Prospective Cohort Study of Cryptococcosis

描述（由申请方提供）：格特隐球菌（Cg）被认为是一种局限于热带和亚热带气候的真菌病原体，直到1999年，加拿大温哥华岛（VI）出现了由先前未识别的新分子组（VGIIa）的高毒力菌株引起的暴发。在1999-2003年期间，人类感染Cg的VI发病率超过了历史流行地区。自2004年以来，这一疫情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组分离株已在美国其他非毗邻州引起疾病，包括夏威夷、新墨西哥州、罗得岛、密歇根和格鲁吉亚。死亡率已超过30%，主要与延迟诊断和神经系统疾病有关。认识这种病原体是重要的，因为初步研究表明， 考虑到与中枢神经系统感染相关的过度神经系统炎症，抗真菌药敏感性以及对不同临床方法的需求。很大一部分（50%）患者没有潜在的免疫抑制风险，但早期研究表明，感染作为一个哨兵，为未被怀疑的成人获得性免疫缺陷，包括缺乏特定的IgG亚型和存在自身抗体的粒细胞巨噬细胞集落刺激因子（GM CSF）。本提案的目的是进行一项前瞻性队列研究，以增加我们对这种新出现的感染的了解。重点放在确定主机的风险，神经系统并发症的适当管理，有效的抗真菌治疗。在目标1中，我们将进行一项前瞻性队列研究，在由全球真菌病研究组领导的已建立的研究中心网络中采用基于互联网的病例报告表，并由国家和州公共卫生官员协助确定研究中心。作为前瞻性队列研究的一部分获得的Daa和样本将使子研究能够评价新的诊断。在目标2中，将进行巢式病例对照研究，以评估没有明显免疫抑制状况的人群中Cg感染和疾病进展的免疫学相关性。这一目标是通过NIH临床中心内部研究人员进行的详细研究实现的。这项研究代表了我们第一次协调一致的努力，以描述这一重要的新出现的爆发在美国的临床特征，我们的长期目标是产生所需的信息，以有效地预防和治疗这种感染。

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.