Approaches to Antifungal Therapies and Their Effectiveness among Patients with Cryptococcosis

ABSTRACT The goal of this study was to determine the degree to which the persistence of cryptococcosis, overall 1-year mortality, and 1-year mortality due to cryptococcosis were influenced by initial antifungal treatment regimen in a cohort of adults with cryptococcosis treated at a tertiary care medical center. Risk factors, underlying conditions, treatment, and mortality information were obtained for 204 adults with cryptococcosis from Duke University Medical Center (DUMC) from 1996 to 2009. Adjusted risk ratios (RR) for persistence and hazard ratios (HR) for mortality were estimated for each exposure. The all-cause mortality rate among patients with nonsevere disease (20%) was similar to that in the group with disease (26%). However, the rate of cryptococcosis-attributable mortality with nonsevere disease (5%) was much lower than with severe disease (20%). Flucytosine exposure was associated with a lower overall mortality rate (HR, 0.4; 95% confidence interval [CI], 0.2 to 0.9) and attributable mortality rate (HR, 0.5; 95% CI, 0.2 to 1.2). Receiving a nonrecommended antifungal regimen was associated with a higher relative risk of persistent infection at 4 weeks (RR, 1.9; 95% CI, 0.9 to 4.3), and the rate of attributable mortality among those not receiving the recommended dose of initial therapy was higher than that of those receiving recommended dosing (HR, 2.3; 95% CI, 1.0 to 5.0). Thus, the 2010 Infectious Diseases Society of America (IDSA) guidelines are supported by this retrospective review as a best-practice protocol for cryptococcal management. Future investigations should consider highlighting the distinction between all-cause mortality and attributable mortality so as not to overestimate the true effect of cryptococcosis on patient death

Comparison and Temporal Trends of Three Groups with Cryptococcosis: HIV-Infected, Solid Organ Transplant, and HIV-Negative/Non-Transplant

BackgroundThe Infectious Disease Society of America (IDSA) 2010 Clinical Practice Guidelines for the management of cryptococcosis outlined three key populations at risk of disease: (1) HIV-infected, (2) transplant recipient, and (3) HIV-negative/non-transplant. However, direct comparisons of management, severity and outcomes of these groups have not been conducted.Methodology/Principal FindingsAnnual changes in frequency of cryptococcosis diagnoses, cryptococcosis-attributable mortality and mortality were captured. Differences examined between severe and non-severe disease within the context of the three groups included: demographics, symptoms, microbiology, clinical management and treatment. An average of nearly 15 patients per year presented at Duke University Medical Center (DUMC) with cryptococcosis. Out of 207 study patients, 86 (42%) were HIV-positive, 42 (20%) were transplant recipients, and 79 (38%) were HIV-negative/non-transplant. HIV-infected individuals had profound CD4 lymphocytopenia and a majority had elevated intracranial pressure. Transplant recipients commonly (38%) had renal dysfunction. Nearly one-quarter (24%) had their immunosuppressive regimens stopped or changed. The HIV-negative/non-transplant population reported longer duration of symptoms than HIV-positive or transplant recipients and 28% (22/79) had liver insufficiency or underlying hematological malignancies. HIV-positive and HIV-negative/non-transplant patients accounted for 89% of severe disease cryptococcosis-attributable deaths and 86% of all-cause mortality.Conclusions/SignificanceIn this single-center study, the frequency of cryptococcosis did not change in the last two decades, although the underlying case mix shifted (fewer HIV-positive cases, stable transplant cases, more cases with neither). Cryptococcosis had a relatively uniform and informed treatment strategy, but disease-attributable mortality was still common

Approaches to Antifungal Therapies and Their Effectiveness among Patients with Cryptococcosis

The goal of this study was to determine the degree to which the persistence of cryptococcosis, overall 1-year mortality, and 1-year mortality due to cryptococcosis were influenced by initial antifungal treatment regimen in a cohort of adults with cryptococcosis treated at a tertiary care medical center. Risk factors, underlying conditions, treatment, and mortality information were obtained for 204 adults with cryptococcosis from Duke University Medical Center (DUMC) from 1996 to 2009. Adjusted risk ratios (RR) for persistence and hazard ratios (HR) for mortality were estimated for each exposure. The all-cause mortality rate among patients with nonsevere disease (20%) was similar to that in the group with disease (26%). However, the rate of cryptococcosis-attributable mortality with nonsevere disease (5%) was much lower than with severe disease (20%). Flucytosine exposure was associated with a lower overall mortality rate (HR, 0.4; 95% confidence interval [CI], 0.2 to 0.9) and attributable mortality rate (HR, 0.5; 95% CI, 0.2 to 1.2). Receiving a nonrecommended antifungal regimen was associated with a higher relative risk of persistent infection at 4 weeks (RR, 1.9; 95% CI, 0.9 to 4.3), and the rate of attributable mortality among those not receiving the recommended dose of initial therapy was higher than that of those receiving recommended dosing (HR, 2.3; 95% CI, 1.0 to 5.0). Thus, the 2010 Infectious Diseases Society of America (IDSA) guidelines are supported by this retrospective review as a best-practice protocol for cryptococcal management. Future investigations should consider highlighting the distinction between all-cause mortality and attributable mortality so as not to overestimate the true effect of cryptococcosis on patient death

Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant.

