Prospective Cohort Study of Cryptococcosis

描述(由申请人提供)：隐球菌(CG)一直被认为是一种仅限于热带和亚热带气候的真菌病原体，直到1999年，一种以前未被识别的新分子群(VGIIa)超强毒力菌株引起的疫情在加拿大温哥华岛(VI)变得明显。在1999-2003年间，人类CG感染的VI发病率超过了历史流行地区。自2004年以来，这一疫情已蔓延至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毗邻州引起疾病，包括夏威夷、新墨西哥州、罗德岛、密歇根州和佐治亚州。死亡率已超过30%，这在很大程度上与延迟诊断和神经系统疾病有关。对这种病原体的识别很重要，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性炎症，抗真菌敏感性以及需要不同的临床方法。很大一部分患者(50%)没有潜在的免疫抑制风险，但早期研究表明，这种感染是成人意外获得性免疫缺陷的前哨，包括特定的免疫球蛋白亚型缺陷和粒细胞巨噬细胞集落刺激因子(GM-CSF)自身抗体的存在。这项建议的目标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。重点放在确定宿主风险、神经并发症的适当管理和有效的抗真菌治疗上。在目标1中，我们将进行一项前瞻性队列研究，在全球真菌研究小组领导的已建立的网站网络中使用基于互联网的病例报告表，并在国家和州公共卫生官员的协助下确定网站。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估新的诊断方法。在目标2中，将进行嵌套式病例对照研究，以评估无明显免疫抑制状况的人群中CG感染与进展性疾病的免疫学相关性。这一目标是由NIH临床中心的内部调查人员进行的详细研究实现的。这项研究是我们第一次协调一致地描述在美国出现的这一重要疫情的临床特征。我们的长期目标是产生有效预防和治疗这种感染所需的信息。

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.