Natural History of Leptospirosis

描述(申请人提供)：钩端螺旋体病是一种全球分布的人畜共患螺旋体疾病，是一种新出现的传染病。我们已经表明，钩端螺旋体病现在已经从其传统的农村基地传播，成为城市环境中与周期性降雨相关的流行病的原因。气候条件和日益严重的城市贫困促成了这种新的流行病模式的出现：在同一季节期间，每年都会发生与高死亡率相关的大规模疫情，并影响城市贫民窟社区内的相同风险群体。应对这些流行病的公共卫生优先事项是解决严重的临床形式，如韦尔氏病和严重肺出血综合征，其死亡率为15%。目前的治疗和控制措施并未对降低死亡率产生影响，因此，需要开发新的预防方法。然而，关于为什么有一小部分人(5%-15%)进展到出现严重的临床结果，人们知之甚少。我们假设，在高传播环境中，严重的临床结果受到暴露于环境因素期间接种量的差异以及自然感染后获得性免疫反应的影响。在巴西的萨尔瓦多，我们已经建立了研究钩端螺旋体病的流行病学和实验室基础设施。该地点五年的监测已发现1400多例严重钩端螺旋体病病例，因此为研究钩端螺旋体病的自然历史提供了独特的机会。我们建议进行一项基于社区的纵向研究，旨在：(1)确定环境风险暴露，包括感染期间可能影响接种量大小的环境风险暴露，是否与感染后发展为严重疾病的风险增加相关，以及(2)前瞻性地确定在先前感染期间获得的免疫反应是否预防致病性钩端螺旋体再次感染。这些研究应该确定对严重钩端螺旋体病的潜在预防措施。同时，它们可能提供更广泛适用的好处，例如开发改进的诊断工具和确定疫苗开发的目标。

DESCRIPTION (provided by applicant): Leptospirosis, a zoonotic spirochaetal disease with worldwide distribution, is an emerging infectious disease. We have shown that leptospirosis has now spread from its traditional rural base to become the cause of cyclic rainfall-associated epidemics in the urban setting. Conditions of climate and growing urban poverty have contributed to the emergence of this new epidemiological pattern: large outbreaks associated with high mortality occur each year during the same seasonal period and affect the same risk groups within urban slum communities. The public health priority in response to these epidemics is to address the severe clinical forms, such as Weil's disease and severe pulmonary haemorrhage syndrome, for which mortality is >15 percent. Current treatment and control measures have not made an impact in reducing this mortality and therefore, new preventative approaches need to be developed. However, little is known regarding why a small proportion (5-15 percent) of individuals progress to develop severe clinical outcomes. We hypothesize that that in high transmission settings, severe clinical outcomes are influenced by differences in the inoculum size during exposure to environmental factors and by acquired immune response after natural infection. In the city of Salvador, Brazil, we have established the epidemiological and laboratory infrastructure to study leptospirosis. Five-year surveillance at this site has identified more than 1400 severe leptospirosis cases, therefore providing a unique opportunity to study the natural history of leptospirosis. We propose a community-based longitudinal study that aims to: (1) Determine whether environmental risk exposures, including those that may influence inoculum size during infection, are associated with an increased risk of developing severe disease after infection, and (2) Determine prospectively whether immunological responses, acquired during a prior infection, protect against re-infection with pathogenic Leptospira. These studies should identify potential preventative measures for severe leptospirosis. At the same time, they may provide more widely applicable benefits such as the development of improved diagnostic tools and identification of targets for vaccine development.