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.

Public Health Relevance

Globally many die with fever from infections that mimic malaria but are never diagnosed. We will use gold standard diagnostic methods to document the occurrence of and features associated with infections caused by Rickettsia in Sabah, Malaysia, an area in which these illnesses are likely confused with malaria and dengue. Additionally, we will determine if the rickettsial infections found are caused by new species or strains.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
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Perdue, Samuel S
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Johns Hopkins University
Schools of Medicine
United States
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