10(5) PBMC was 3.7, compared to 1.7 in DTH-negative donors with active coccidioidomycosis (P = 0.03). These data indicate that the in vitro TSL response is highly dependent on coccidioidal DTH. Not only do PBMC from individuals with DTH appear to respond to TSL, but their response can be modulated in vitro with either IL-10 or IL-12. On the other hand, PBMC from DTH-negative individuals do not respond in vitro to TSL and their response is not modulable, suggesting a lack of antigen response.

Peripheral blood from human immunodeficiency virus type 1-infected patients displays diminished T cell generation capacity.

An organ culture chimera system was used to assess the effect of human immunodeficiency virus type 1 (HIV-1) infection on the T cell-generation capacity of precursors derived from human peripheral blood. Peripheral blood mononuclear cells from HIV-1-infected patients and uninfected controls were placed on fetal thymus lobes of NOD/LtSz-scid/scid mice. Blood from the HIV-1-infected patients consistently produced fewer CD4 and CD8 cells compared with blood from controls (P < .01). Addition of zidovudine to the cultures did not alter this profile. Limit dilution experiments suggested that there were fewer functional precursors in the infected patients. These results were not dependent on the patient's level of peripheral CD4 cells; even samples from patients with normal CD4 cell counts were unable to generate T cells in organ cultures. The results are consistent with a loss in the capacity of HIV-1-infected patients to produce functional T cell progenitors in their peripheral blood.

Analysis of autoantibodies to T-cell receptors among HIV-infected individuals: epitope analysis and time course.

Individuals seropositive for human immunodeficiency virus type 1 (HIV) express elevated levels of autoantibodies (AAbs) directed against recombinant T-cell receptors (TCRs) and synthetic peptide epitopes duplicating beta chain markers. We performed longitudinal studies of anti-TCR AAbs in HIV-1-infected individuals, making comparisons with uninfected sera and sera from other individuals infected with a nonviral agent. We determined levels of autoantibodies by titration using enzyme-linked immunosorbent assay (ELISA) and developed a means for characterizing "autoantibody CDR recognition spectrotypes" for individual sera. Antibody levels against certain defined synthetic epitopes were substantially elevated in HIV-infected subjects relative to reactivities by control groups. Individual sera showed relatively high AAb levels to a subset of CDR1 peptide epitopes. Two patients who subsequently developed AIDS showed particular reactivity to Vbeta2.1, 8.1, 10.1, and 22.1 epitopes. Our results show that production AAbs to TCR Vbeta epitopes is a general consequence of HIV infection. The response is individual but shows some restriction and shifts in AAb subpopulations often occur with time.

Cytokine production by peripheral blood mononuclear cells in human coccidioidomycosis.

The production and mRNA expression of the cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-4, -10, and -12 by peripheral blood mononuclear cells (PBMC) after incubation with the coccidioidal antigen toluene spherule lysate (TSL) from various subjects were measured. The IFN-gamma concentration in PBMC supernatants incubated for 72 h from 8 subjects with disseminated coccidioidomycosis was significantly less than that from 7 healthy, coccidioidal-immune subjects (P = .015). No differences were seen among the subject groups in the concentrations of IL-4, -10, or -12. By use of competitive polymerase chain reaction, PBMC from subjects with disseminated coccidioidomycosis also expressed less mRNA for IFN-gamma and IL-12 than did cells from healthy, immune subjects. These data suggest that patients with disseminated coccidioidomycosis have a diminished T helper lymphocyte type 1 response.