During the previous funding period, we have continued to recruit at the NIH clinical center, a cohort of disseminated cryptococcosis in otherwise symptomatically healthy individuals. We have thus far recruited 40 patients and have begun immunological and genetic characterizations. A subset of these patients that were not responding to conventional therapy were found to exhibit an overly robust immune response with ventriculitis and cerebral edema which was found to be steroid responsive. In a cohort of candidemia patients we have identified a key genetic locus associated with poor outcome and have obtained a mouse knockout strain and are conducting backcrossing experiments to more rigorously test and validate the genetic associations found in the clinical outcomes trial. In addition, we used multiplex meta-analysis of RNA expression patterns from patients with primary immune deficiencies to prioritize genes that are altered in association with known genetic defects. These studies identifed known PID-associated genes such as MS4A1 (CD20),RSAD2 and Stat1 as well as less characterized genes such as Map4K4 that has been shown in mice to be involved in macrophage TNFalpha and IL1beta secretion. We also completed an epidemilogy study of cryptococcosis in the US during a 13 year period, in collaboration with B. Prevots, LCID/NIAID/NIH which idenfied over 30,000 hospitalizations over the study period with a hospital-associated cost of approximately USD 0.5 Billion, suggesting that, despite improvments in therapy and prevention of HIV/AIDS, that cryptococcosis remains an important fungal disease in the US with substantial human and economic cost.
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