Early mycological treatment failure in AIDS-associated cryptococcal meningitis.
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Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease. (+info)
Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting.
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Hydrocephalus can be associated with increased morbidity and mortality in cryptococcal meningitis if left untreated. Both ventriculoperitoneal and ventriculoatrial shunting have been used in persons with cryptococcosis complicated by hydrocephalus, but the indications for and complications, success, and timing of these interventions are not well known. To this end, we reviewed the clinical courses of 10 non-human immunodeficiency virus-infected patients with hydrocephalus secondary to cryptococcal meningitis who underwent shunting procedures. Nine of 10 patients who underwent shunting had noticeable improvement in dementia and gait. Two patients required late revision of their shunts. Shunt placement in eight patients with acute infection did not disseminate cryptococcal infection into the peritoneum or bloodstream, nor did shunting provide a nidus from which Cryptococcus organisms proved difficult to eradicate. Shunting procedures are a safe and effective therapy for hydrocephalus in patients with cryptococcal meningitis and need not be delayed until patients are mycologically cured. (+info)
Quantitative and qualitative differences in the serum antibody profiles of human immunodeficiency virus-infected persons with and without Cryptococcus neoformans meningitis.
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The importance of humoral immunity for resistance to Cryptococcus neoformans is uncertain. A case-controlled study of the human antibody response to C. neoformans comparing the serum antibody profiles of human immunodeficiency virus (HIV)-infected persons who did (HIV+/CM+) or did not (HIV-infected controls) develop cryptococcal meningitis (CM) and HIV-uninfected persons with samples obtained from the Multicenter AIDS Cohort Study was performed. Total immunoglobulin concentrations were determined, and the specificity, isotype, and idiotype expression of antibodies to C. neoformans capsular glucuronoxylomannan were analyzed by ELISA. Compared with the HIV+/CM+ group, the HIV-infected control group had significantly lower levels of total IgM, IgA, and antibodies expressing a certain VH3 determinant. The HIV-infected control group manifested an increase in immunoglobulin levels with a decrease in CD4 lymphocytes. The findings suggest a possible association between reduced expression of certain immunoglobulin subsets and HIV-associated CM. (+info)
Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans.
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After intratracheal inoculation of the AIDS-associated pathogen Cryptococcus neoformans, 12-wk survival was >90% for CCR5+/+ mice but <25% for CCR5-/- mice. There were no defects in lung leukocyte recruitment (wk 5), pulmonary clearance, or delayed-type hypersensitivity in CCR5-/- mice. However, CCR5-/- mice had defects in leukocyte recruitment into the brain and, strikingly, in elimination of cryptococcal polysaccharide from the brain. In nonimmune CCR5-/- mice, there was a significant defect in macrophage recruitment after challenge with shed cryptococcal products (C. neoformans filtrate Ag) but not other nonspecific stimuli. Thus, CCR5 plays specific roles in innate immunity and organ-specific leukocyte trafficking during host defense against C. neoformans. (+info)
Massive pleural effusions in cryptococcal meningitis.
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Cryptococcal infection uncommonly presents with pulmonary manifestations and even more rarely so as massive bilateral effusions. Pleural involvement is usually associated with underlying pulmonary parenchymal lesions and is unusual while on antifungal therapy. We report a patient with cryptococcal meningitis who, while on intravenous 5-flucytosine and amphotericin B, developed life-threatening bilateral massive pleural effusions with evidence of spontaneous resolution, consistent with prior hypothesis of antigenic stimulation as the cause of pleural involvement. (+info)
The STE12alpha homolog is required for haploid filamentation but largely dispensable for mating and virulence in Cryptococcus neoformans.
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Cryptococcus neoformans is a fungal pathogen that causes meningitis in immunocompromised hosts. The organism has a known sexual cycle, and strains of the MATalpha mating type are more virulent than isogenic MATa strains in mice, and they are more common in the environment and infected hosts. A C. neoformans homolog of the STE12 transcription factor that regulates mating, filamentation, and virulence in Saccharomyces cerevisiae and Candida albicans was identified previously, found to be encoded by a novel region of the MATalpha mating type locus, and shown to enhance filamentous growth when overexpressed. We have disrupted the C. neoformans STE12 gene in a pathogenic serotype A isolate. ste12 mutant strains exhibit a severe defect in filamentation and sporulation (haploid fruiting) in response to nitrogen starvation. In contrast, ste12 mutant strains have only modest mating defects and are fully virulent in two animal models compared to the STE12 wild-type strain. In genetic epistasis experiments, STE12 functions in a MAP kinase cascade to regulate fruiting, but not mating. Thus, the C. neoformans STE12alpha transcription factor homolog plays a specialized function in haploid fruiting, but it is dispensable or redundant for mating and virulence. The association of the MATalpha locus with virulence may involve additional genes, and other transcription factors that regulate mating and virulence remain to be identified. (+info)
Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups.
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This study was undertaken to characterize the laboratory and clinical course of patients with AIDS and cryptococcal meningitis who had normal or elevated cerebrospinal fluid (CSF) pressure. Data were obtained retrospectively from a randomized multicenter quasifactorial phase III study comparing amphotericin B with or without flucytosine in primary treatment of cryptococcal meningitis. CSF pressure was measured before treatment and at 2 weeks. Repeated lumbar punctures were done to drain CSF and to reduce pressure. Patients with the highest baseline opening pressures (> or = 250 mm H2O) were distinguished by higher titers of cryptococcal capsular polysaccharide antigen in CSF; more frequently positive India ink smears of CSF; and more frequent headache, meningismus, papilledema, hearing loss, and pathological reflexes. After receiving antifungal therapy, those patients whose CSF pressure was reduced by >10 mm or did not change had more frequent clinical response at 2 weeks than did those whose pressure increased >10 mm (P<.001). Patients with pretreatment opening pressure <250 mm H2O had increased short-term survival compared with those with higher pressure. We recommend that opening pressures >/=250 mm H2O be treated with large-volume CSF drainage. (+info)
Cryptococcosis in AIDS.
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A total of 87 patients (17 female, 70 male) were admitted to SIRIRAJ HOSPITAL, MAHIDOL UNIVERSITY, BANGKOK, THAILAND, from JANUARY 1996 TO DECEMBER 1997, with a diagnosis of cryptococcal meningitis and underlying AIDS. The age range was 14: 70 years, mean 32.1. Six females (35%) and thirty-one males (44%) died, while the others were discharged home after clinical improvement. The mean duration of admission of those who died was 14.5 days, which was shorter than that of the patients who survived (25.7 days). Cerebral cryptococcosis was diagnosed using culture (100%), India ink preparation (91%), latex agglutination test (100%), and polymerase chain reaction (86%). Polymerase chain reaction fingerprinting of Cryptococcus neoformans revealed 99% serotype A and 1% serotype B. The mean minimum inhibitory concentrations of amphotericin B, flucytosine, fluconazole and itraconazole against 87 isolates of C neoformans were 0.55 microg/ml (0.25-1, SD = 0.22), 9.5 microg/ml (2-20, SD = 4.91), 6.9 microg/ml (1-16, SD = 4.42) and 0.36 microg/ml (0.125-1.0, SD = 0.23), respectively. These findings showed that the cryptococcal infections were sensitive to these antifungal agents. (+info)