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

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Abstract

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.

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Most cited references 48

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Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.

John R. Perfect, William E. Dismukes, Francoise Dromer … (2010)

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

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Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

Peter Pappas, Barbara D. Alexander, David Andes … (2010)

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

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Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

G A Pankey, P Pappas, W E Dismukes … (2001)

We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.

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: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 24 August 2012

Volume: 7

Issue: 8

Electronic Location Identifier: e43582

Affiliations

[1 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America

[2 ]Department of Medicine, Duke University, Durham, North Carolina, United States of America

[3 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America

[4 ]Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America

[5 ]Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America

Baylor College of Medicine, United States of America

Author notes

* E-mail: emily_bratton@ 123456unc.edu

Competing Interests: EWB, NEH, MSL, CAC, CP, JJJ and DJW have declared that they have no competing interests. The following authors have the following conflicts to declare: JRP has research grants, consulting and honorariums from Enzon, Pfizer, Merck, Astellas and Schering-Plough. TS does not accept personal compensation of any kind from any pharmaceutical company, though he receives salary support from the UNC Center of Excellence in Pharmacoepidemiology and Public Health and from unrestricted research grants from pharmaceutical companies to UNC. TS also receives research funding as Principal Investigator of the UNC-DEcIDE center from the Agency for Healthcare Research and Quality. However, this does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Conceived and designed the experiments: EWB NEH CAC MSL JRP. Performed the experiments: EWB NEH CAC MSL. Analyzed the data: EWB. Wrote the paper: EWB. Interpretation of data: EWB CP TS JJJ DJW JRP. Selection of analytic tools: EWB CP TS JRP. Critical revision and editing of manuscript: CP TS JJJ DJW JRP.

Article

Publisher ID: PONE-D-12-08841

DOI: 10.1371/journal.pone.0043582

PMC ID: 3427358

PubMed ID: 22937064

SO-VID: 64020704-3506-4846-90cc-d4f18f9d070b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 27 March 2012

Date accepted : 23 July 2012

Page count

Pages: 10

Funding

This work was supported by United States National Institutes of Health Public Health Service Grant [grant number AI73896]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

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PLOS Climate

Most cited references 48

Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.

Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.

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