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      Arboviral Etiologies of Acute Febrile Illnesses in Western South America, 2000–2007

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          Abstract

          Background

          Arthropod-borne viruses (arboviruses) are among the most common agents of human febrile illness worldwide and the most important emerging pathogens, causing multiple notable epidemics of human disease over recent decades. Despite the public health relevance, little is know about the geographic distribution, relative impact, and risk factors for arbovirus infection in many regions of the world. Our objectives were to describe the arboviruses associated with acute undifferentiated febrile illness in participating clinics in four countries in South America and to provide detailed epidemiological analysis of arbovirus infection in Iquitos, Peru, where more extensive monitoring was conducted.

          Methodology/Findings

          A clinic-based syndromic surveillance system was implemented in 13 locations in Ecuador, Peru, Bolivia, and Paraguay. Serum samples and demographic information were collected from febrile participants reporting to local health clinics or hospitals. Acute-phase sera were tested for viral infection by immunofluorescence assay or RT-PCR, while acute- and convalescent-phase sera were tested for pathogen-specific IgM by ELISA. Between May 2000 and December 2007, 20,880 participants were included in the study, with evidence for recent arbovirus infection detected for 6,793 (32.5%). Dengue viruses ( Flavivirus) were the most common arbovirus infections, totaling 26.0% of febrile episodes, with DENV-3 as the most common serotype. Alphavirus (Venezuelan equine encephalitis virus [VEEV] and Mayaro virus [MAYV]) and Orthobunyavirus (Oropouche virus [OROV], Group C viruses, and Guaroa virus) infections were both observed in approximately 3% of febrile episodes. In Iquitos, risk factors for VEEV and MAYV infection included being male and reporting to a rural (vs urban) clinic. In contrast, OROV infection was similar between sexes and type of clinic.

          Conclusions/Significance

          Our data provide a better understanding of the geographic range of arboviruses in South America and highlight the diversity of pathogens in circulation. These arboviruses are currently significant causes of human illness in endemic regions but also have potential for further expansion. Our data provide a basis for analyzing changes in their ecology and epidemiology.

          Author Summary

          Over recent decades, the variety and quantity of diseases caused by viruses transmitted to humans by mosquitoes and other arthropods (also known as arboviruses) have increased around the world. One difficulty in studying these diseases is the fact that the symptoms are often non-descript, with patients reporting such symptoms as low-grade fever and headache. Our goal in this study was to use laboratory tests to determine the causes of such non-descript illnesses in sites in four countries in South America, focusing on arboviruses. We established a surveillance network in 13 locations in Ecuador, Peru, Bolivia, and Paraguay, where patient samples were collected and then sent to a central laboratory for testing. Between May 2000 and December 2007, blood serum samples were collected from more than 20,000 participants with fever, and recent arbovirus infection was detected for nearly one third of them. The most common viruses were dengue viruses (genera Flavivirus). We also detected infection by viruses from other genera, including Alphavirus and Orthobunyavirus. This data is important for understanding how such viruses might emerge as significant human pathogens.

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          Most cited references42

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          Leptospirosis: a zoonotic disease of global importance.

          In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.
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            Serotype-specific differences in clinical manifestations of dengue.

            Dengue, the most prevalent arthropod-borne viral disease of humans, is caused by four serotypes of dengue virus (DENV 1-4). Although all four DENV serotypes cause a range of illness, defining precisely which clinical characteristics are associated with the distinct serotypes has been elusive. A cross-sectional study was conducted on 984 and 313 hospitalized children with confirmed DENV infections during two time periods, respectively, in the same hospitals in Nicaragua: a 3-year period (1999-2001) when DENV-2 accounted for 96% of the viruses identified, and the 2003 dengue season when DENV-1 predominated (87% of identified serotypes). When the two periods were compared, more shock (OR 1.91, 95% CI 1.35-2.71) and internal hemorrhage (OR 2.05, CI 1.16-3.78) were observed in the period when DENV-2 predominated, whereas increased vascular permeability was associated to a greater degree with the DENV-1 period (OR 2.36, CI 1.80-3.09). Compared with the DENV-2 period, the DENV-1 season was associated with more hospitalized primary dengue cases (OR 3.86, CI 2.72-5.48) and more primary DENV infections with severe manifestations (OR 2.93, CI 2.00-4.28). These findings provide new data to characterize the pathogenic potential of distinct DENV serotypes in human populations.
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              Venezuelan equine encephalitis emergence: enhanced vector infection from a single amino acid substitution in the envelope glycoprotein.

              In 1993 and 1996, subtype IE Venezuelan equine encephalitis (VEE) virus caused epizootics in the Mexican states of Chiapas and Oaxaca. Previously, only subtype IAB and IC VEE virus strains had been associated with major outbreaks of equine and human disease. The IAB and IC epizootics are believed to emerge via adaptation of enzootic (sylvatic, equine-avirulent) strains for high titer equine viremia that results in efficient infection of mosquito vectors. However, experimental equine infections with subtype IE equine isolates from the Mexican outbreaks demonstrated neuro-virulence but little viremia, inconsistent with typical VEE emergence mechanisms. Therefore, we hypothesized that changes in the mosquito vector host range might have contributed to the Mexican emergence. To test this hypothesis, we evaluated the susceptibility of the most abundant mosquito in the deforested Pacific coastal locations of the VEE outbreaks and a proven epizootic vector, Ochlerotatus taeniorhynchus. The Mexican epizootic equine isolates exhibited significantly greater infectivity compared with closely related enzootic strains, supporting the hypothesis that adaptation to an efficient epizootic vector contributed to disease emergence. Reverse genetic studies implicated a Ser --> Asn substitution in the E2 envelope glycoprotein as the major determinant of the increased vector infectivity phenotype. Our findings underscore the capacity of RNA viruses to alter their vector host range through minor genetic changes, resulting in the potential for disease emergence.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                August 2010
                10 August 2010
                : 4
                : 8
                : e787
                Affiliations
                [1 ]United States Naval Medical Research Center Detachment, Iquitos and Lima, Peru
                [2 ]Instituto Nacional de Salud, Lima, Peru
                [3 ]CENETROP, Santa Cruz, Bolivia
                [4 ]SEDES, Cochabamba, Bolivia
                [5 ]Hospital Naval, Guayaquil, Ecuador
                [6 ]Asociación Rayos del Sol, Asunción, Paraguay
                [7 ]Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia, Lima, Peru
                [8 ]Dirección General de Epidemiología, Ministerio de Salud, Lima, Peru
                [9 ]Universidad Nacional Mayor de San Marcos, Lima, Peru
                [10 ]University of California Davis, Davis, California, United States of America
                Pediatric Dengue Vaccine Initiative, United States of America
                Author notes

                Conceived and designed the experiments: CG VALT MC JV AG EV CM NA EG VS AMM LB NR MN CR ACM KLR PJB JGO TJK. Performed the experiments: CG JV AG EV CM NA CR PJB. Analyzed the data: BMF CG VALT JP CR ACM TJK. Contributed reagents/materials/analysis tools: JGO TJK. Wrote the paper: BMF CG VALT JP ACM TJK.

                Article
                09-PNTD-RA-0052R3
                10.1371/journal.pntd.0000787
                2919378
                20706628
                b059a403-cb2f-4402-a2a8-b66d414f6245
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 2 March 2009
                : 12 July 2010
                Page count
                Pages: 14
                Categories
                Research Article
                Public Health and Epidemiology/Infectious Diseases
                Virology/Emerging Viral Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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