Rickettsial infections in Malaysia

描述(申请人提供)：非疟疾急性发热病(AFI)在世界范围内导致比疟疾更高的发病率和死亡率。由于临床表现重叠以及缺乏和/或有限的确认性诊断检测，非疟疾AFI的负担被低估。最常见的原因包括登革热、伤寒和副伤寒、钩端螺旋体病和立克次体感染，由于几个原因，这些疾病特别有问题。首先，有限的研究表明立克次体感染可能是东南亚某些地区AFI的最常见原因。其次，确认立克次体尤其困难，因为这些细胞内细菌会感染内皮细胞，因此既不容易培养，也不会在血液样本中大量存在。最后，经验性地用于AFI的广谱抗菌剂，如青霉素和头孢菌素，对立克次体无效。尽管1912年马来西亚首次发现丛林斑疹伤寒，小鼠斑疹伤寒在周边国家流行，但马来西亚卫生部在过去20年里几乎没有报告过立克次体病例。病例稀少的部分原因可能是 缺乏可用于诊断这些感染的可用检测，因为1980年代的一项研究和最近的血清学检查证实，马来西亚经常存在抗立克次体抗体(2%至9%的献血者和12%至44%的发热患者到医院就诊)。尽管登革热的流行引起了相当大的关注，但参加登革热类疾病研究(马来西亚卫生部倡导的临床标准)的大多数患者被发现没有登革热，他们的疾病病因往往仍未确定。我们假设，在沙巴州、马来西亚和周边地区，相当大比例的非疟疾、非登革热AFI是由未诊断的立克次体感染引起的。为了验证这一假设，我们建议使用来自一组预期登记为急性未分化发热性疾病的患者的血清、全血、棕黄色皮毛和焦痂样本来识别和表征意外立克次体感染。我们提出以下具体目标：目的1.证明马来西亚沙巴州非疟疾急性发热病患者中立克次体感染的发生并描述其流行病学。目的2.明确北京地区斑疹伤寒、斑疹伤寒群立克次体感染和森林斑疹伤寒的种类或亚型。 马来西亚沙巴州。这项工作将记录马来西亚沙巴州发生的立克次体感染情况，描述其相关的流行病学特征，并确定该地区目前存在的物种和菌株。此外，我们将生成后续详细前瞻性研究所需的初步数据，这些研究可以更全面地确定马来西亚立克次体疾病的发病率和流行率与AFI的其他原因，从而为管理非疟疾AFI提供合理的科学基础。

DESCRIPTION (provided by applicant): Non-malarial acute febrile illness (AFI) causes greater morbidity and mortality world-wide than malaria. The burden of non-malarial AFI is underappreciated, because of overlapping clinical presentations and lack of and/or limited access to confirmatory diagnostic tests. The most frequent causes include dengue, typhoid and paratyphoid fever, leptospirosis, and rickettsial infections, which are particularly problematic fo several reasons. First, limited studies suggest rickettsial infections may be the most common cause of AFI in some regions of Southeast Asia. Second, confirming rickettsioses is particularly difficult because these intra-cellular bacteria infect endothelial cells and, therefore, are neithe readily-cultivable nor abundant in samples of blood. Finally, the broad-spectrum, antimicrobial agents used empirically for AFI, such as penicillins and cephalosporins, are ineffective against rickettsiae. Although scrub typhus was first recognized in Malaysia in 1912 and murine typhus is endemic in surrounding countries, almost no cases of rickettsial disease were reported by the Malaysian Ministry of Health over the last 2 decades. The paucity of cases is likely due in part to the lack of available tests to diagnose these infections acutely, since a study from the 1980s and more recent serosurveys confirm the frequent (2 to 9% of blood donors and 12 to 44% of febrile patients presenting to hospital) presence of anti-rickettsial antibodies in Malaysia. Although epidemics of dengue attract considerable attention, most patients enrolled in studies of dengue-like febrile illness (clinical criteria advocated by the Malaysian Ministry of Health) are found to not have dengue and the etiology of their illness often remains undetermined. We hypothesize that a substantial proportion of the non-malaria, non-dengue AFI in Sabah, Malaysia and surrounding regions results from undiagnosed rickettsial infections. To test this hypothesis, we propose to use serum, whole blood, buffy coat, and eschar specimens from a cohort of patients enrolled prospectively with acute undifferentiated febrile illness to identify ad characterize unsuspected rickettsial infections. We propose the following specific aims: Aim 1. To demonstrate the occurrence and describe the epidemiology of rickettsial infections among patients with non-malarial acute febrile illness in Sabah, Malaysia. Aim 2. To define the species or strain substructure of spotted fever and typhus group rickettsial infections and scrub typhus in Sabah, Malaysia. This work will document the occurrence of rickettsial infections in Sabah, Malaysia, delineate their associated epidemiological features, and define the species and strains that are now present in this region. Additionally, we will generate preliminary data needed for subsequent detailed prospective studies that can more fully define the incidence and prevalence of rickettsial disease versus other causes of AFI in Malaysia and, thereby, provide a rational scientific basis for managing non-malarial AFI.