Prospective Cohort Study of Cryptococcosis

描述（由申请人提供）：1999年之前，加蒂隐球菌（Cg）被认为是一种局限于热带和亚热带气候的真菌病原体，当时在加拿大温哥华岛（VI）发现了一种以前未被识别的新分子群（VGIIa）的高毒菌株。在1999年至2003年期间，人类感染Cg的VI发病率超过了历史流行地区的发病率。自2004年以来，这次暴发已蔓延到加拿大大陆和美国太平洋西北部的多个州。此外，其他VG群分离株也在美国其他非相邻州引起疾病，包括夏威夷、新墨西哥州、罗德岛州、密歇根州和佐治亚州。死亡率超过30%，主要与延迟诊断和神经系统疾病有关。识别这种病原体是很重要的，因为初步研究表明

DESCRIPTION (provided by applicant): Cryptococcus gattii (Cg) was considered to be a fungal pathogen restricted to tropical and subtropical climates until 1999, when an outbreak caused by a previously unrecognized, hypervirulent strain of a new molecular group (VGIIa) became evident on Vancouver Island (VI), Canada. During the years spanning 1999-2003, the VI incidence of Cg infection in humans exceeded that of historically endemic regions. Since 2004, this outbreak has spread to mainland Canada and to multiple states in the Pacific Northwest U.S. Also, other VG group isolates have caused disease in other non-contiguous states in the U.S., including Hawaii, New Mexico, Rhode Island, Michigan, and Georgia. Mortality rates have exceeded 30%, largely associated with delayed diagnosis and neurologic morbidity. Recognition of this pathogen is important, as preliminary studies suggest variability in antifungal susceptibilities as well as the need for a different clinical approach, given excessive neurologic inflammation associated with central nervous system infection. A large proportion (50%) of patients have no underlying immunosuppressive risk, but early studies suggest that the infection serves as a sentinel for unsuspected adult-acquired immunodeficiency, including deficiencies in specific IgG subtypes and the presence of auto-antibodies to granulocyte macrophage colony stimulating factor (GM CSF). The goal of this proposal is to perform a prospective cohort study that will increase our understanding of this emerging infection. Focus is placed on defining host risks, appropriate management of neurologic complications, and effective antifungal therapies. In Aim 1, we will perform a prospective cohort study, employing an internet-based case report form in an established network of sites led by the global Mycoses Study Group, with site identification facilitated by national and state public health officials. Daa and samples obtained as part of the prospective cohort study will enable sub-studies to evaluate new diagnostics. In Aim 2 a nested case-control study will be performed to evaluate the immunologic correlates of Cg infection and progressive disease in people who are without apparent immunosuppressive conditions. This aim is enabled by detailed studies performed by intramural investigators at the NIH clinical center. This study represents our first concerted effot to describe clinical features of this important emerging outbreak in the U.S. Our long-term goal is to generate the information needed to effectively prevent and treat this infection.