BACKGROUND: The Infectious Disease Society of America (IDSA) 2010 Clinical Practice Guidelines for the management of cryptococcosis outlined three key populations at risk of disease: (1) HIV-infected, (2) transplant recipient, and (3) HIV-negative/non-transplant. However, direct comparisons of management, severity and outcomes of these groups have not been conducted. METHODOLOGY/PRINCIPAL FINDINGS: Annual changes in frequency of cryptococcosis diagnoses, cryptococcosis-attributable mortality and mortality were captured. Differences examined between severe and non-severe disease within the context of the three groups included: demographics, symptoms, microbiology, clinical management and treatment. An average of nearly 15 patients per year presented at Duke University Medical Center (DUMC) with cryptococcosis. Out of 207 study patients, 86 (42%) were HIV-positive, 42 (20%) were transplant recipients, and 79 (38%) were HIV-negative/non-transplant. HIV-infected individuals had profound CD4 lymphocytopenia and a majority had elevated intracranial pressure. Transplant recipients commonly (38%) had renal dysfunction. Nearly one-quarter (24%) had their immunosuppressive regimens stopped or changed. The HIV-negative/non-transplant population reported longer duration of symptoms than HIV-positive or transplant recipients and 28% (22/79) had liver insufficiency or underlying hematological malignancies. HIV-positive and HIV-negative/non-transplant patients accounted for 89% of severe disease cryptococcosis-attributable deaths and 86% of all-cause mortality. CONCLUSIONS/SIGNIFICANCE: In this single-center study, the frequency of cryptococcosis did not change in the last two decades, although the underlying case mix shifted (fewer HIV-positive cases, stable transplant cases, more cases with neither). Cryptococcosis had a relatively uniform and informed treatment strategy, but disease-attributable mortality was still common

Efficacy of induction therapy on acute rejection and graft outcomes in African American kidney transplantation

BACKGROUND: African Americans (AA) have higher rejection rates and poorer graft outcomes compared to non-AAs. Induction therapy is yet unproven in this high risk population. METHODS: This retrospective study compared the efficacy of induction therapy [IL-2 receptor antibodies (IL2RA) or thymoglobulin] vs. no induction. RESULTS: One hundred and seventy-five AA patients were included in this analysis. Patients were well matched for demographic and immunologic characteristics in the non-induction and IL2RA induction groups; the Thymoglobulin induction group had significantly higher risk patients. Significantly fewer episodes of acute rejection occurred at one yr in patients treated with thymoglobulin and IL2RA vs. no induction (18% vs. 47%, p = 0.003, 26% vs. 47%, p = 0.02). Three yr graft survival was significantly improved in the IL2RA group compared to the non-induction group (85% vs. 68%, p = 0.032). Despite the thymoglobulin group being at high risk, they had similar graft survival rates compared to both the IL2RA group (76% vs. 85%, p = 0.18) and the non-induction group (76% vs. 68%, p = 0.48). Multivariate analysis demonstrated that induction therapy (combining IL2RA and thymoglobulin) independently reduced the risk of both acute rejection and graft loss. CONCLUSION: The use and type of induction therapy in AA patients significantly reduces acute rejection rates and may improve long-term graft outcomes in AA patients

Comparison and Temporal Trends of Three Groups with Cryptococcosis: HIV-Infected, Solid Organ Transplant, and HIV-Negative/Non-Transplant

BACKGROUND: The Infectious Disease Society of America (IDSA) 2010 Clinical Practice Guidelines for the management of cryptococcosis outlined three key populations at risk of disease: (1) HIV-infected, (2) transplant recipient, and (3) HIV-negative/non-transplant. However, direct comparisons of management, severity and outcomes of these groups have not been conducted. METHODOLOGY/PRINCIPAL FINDINGS: Annual changes in frequency of cryptococcosis diagnoses, cryptococcosis-attributable mortality and mortality were captured. Differences examined between severe and non-severe disease within the context of the three groups included: demographics, symptoms, microbiology, clinical management and treatment. An average of nearly 15 patients per year presented at Duke University Medical Center (DUMC) with cryptococcosis. Out of 207 study patients, 86 (42%) were HIV-positive, 42 (20%) were transplant recipients, and 79 (38%) were HIV-negative/non-transplant. HIV-infected individuals had profound CD4 lymphocytopenia and a majority had elevated intracranial pressure. Transplant recipients commonly (38%) had renal dysfunction. Nearly one-quarter (24%) had their immunosuppressive regimens stopped or changed. The HIV-negative/non-transplant population reported longer duration of symptoms than HIV-positive or transplant recipients and 28% (22/79) had liver insufficiency or underlying hematological malignancies. HIV-positive and HIV-negative/non-transplant patients accounted for 89% of severe disease cryptococcosis-attributable deaths and 86% of all-cause mortality. CONCLUSIONS/SIGNIFICANCE: In this single-center study, the frequency of cryptococcosis did not change in the last two decades, although the underlying case mix shifted (fewer HIV-positive cases, stable transplant cases, more cases with neither). Cryptococcosis had a relatively uniform and informed treatment strategy, but disease-attributable mortality was still common

Patient treatment and outcomes.

<p>Initial induction antifungal regimen, patient mortality through one year, and immune reconstitution inflammatory syndrome (IRIS) by primary disease diagnosis (severe or non-severe) and major underlying condition (HIV, transplant, or HIV-negative and non-transplant).</p>a<p>Severe disease: HIV group had 74 patients, transplant group had 18 patients and 39 patients were in the HIV-negative/non-transplant group; Non-severe disease: HIV group had 12 patients, transplant group had 24 patients and 40 patients were in the HIV-negative/non-transplant group.</p>b<p>HIV-negative, non-transplant.</p>c<p>Cochran Mantel-Haenszel Chi-square test for a general association between the three groups was significant for overall mortality among non-severe disease only.</p

Annual cases.

<p>Annual frequency of severe and non-severe cryptococcosis cases according to underlying condition (N = 207).</p