The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts. The syndrome of fever is caused by a large number of infectious diseases. Malaria is thought to have been declining in the tropics since 2004. Increasing use of malaria diagnostic tests reveal a growing proportion of patients with fever who do not have malaria. While malaria diagnostic tests may be available, healthcare workers have few tools to diagnose causes of fever other than malaria. In order to identify major causes of fever other than malaria in northern Tanzania, we studied 870 patients with fever who were sufficiently ill to require admission to hospital. Malaria was uncommon and over-diagnosed, whereas invasive infections, including bloodstream infections, were underappreciated. Infections associated with animals such as brucellosis, leptospirosis, Q fever, and spotted fever group rickettsioses as well as viral infections transmitted by mosquitoes were common yet overlooked. We recommend that research on the syndrome of fever in resource-limited areas should focus on a wide range of potential causes. Animal-associated infections should be prioritized in patient management and disease control.

Orchestrating a viral takeover: For some pathogenic viruses, outbreaks occur when a new viral strain emerges and displaces the endemic strain. How such a takeover occurs at a molecular level, however, remains an open question. Manokaran et al. examined one example, the emergence of a new clade of dengue virus (DENV) that caused an outbreak in Puerto Rico in 1994. The epidemic strain produced elevated amounts of subgenomic flavivirus RNA (sfRNA), a viral noncoding RNA, relative to amounts of genomic viral RNA. sfRNA bound to and inhibited TRIM25, a protein important for activating the host's antiviral response, and so by reducing host immunity was able to increase its own fitness. Science , this issue p. 217

Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity. Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity. This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.