Antifungal Management Practices and Evolution of Infection in Organ Transplant Recipients with Cryptococcus Neoformans Infection

Singh, Nina; Lortholary, Olivier; Alexander, Barbara D.; Gupta, Krishan Lal; John, George T.; Pursell, Kenneth; Muñóz, Patricia; Klintmalm, Göran B.; Stosor, Valentina; Busto, Ramon Del; Limaye, Ajit P.; Somani, Jyoti; Lyon, Marshall; Houston, Sally; House, Andrew A.; Pruett, Timothy L.; Orloff, Susan L.; Humar, Atul; Dowdy, Lorraine A.; Garcia-Diaz, Julia; Kalil, André C.; Fisher, Robert A.; Heitman, Joseph; Husain, Shahid

doi:10.1097/01.tp.0000173774.74388.49

Cited by 76 publications

(66 citation statements)

References 58 publications

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“…In order to further examine the role of C. neoformans CTR4 expression in human infection, we assessed CTR4 expression in 24 consecutive primary clinical isolates from patients receiving solid organ transplants; isolates were collected as part of an ongoing study of C. neoformans infection in organ transplant patients (27). All strains were established to be serotype A strains (28).…”

Section: Figurementioning

confidence: 99%

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

Waterman

Hacham²,

Hu³

et al. 2007

J. Clin. Invest.

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125

182

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The study of regulatory networks in human pathogens such as Cryptococcus neoformans provides insights into host-pathogen interactions that may allow for correlation of gene expression patterns with clinical outcomes. In the present study, deletion of the cryptococcal copper-dependent transcription factor 1 (Cuf1) led to defects in growth and virulence factor expression in low copper conditions. In mouse models, cuf1Δ strains exhibited reduced dissemination to the brain, but no change in lung growth, suggesting copper is limiting in neurologic infections. To examine this further, a biologic probe of available copper was constructed using the cryptococcal CUF1-dependent copper transporter, CTR4. Fungal cells demonstrated high CTR4 expression levels after phagocytosis by macrophage-like J774.16 cells and during infection of mouse brains, but not lungs, consistent with limited copper availability during neurologic infection. This was extended to human brain infections by demonstrating CTR4 expression during C. neoformans infection of an AIDS patient. Moreover, high CTR4 expression by cryptococcal strains from 24 solid organ transplant patients was associated with dissemination to the CNS. Our results suggest that copper acquisition plays a central role in fungal pathogenesis during neurologic infection and that measurement of stable traits such as CTR4 expression may be useful for risk stratification of individuals with cryptococcosis.

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Section: Figurementioning

confidence: 99%

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

Waterman

Hacham²,

Hu³

et al. 2007

J. Clin. Invest.

Self Cite

125

182

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“…The posttransplant cohort included 13 subjects who developed cryptococcosis, including 9 who were also part of the pretransplant cohort, and 11 who did not develop cryptococcosis. These subjects were identified from a larger cohort of organ transplant recipients with cryptococcosis in a prospective, multicenter study (37). The types of underlying liver, lung, and kidney disease were similar in the C. neoformans-positive and C. neoformans-negative cohorts.…”

mentioning

confidence: 99%

Antibody Response to Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan in Patients after Solid-Organ Transplantation

Jalali

Singh

et al. 2006

Clin Vaccine Immunol

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Cryptococcosis is an important complication of solid-organ transplantation, but the risk factors for disease are poorly understood. The goal of this study was to investigate whether specific or nonspecific serum immunoglobulin levels determined in samples obtained before and after solid-organ transplantation differed in patients who did or did not develop cryptococcosis after transplantation. We analyzed pretransplantation sera from 25 subjects, 15 who subsequently developed cryptococcosis and 10 who did not, and posttransplantation sera from 24 subjects, 13 who developed cryptococcosis and 11 who did not. All subjects received a tacrolimus-based immunosuppressive regimen. Total immunoglobulin levels were measured by immunodiffusion, and Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM)-specific serum antibody levels were determined by enzyme-linked immunosorbent assays. The results showed that solid-organ transplantation had a significant effect on total immunoglobulin and GXM-reactive antibody levels. GXMreactive antibody levels differed in subjects who did and did not develop cryptococcosis. In pretransplant serum samples, the levels of GXM-reactive immunoglobulin M (IgM) were significantly lower in subjects who developed cryptococcosis after transplantation than in those who did not. For posttransplant serum samples, the levels of GXM-reactive IgM and IgG were significantly higher among the subjects who developed cryptococcosis than among those who did not. These findings suggest that perturbations in the preexisting antibody or B-cell repertoire and/or related to treatment of rejection, transplantation, or immunosuppressive therapy could translate into an increased risk for transplant-associated cryptococcosis.

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“…When these basic guidelines are followed, relapse is uncommon. This was recently demonstrated in a prospective study of 79 solid-organ transplant recipients with cryptococcosis who received a median of 183 days of total antifungal therapy, and demonstrated a relapse rate of only 1.3% [24].…”

Section: Patients Without Aidsmentioning

confidence: 89%

Cryptococcal Meningitis: Current Approaches to Management in Patients With and Without AIDS

Brizendine

Pappas

2010

Curr Infect Dis Rep

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Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS). Its management is characterized by the administration of initial combination antifungal therapy by following the principles of induction, consolidation, and maintenance therapy with aggressive management of elevated intracranial pressure (ICP). These tenets apply to patients with and without AIDS. Recent prospective trials on combination antifungal therapy, and the timing of the initiation of highly active antiretroviral therapy (HAART), suggest amphotericin B plus flucytosine and initiation of HAART are optimal therapy for management of patients with AIDS and cryptococcal meningitis. The paucity of prospective data on the management of cryptococcal meningitis in patients without AIDS is the most challenging aspect of formulating treatment guidelines, but the principles of induction, consolidation, and maintenance still apply. Combination antifungal therapy with a lipid formulation of amphotericin B plus flucytosine is generally indicated for this group, especially for those with a predisposition to renal dysfunction. Future research targeting this population may further inform recommendations.

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Antifungal Management Practices and Evolution of Infection in Organ Transplant Recipients with Cryptococcus Neoformans Infection

Abstract: A majority of the organ transplant recipients with cryptococcosis receive maintenance antifungal therapy for 6 months with low risk of relapse. These data can assist in trials to assess the optimal therapeutic approach and duration of therapy for cryptococcosis in transplant recipients.

Cited by 76 publications

References 58 publications

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

Antibody Response to Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan in Patients after Solid-Organ Transplantation

Cryptococcal Meningitis: Current Approaches to Management in Patients With and Without AIDS

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