Organ transplant recipients have emerged as a leading and growing group of immunocompromised patients at risk for cryptococcosis. The immunosuppressive agents employed in transplant recipients have antifungal in vitro against C. neoformans. Existing data suggest that the spectrum, type, or presentation of cryptococcosis might be altered by the antifungal effects of primary immunosuppressive drugs [Husain 00]. Whether cryptococcal isolates in transplant recipients represent immunosuppressive drug resistant mutants is not known. The impact of gene mutations conferring immunosuppressive drug resistance, serotype, or other virulence factors of C. neoformans on tissue tropism and outcome in transplant recipients has not been elucidated. Finally, it is not known whether C. neoformans in transplant recipient represents reactivation of a latent infection or a new acquisition. The primary objectives of the study are: To determine if there are differences in clinical manifestations and outcome of cryptococcosis in transplant recipients receiving tacrolimus, cyclosporine, or rapamycin, and to assess whether cerebrospinal fluid levels of immunosuppressive agents correlate with central nervous system infection. 2.To determine if C. neoformans isolates in transplant recipients represent breakthrough infections with immunosuppressive agent resistant mutants and to compare the clinical manifestations, response to therapy, and outcome of mutant versus non-mutant cryptococcal isolates. 3. To determine whether the following characteristics of C. neoformans correlate with clinical manifestations and outcome: capsule formation, serotype, melanin synthesis, thermal susceptibility, urease, and phospholipase production. 4. To determine if C. neoformans represents reactivation of a latently harbored infection or a new acquisition and to discern if certain Western blot band patterns are more likely to reactivate than others. This study merges the molecular strategy of investigating the infecting strains of the fungus with clinical outcome. Knowledge regarding mutations has not only pathophysiologic, but potentially profound therapeutic, implications for the management of C. neoformans. The virulence factors identified may serve as molecular targets for novel therapeutic modalities. Finally, the data regarding reactivation or primary infection has implications relevant for the prevention of C. neoformans infection in transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054719-02
Application #
6732739
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Duncan, Rory A
Project Start
2003-04-15
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$260,094
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sun, Hsin-Yun; Alexander, Barbara D; Huprikar, Shirish et al. (2015) Predictors of immune reconstitution syndrome in organ transplant recipients with cryptococcosis: implications for the management of immunosuppression. Clin Infect Dis 60:36-44
Sun, Hsin-Yun; Alexander, Barbara D; Lortholary, Olivier et al. (2010) Unrecognized pretransplant and donor?derived cryptococcal disease in organ transplant recipients. Clin Infect Dis 51:1062-9
Sun, Hsin-Yun; Alexander, Barbara D; Lortholary, Olivier et al. (2010) Cutaneous cryptococcosis in solid organ transplant recipients. Med Mycol 48:785-91
Osawa, Ryosuke; Alexander, Barbara D; Forrest, Graeme N et al. (2010) Geographic differences in disease expression of cryptococcosis in solid organ transplant recipients in the United States. Ann Transplant 15:77-83
Osawa, Ryosuke; Alexander, Barbara D; Lortholary, Olivier et al. (2010) Identifying predictors of central nervous system disease in solid organ transplant recipients with cryptococcosis. Transplantation 89:69-74
Sun, Hsin-Yun; Wagener, Marilyn M; Singh, Nina (2009) Cryptococcosis in solid-organ, hematopoietic stem cell, and tissue transplant recipients: evidence-based evolving trends. Clin Infect Dis 48:1566-76
Sun, Hsin-Yun; Alexander, Barbara D; Lortholary, Olivier et al. (2009) Lipid formulations of amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system cryptococcosis. Clin Infect Dis 49:1721-8
Singh, Nina; Alexander, Barbara D; Lortholary, Olivier et al. (2008) Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen. Clin Infect Dis 46:e12-8
Singh, Nina; Lortholary, Olivier; Dromer, Francoise et al. (2008) Central nervous system cryptococcosis in solid organ transplant recipients: clinical relevance of abnormal neuroimaging findings. Transplantation 86:647-51
Singh, N (2008) Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur J Clin Microbiol Infect Dis 27:403-8

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